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Current Medicinal Chemistry, 2011, 18, 1672-1703
Cinnamic Acid Derivatives as Anticancer Agents-A Review

P. De1,2, M. Baltas*,1,2 and F. Bedos-Belval1,2
1
Universit de Toulouse, UPS, LSPCMIB (Laboratoire de Synthse et Physico-Chimie de Molcules dIntrt Biologique), 118, Route de Narbonne, F-31062 Toulouse Cedex 9, France CNRS, LSPCMIB (Laboratoire de Synthse et Physico-Chimie de Molcules dIntrt Biologique), 118, Route de Narbonne, F-31062 Toulouse Cedex 9, France
Abstract: Cinnamic acid and its phenolic analogues are natural substances. Chemically, in cinnamic acids the 3-phenyl acrylic acid functionality offers three main reactive sites; substitution at the phenyl ring, addition at the , -unsaturation and the reactions of the carboxylic acid functionality. Owing to these chemical aspects cinnamic acid derivatives received much attention in medicinal research as traditional as well as recent synthetic antitumor agents. We observed that in spite of their rich medicinal tradition, cinnamic acid derivatives and their anticancer potentials remained underutilized for several decades since the first published clinical use in 1905. In last two decades, there has been huge attention towards various cinnamoyl derivatives and their antitumor efficacy. This review provides a comprehensive and unprecedented literature compilation concerning the synthesis and biological evaluation of various cinnamoyl acids, esters, amides, hydrazides and related derivatives in anticancer research. We envisage that our effort in this review contributes a much needed and timely addition to the literature of medicinal research.
Keywords: Anticancer agents, caffeic acid, cinnamic acid, cinnamide, cinnamoyl ester, cinnamic hydrazide. 1. INTRODUCTION Cinnamic acid (1) has a long history of human use as a component of plant-derived scents and flavourings [1]. It belongs to the class of auxin, which is recognized as plant hormones regulating cell growth and differentiation [2]. The cinnamoyl functionality is also present in a variety of secondary metabolites of phenylpropanoid biosynthetic origin. Those containing a sesquiterpenyl, monoterpenyl and isopentenyl chain attached to a 4-hydroxy group represent quite a rare group of natural products [3a]. The hydroxyl cinnamic acids are natural products arising from the deamination of the phenyl alanine (2); they are important constituents in the biochemical pathway in plants leading to the lignin [4], the second most abundant biopolymer after cellulose [5], resulting from the oxidative polymerization [6] of the three hydroxycinnamoyl alcohols, i.e., p-coumaryl, coniferyl, sinapyl alcohols. Natural hydroxyl cinnamates are extremely potent antitumor agents [3a-c]. Chemically, it is an aromatic fatty acid composed of a phenyl ring substituted with an acrylic acid group, commonly in the trans-geometry and has low toxicity in human exposure. Cinnamic acid possesses an , -unsaturated carbonyl moiety, which can be considered as a Michael acceptor, an active moiety often employed in the design of anticancer drugs [7]. In addition, a number of , -unsaturated ketones have demonstrated preferential activity toward thiol [8]. Alkylation with a cellular thiol such as glutathione (GSH) and/or lcystine may also occur with cinnamates leading to adducts at the position. Hence, , -unsaturated carbonyl-containing compounds may be free from problems of mutagenicity [8]. Although the cinnamaldehydes and chalcones are analogous compounds and known for their variety of medicinal usage, we restrict our discussion to the acid, ester, amide, hydrazide and related derivatives of cinnamic acid because of their lesser known attributes towards anticancer activities. 2.CINNAMIC ACIDS AND SALTS 2.1. Introduction In 1905, the sodium salts of 1 and ortho-coumaric acid (3) (Fig. 1) were administered to cancer-patients by Dr. Drage [9] for patients compliance on an experimental basis. He expressed hope to
*Address correspondence to this author at the Universit de Toulouse, UPS, LSPCMIB (Laboratoire de Synthse et Physico-Chimie de Molcules dIntrt Biologique), 118, Route de Narbonne, F-31062 Toulouse Cedex 9, France; Tel: 00 33 (0)5 61 55 62 89: Fax: 00 33 (0)5 61 55 60 11; E-mail: baltas@chimie.ups-tlse.fr 0929-8673/11 $58.00+.00
develop these molecules as anticancer drugs in future. In spite of its rich medicinal tradition, cinnamic acid derivatives and their anticancer potentials remained underutilized for several decades. There was insufficient study on the molecular mechanism of anticancer effects of naturally occurring cinnamic acid derivatives and in most cases targets were unknown. 2.2. Natural Resources Cinnamic acid (1) and its natural analogues are known for the treatment of cancer for over centuries. Ginsenoside Rg1 (4), cinnamic acid, and tanshinone IIA (5) (RCT) are effective constituents of Ginseng, Xuanshen, and Danshen, respectively. They were valued in Chinese traditional medicine for maintaining youth, promoting longevity, and balancing whole body yin and yang to prevent diseases. In an exploratory report by Li et al., ginsenoside Rg1, cinnamic acid, and tanshinone IIA (RCT) were administered to osteosarcoma MG-63 cells [10], the most common histological form of primary bone cancer, and decreased nucleoplasmin expression in nuclear matrix in association with induced nucleoplasmin translocation from nucleolus to nucleoplasm and cytoplasm was observed. Importantly, further investigation by Shi et al. [11] revealed that RCT regulated c-myc and c-fos oncogenes, P53 and Rb tumor suppressor genes, down regulated prohibitin, a tumor suppressive protein, in nuclear matrix and changed prohibitin trafficking from nucleolus to cytoplasm. However, the exact role of cinnamic acid in RCT combination remained unresolved. Ekmekcioglu et al. investigated the effect of 1 on cell proliferation and on the differentiation markers alkaline phosphatase, sucrase and aminopeptidase N in human colon adenocarcinoma cells (Caco-2). Their study revealed that 1 (2.58.0 mM) is an antiproloferative agent and importantly, inhibits the DNA synthesis of growing cells [12]. The antiproliferative effect occurred rapidly after 2 h of treatment with 8.0 mM cinnamic acid and reached nearly maximal values after 8 h of treatment. Sucrase and aminopeptidase-N activities were stimulated under cinnamic acid treatment (4.08.0 mM), while alkaline phosphatase activity was inhibited in postconfluent cells (8.0 mM). Similar effects on enzyme activities were seen in non-proliferating cells. However, intracellular cAMP levels were decreased significantly after 1 h of treatment with 1 (8.0 mM), suggesting that 1 induces its effects on enzyme activities partly by modulating the cAMP signaling pathway. The mechanisms resulting in tumor growth inhibition are not definitely clear at the moment but it seems that cinnamic acid partly exerts its antiproliferative effects by inhibition of protein isoprenylation which in turn inhibits mitogenic signal transduction [13]. It has
2011 Bentham Science Publishers Ltd.
Current Medicinal Chemistry, 2011 Vol. 18, No. 11
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OH HO H OH H HO 1 COOH 3 COOH O H H OH 5 O OH OH OH Ginsenoside Rg 1

Fig. (1). Cinnamic acid, ortho-coumaric acid, Ginsenoside Rg1 and Tashinone IIA.
O H O
OH O OH
Tashinone IIA
Cinnamic acid
o-Coumaric acid HO
been also described that some cinnamoyl analogs act as specific protein tyrosine kinase inhibitors which resulted in tumor cell growth inhibition [14]. Protein isoprenylation allows the proteins such as p21-Ras and nuclear lamine B [15] the anchorage to cell membrane in order to perform related biological activities. In an interesting report, observed induction of cytostasis and a reversal of malignant properties of human tumor cells in vitro by 1 were attributed to it by Liu et al. [13]. Reduction of cell proliferation by 50% (IC50) was observed in glioblastoma, melanoma, prostate and lung carcinoma cells using compound 1 in 1-4.5 mM concentration range. It induced cell differentiation evidenced by morphological changes and increased melanine production as observed in melanoma cell model. Melanoma cells are highly invasive in vivo and thus it is significant that in a modified Boyden chambers with matrigel coated filters, treatment of melanoma 1011, SKMEL28, A375 (M) cells with 5 mM cinnamic acid for 3 days resulted in 75-95% loss of invasiveness or the capacity to degrade and cross tissue barrier. Importantly, the reduced invasiveness is associated with modulation of expression of genes implicated in tumor metastasis and immunogenicity. The decreased expression of colleagenase in A375 (M) cells accompanying with increase in the expression of protease inhibitor TIMP-2 [16], a metalloproteinase, suggests that the net proteolytic activity might have been reduced by 1 resulting in the loss of invasiveness. Cell cultures of lavender (Lavandula officinalis) analysis for the metabolite profile under normal growth conditions and under anoxic stress as well as after jasmonic acid treatment indicated the induction of the synthesis of caffeic acid (7) (Scheme 1). It has been demonstrated by Nitzsche et al. [17] that 7 has a low in vitro cytotoxic potential against acute myeloid leukemia (HL-60) cells. This pharmacologically beneficial property in combination with their low toxicity makes 7 an interesting molecule in anticancer research. Caffeic acid (7) is a well-known phenolic phytochemical present in many foods, including coffee. Recent studies suggested that
caffeic acid exerts anticarcinogenic effects, but little is known about the underlying molecular mechanisms and specific target proteins. Kang et al. [18] found that Fyn, one of the members of the nonreceptor protein tyrosine kinase family, was required for ultraviolet (UV) B-induced cyclooxygenase-2 (COX-2) expression, and 7 suppressed UVB-induced skin carcinogenesis by directly inhibiting Fyn kinase activity. UVB not only initiates DNA damage but also causes alterations in signaling molecules involved in tumor promotion, thereby acting as a complete carcinogen. Among the many genes that are abnormally altered by UVB, the cyclooxygenases-2 (cox-2) gene, which is known to be overexpressed in response to UVB in both mouse and human skin, serves as an early skin marker of UVB exposure [19-23]. It was revealed that 7 effectively induced the downregulation of COX-2 expression at the transcriptional level mediated through the inhibition of activator protein-1 (AP-1) and nuclear factor-kB (NF- B) transcription activity. Fyn kinase activity was suppressed effectively by 7 and downstream mitogenactivated protein kinases (MAPKs) were subsequently blocked. Pull-down assays revealed that caffeic acid (7) directly binds with Fyn and non-competitively with adenosine triphosphate. In vivo data from mouse skin also supported the idea that caffeic acid suppressed UVB-induced COX-2 expression by blocking Fyn kinase activity (Fig. 7), suggesting that this compound could act as a potent chemopreventive agent against skin cancer. Importantly, quantitative structure-activity relationship results (QSAR) by Verma et al. have shown [24] that the different activities of caffeic acid and its derivatives are largely dependent on their hydrophobicity or molar refractivity, with a bilinear correlation being the most important. 2.3. Commercial Source 17-Hydroxysteroid dehydrogenase (17-HSD) type 5, commonly known as AKR1C3, is a member of the aldoketo reductase (AKR) superfamily [25]. 17-HSDs catalyze the final step in the biosynthesis of the sex hormones [26]. They have a key role in the human
OCH3
HO
HO
HO
HO
HO 6 H2N COOH 1 COOH COOH p-Coumaric acid 2 Phenylalanine Cinnamic acid 7
H3CO COOH Caffeic acid
8 Ferulic acid
H3CO 9 COOH Sinapinic acid COOH
Scheme 1. Biosynthetic route of cinnamic acid and its phenolic analogues.
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De et al.
O MeO OH 9a OMe O OH 13 OH CF3 10
O OH Me 11 O OH O 14 O
O OH HOOC O OH 15 12
O OH
MeO
Fig. (2). Different cinnamic acid derivatives tested for AKRlC3 inhibition.
hormonal regulation and operate by converting the inactive 17keto-steroids into their active 17 -hydroxy forms, or vice versa, using NADPH or NADP+ as cofactors. AKR1C3 is an emerging therapeutic target in the treatment of hormone-dependent forms of cancer, such as prostate cancer, breast cancer and endometrial cancer. A series of commercially available cinnamic acids and related compounds have been evaluated for inhibitory activities of AKR1C3 by Br z c et al. [27]. The initial structureactivity relationships revealed by the study show compounds 1, 7 and 9a15 are potent inhibitors of AKR1C3 (Fig. 2) (Fig. 7). Cinnamic acid (1) was a good inhibitor of AKR1C3 (IC50 = 50 FM) so as 3,4,5trimethoxycinnnamic acid (9a) (IC50 = 49 FM), a methyl ether of sinapinic acid (9) and 3-trifluoromethylcinnamic acid (14) (IC50 = 43 FM). Thus, the small hydrophobic substitutions of methoxy or trifluoromethyl groups do not alter the inhibitory activity of 1. The best inhibitor in the series was 2-methylcinnamic acid (11) (IC50 = 6.4 FM). In this compound, the aromatic ring remains unsubstituted, and a methyl substitution is introduced into the -position next to the carboxylate. When a carboxylic group is present in the para-position of the phenyl ring such as in 12 (34% inhibition at 50 FM), the inhibitory activity drops. Also the hydroxylated cinnamic acid derivatives m-coumaric acid (13) (34% inhibition at 50 FM) and caffeic acid (7) (18% inhibition at 50 FM) were only weak inhibitors of the enzyme. Evidently, substitution of the phenyl ring with polar substituents decreases the inhibition of AKR1C3. Coumarin-3-carboxylic acid (14) (30% inhibition at 50 FM), a rigid cinnamic acid derivative, is also a poor inhibitor. Finally, the weaker activity of the saturated compound 3-cyclohexylpropanoic acid (15) (IC50 > 100 FM), as compared to 1, demonstrates that the presence of both the aromatic ring and the , -unsaturated carboxylic acid are important for good inhibitory activity. 2.4. Prenylated Cinnamic Acids Prenylated derivatives of cinnamic acids form an important class of compounds due to their ability to inhibit prenyltransferases. Prenyltransferases such as farnesyltransferase (FTase) and geranylgeranyltransferase I (GGTase I) are excellent targets for designing novel anticancer drugs since the small GTPases of the Ras superfamily are involved in neoplastic transformation [28]. For example, Ras-proteins which are farnesylated and Rho- and Ral-proteins which are geranylgeranylated are found persistently activated in
O OH HO 16 Artepillin C O O
human cancers. Furthermore, a large number of studies demonstrated the involvement of these GTPases in uncontrolled cell division, resistance to apoptosis, angiogenesis, invasion and metastasis [28, 29]. FTase and GGTase I transfer the 15-carbon farnesyl and the 20-carbon geranylgeranyl, respectively, from farnesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP) to the cysteine of proteins that end with CaaX sequence (C = cysteine, a = aliphatic amino acid, and X = any amino acid) at their carboxyl termini. FTase prefers when X is methionine or serine, whereas GGTase I prefers when X is leucine or isoleucine. To date most FTase and GGTase I inhibitors have focused on the development of inhibitors that compete with the CaaX binding site, and only a few have targeted the FPP and GGPP binding sites. Importantly, posttranslational modifications of small GTPases by FTase or GGTase I are required for their cancer causing activity. Propolis is a resinous hive product collected by honeybees from various plant sources. It has a pleasent aromatic odour and yellowgreen to dark brown color depending on its age and source [30]. Propolis from temperate zones contains predominantly phenolic compounds including flavonoids and cinnamic acid derivatives [31]. On the other hand, diterpenes and prenylated compounds are present, together with lignans, flavonoids and other classes of compounds, in tropical propolis of the South-American continent [32]. The difference in composition of propolis mainly arises due to difference in vegetations. However, propolis, obtained from different regions, have similar biological properties [33]. It has a long history of traditional usage as folk medicine in Europe and Japan since 300 BC [31]. The ethanolic extract of Brazillian propolis contains three prenylated cinnamic acid derivatives, namely Artepillin C (16), Baccharin (17) and Drupanin (18), (Fig. 3) with remarkable antitumor activity [34]. Among them 16 is known to exert antitumor activity by induction of apoptosis in human cancer cell lines in vitro and in vivo [35-38]. It was also shown to be safe in animal models [38, 39]. Drupanin (18) has a better cycotoxicity profile than 24 on normal blood lymphocytes stimulated with ConA (ConcanavalinA; a lectine protein, bind with Mn2+ and Ca2+ and has affinity for glucose nad mannose [40]). Importantly, all three compounds showed growth inhibitory efficacy towards human gastric, colon cancer and leukemia cell lines at 15 M.
O OH 17 Baccharin HO 18 Drupanin
O OH
Fig. (3). Active components of Brazillian propolis.
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HO i
HO ii
RO iii
RO
6a COOH COOEt COOEt 19a, R = Isopentenyl 20a, R = Geranyl COOH 21a, R = Farnesyl O O 22 O 23 MeO OH COOH 19b, R = Isopentenyl 20b, R = Geranyl 21b, R = Farnesyl
Scheme 2. Synthesis of prenylated cinnamic acids. Reagent and conditions: i) EtOH, H2 SO4 (c.), reflux. ii) RBr, K2 CO3 , Acetone, reflux. iii) saponification.
Significantly, as shown by Epifano et al., farnesyloxy- and geranyloxycinnamic acids have been found to be potential lead compounds of a novel class of selective GGTase I inhibitors [3a]. The most potent compound was the farnesyloxy derivative of transpara-coumaric acid (21b) (Scheme 2) that inhibited GGTase I with an IC50 value of 28 EM. Substituting the farnesyl side chain with a geranyl one as in (20b) (IC50 = 39 EM) or an isopentenyl one as in (19b) (IC50 =100 EM) decreases the ability of the prenyloxy derivative to inhibit GGTase I (Table 1), suggesting that the length of the isoprenyl moiety is crucial for fully occupying the 20-carbon GGPP binding pocket of this enzyme. Benzoic acid derivative (22) are totally inactive towards inhibition of both enzymes suggesting that , -unsaturated double bond is a main structural feature for compounds to be active as GGTase I inhibitors. Furthermore, free acids are by far better GGTase I inhibitors than the corresponding ethyl esters, indicating that the binding pocket in GGTase I requires a negatively charged carboxylate anion that probably mimics the negatively charged pyrophosphate of the GGPP molecule.
Table 1. Biological Activities of Cinnamoyl Prenylated Derivatives
Inhibition (%) FTase 19b 20a 20b 21b 22 43.2 (n=2) -7.4 22.1 12.7 23.0 16.2 (n=2) 17.6 (n = 2) GGTase 46.4 (n = 2) 7.5 21.5 72.4 9.4 93.5 (n=2) 0 (n = 1) 100 39 9.5 28 (n=1) IC50 (8M)
Compound
Cdc25A is responsible for regulating the G1S cell cycle transition (Fig. 4) [42]. Cdc25 phosphatases are also known to play important roles in cancer cell growth. Increased expression of Cdc25A and Cdc25B has been reported in several tumors of different tissue origins [43-47] and overexpression of Cdc25A and Cdc25B together with activated Ras induces oncogenic transformation of normal fibroblast cells [48]. Compound 24 had mixed inhibition kinetics for Cdc25A and Cdc25B. It caused cell cycle arrest in the G1 phase in human lung cancer cells (A549 and SBC-5) but not cell cycle arrest in the G2/M phase. After treatment with TPY-835, the activation of Cdk2 was suppressed and phosphorylation of the retinoblastoma (Rb) protein was decreased in SBC-5 cells. This is in contrast with roscovitine (25), (Fig. 5) a potent inhibitor of CDK2/cyclin E with an IC50 value of 0.1 M [49] which induces G1 and G2/M phase arrest and inhibits Rb phosphorylation, but without affecting the Cdk2 activation process. In addition, TPY-835 induced an increase of the sub-G1 phase cell population after 4872 h of treatment. The growth inhibitory effects of TPY-835 against cisplatin (CDDP)-, camptothecin- and 5-Fluoro Uracil-resistant cell lines were comparable to the growth inhibitory effect on their parental lines, thus indicating that TPY-835 did not show cross-resistance to these cell lines. 2.6. Adamentyl Cinnamic Acid Dowson et al. [50] reported that (E)-4-[3 -(1-adamantyl)4 hydroxyphenyl]-3-chloro cinnamic acid (28a; Scheme 3) has promising anticancer activity than its tetrazol, thiazolone or hydroxamic acid derivatives. This compound was synthesized from 3chloro-4-hydroxy benzaldehyde via Suzukitype coupling with adamentyl-substituted phenyl boronic acid derivative (27a). Compound 28a was found to inhibit cancer cell growth and it is believed to induce apoptosis as well. The growth of leukemic cell line (KG1AML) was found to be inhibited by 28a in 35% and 55% with 1 M and 5 M concentrations respectively. It is believed that it has shown antiangeogenic activity by modulating antiproliferative or apoptotic pathway in the tumor microvasculator. 3. CINNAMOYL ESTERS
It is notworthy that 3-(4 -geranyloxy-3 -methoxyphenyl)-2trans propenoic acid (23) was isolated in 1966 from the bark of Acronychia baueri Schott, an Australian small plant belonging to the family of Rutaceae. 23 showed a series of interesting biological effects such as cancer chemoprevention by dietary feeding in rats and other effects closely related to cancer growth and development that were recently reviewed by Curini et al. [39]. 2.5. cis-Cinnamic Acid Derivative
3.1. Introduction In an interesting report by Aoyagi and co-workers [41], a new cis-cinnamic acid derivative (24; TPY-835) was found to inhibit Cdc25A and Cdc25B activity (IC50 = 5.1 and 5.7 EM, respectively) in a concentration dependent manner. The Cdc25 dual-specificity phosphatases (DSPases) are important regulators of cell cycle progression, transactivating cyclin-dependent kinases (Cdk) by dephosphorylating phosphorylated sites at Thr14 and Tyr15. Cinnamoates form a class of anticancer agents. The variation in esters arises from both natural resources as well as synthesized compounds. A lot of naturally occurring and biologically active alcohols have been linked with cinnamoyl residues through the ester linkage to amend their anticancer efficacy.
De et al.
Fig. (4). Compounds active in deferent phases of cancer cell cycle.
HN N N N Cl 24 TPY 835
Fig. (5). TPY 835 and Roscovitine.
N N HO NH
S COOH
25 Roscovitine
CHO i HO Cl 26 BnO
CHO ii BnO Cl 26a Cl 26b
COOEt iii, iv TfO Cl 26c
COOEt
Br v, i, vi HO 27 BnO
B(OH)2
vii 27a
COOH viii Cl 28
COOEt
BnO 28a
Cl
BnO
Scheme 3. Synthesis of (E)-4-[3 -(1-adamantyl)-4 -hydroxyphenyl]-3-chlorocinnamic acid. Reagents and conditions: i) PhCH2Br, K2CO 3, acetone, reflux. ii) [(EtO)2 P(O)CH2CO 2Et, KN(TMS) 2, THF, -78 C. iii) BBr3 , CH2 Cl2 , -78 C; H3O +. iv) Tf2O, pyridine (Py), CH2 Cl2 , 0C to rt. v) 1-AdOH, conc. H2SO4, CH2 Cl2 . vi) n-BuLi, -78 C; B(Oi-Pr)3, -78C to rt; dil. HCl. vii) Pd(PPh3) 4, 2 M Na2CO 3, LiCl, DME, reflux. viii) Saponification.
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HO
OH
HO
30 H 4-Hydroxyphenyllactic acid O COOH O HO H 31 p-Coumaroyl-4-hydroxyphenyllactic acid OH
HO
HO
6 COOH 2 Phenylalanine H2N COOH p-Coumaric acid
29 O
CoA
O HO O HO H 32 Rosmarinic acid OH COOH OH
Scheme 4. Rosmarinic acid biosynthesis
3.2. Natural Resources The major metabolite synthesized in the cell culture of lavender [17], along with 7, is (S)-2-[(E)-3-(3,4-dihydroxyphenyl)acryoxy]3-(3,4-dihydroxyphenyl)propanoic acid, known as rosmarinic acid (32). These compounds have the same biosynthetic precursor, phenyl alanine (Scheme 4) and have a low in vitro cytotoxic potential on acute myeloid leukemia (HL-60) cells. Thus, 7 and 32 became interesting compounds for further investigations concerning their biological effects. The methanolic extract of Netherlands propolis [51], a temperate propolis, showed antiproliferative activity towards livermetastatic murine colon 26-L5 carcinoma with an efficiency concentration 50% (EC50) value of 3.5 g/mL. Purification and analysis of the MeOH-extract led to the isolation of four flavonoids and nine cinnamic and caffeic acid derivatives. Interestingly, while assessing the individual antitumor efficacy, the benzyl (7a), phenethyl (CAPE; 7b) and cinnamyl (7c) caffeates (Fig. 5) were found to be potent anti proliferative agents toward colon 26-L5 carcinoma with EC50 values of 0.288, 1.76 and 0.114 g/mL respectively. The hypothesis that their antioxidative efficacy is playing a crucial role in their antiproliferative activities was supported by the similar 2,2-diphenylpicrylhydrazyl (DPPH) radical scavenging activity of these caffeates to that of tocopherol. Among these components of propolis, caffeic acid phenethyl ester (CAPE; 7b) has been used as a folk medicine. It has several biological activities including antioxidation, anti-inflammation and inhibition of tumor growth. CAPE has the potential in radiation therapy as potentiating agent [52]. Besides, it has significant effect on tumor invasion and metastasis by determining the regulation of matrix metalloproteinases
O O HO OH 7a Benzylcaffeate HO OH 7b O O
(MMPs). Matrix metalloproteinases, which are zinc-dependent proteolytic enzymes, play a pivotal role in tumor metastasis by cleavage of extracellular matrix (ECM) as well as nonmatrix substrates. Matrix metalloproteinases mediate invasion and metastasis [53, 54]. The influence of CAPE on the gene expression of MMPs (MMP-2, MMP-9, MT1-MMP), tissue inhibitor of metalloproteinase-2 (TIMP-2) and in vitro invasiveness of human fibrosarcoma cells were tested by Hwang et al. [55]. Dose dependent decreases in MMP and TIMP-2 mRNA levels were observed in CAPE-treated HT1080 human fibrosarcoma cells. Lee et al. [56] investigated the effect of 7b on the invasive phenotype of SKHep1 human hepatocellular carcinoma cells (SK-Hep1 cells). CAPE effectively suppressed SK-Hep1 cell invasion in a dose-dependent manner. The constitutive expression of MMP-2 and MMP-9 in SK-Hep1 cells was almost completely abolished by treatment with 12.5 M CAPE. CAPE also significantly inhibited nuclear factor kappa B (NF- B) DNA-binding activity in SK-Hep1 cells. The authors suggested that CAPE exerts antimetastatic potential through inhibition of MMP-2 and MMP-9 expression, possibly by targeting NF- B in hepatocellular carcinoma [57]. Previous studies by Natarajan et al. [58] showed that 7b also inhibited the activation of NF- B induced by various agents producing ROS in human histiocytic cells and coronary artery endothelial cells. 7b inhibits the growth of tumor cells and is a known inhibitor of nuclear factor kappa beta (NF- B), which is constitutively active in cholangiocarcinoma (CCH; cancers of both intrahepatic and extrahepatic origin) cells. NF- B activity not only protects cancer cells from apoptotic cell death but also enhance their growth activity [59]. Onori et al. [60] evaluated the effects of CAPE on CCH growth both in vitro and in vivo. Inhibition of NFB DNA-binding activity was confirmed in nuclear extracts treated
O O HO OH
7c Cinnamoylcaffeate
Phenethylcaffeate
Fig. (6). Benzyl, phenethyl and cinnamoyl caffeate.
De et al.
Fig. (7). Representative pathway for metastasis (colorectal) (numbers encircled with dotted line represent the compounds and their approximate location of action).
with CAPE at 50, 40 and 20 M. CAPE decreases the expression of NF- B1 (p50) and RelA (p65). CAPE decreased the growth of a number of CCH cells but not normal cholangiocytes. However, tumor growth was found to be decreased and tumor latency was increased 2-fold in CAPE compared to vehicle-treated nude mice. Teitelbaum et al. [61] showed that the receptor activator NF- B ligand (RANKL)-activated signaling is essential for osteoclast differentiation, activation and survival. Osteoclasts are multinucleated bone-resorbing cells derived from precursors of the monocytemacrophage lineage. Low concentrations of CAPE (<1 M) dose dependently inhibited RANKL-induced osteoclastogenesis in RAW264.7 cell and bone marrow macrophage (BMM) cultures, as well as decreasing the capacity of human osteoclasts to resorb bone.
CAPE inhibited both constitutive and RANKL-induced NF- B and nuclear factor of activated T cells (NFAT; [62,63]) activation, concomitant with delayed I B degradation and inhibition of p65 nuclear translocation. At higher concentrations, CAPE induced apoptosis and caspase 3 activities of RAW264.7 and disrupts the microtubule network in osteoclast like (OCL) cells. These results [64] demonstrated that inhibition of NF- B and NFAT activation by CAPE results in the attenuation of osteoclastogenesis and bone resorption (Fig. 7). Jin et al. [65] investigated the mechanism of CAPE-induced apoptosis in human myeloid leukemia U937 cells. It was found that the apoptotic action of the CAPE was accompanied by release of cytochrome C, reduction of Bcl-2 expression, increase of Bax ex-
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O O 7b OH O OH Cu(II)
H O I Cu(II) O H
Cu(II)
O2
H2O2
Cu(I) O O III O O O2 O2 II O
O2
H O Cu(I) O H
Cu(I) H2O2
Cu(II) OH Oxidative DNA damage
Carcinogenesis
Scheme 5. Possible mechanism of oxidative DNA damage induced by CAPE plus Cu(II).
pression, activation/cleavage of caspase-3 and activation/cleavage of PARP in U937 cells. The authors suggested that CAPE does not affect Fas protein, an initial mediator in the death signaling, or phospho-eIF2a [66] and CHOP [69], crucial mediators in endoplasmic reticulum (ER)-mediated apoptosis. CAPE may modify the enzyme activity of cytochrome P450 (CYP) isoforms involved in diethylnitrosamine (DEN) activation. Beltrn-Ramrez et al. [68] suggested that CAPE modifies the enzymatic activity of CYP isoforms involved in the activation of DEN, such as CYP1A1/2 and CYP2B1/2. Thus, CAPE shows anticarcinogenic properties in the modified resistant hepatocyte model when administered before initiation or promotion of hepatocarcinogenesis process; however, information about the mechanism underlying this chemoprotection is limited. The prooxidant effect of caffeic acid phenyl ester (CAPE) and its structural analogues on supercoiled pBR322 plasmid DNA strand breakage and calf thymus DNA damage in the presence of Cu(II) ions has been studied by Wang et al. [69] It was found that CAPE exhibit remarkably higher activity in the DNA damage than the ones bearing no ortho-dihydroxyl functionality due to the stabilization of oxidative intermediate derived from CAPE and Cu(II)/Cu(I) redox cycles (Scheme 5). The prooxidant action of phenolic compounds rather than their antioxidant action may be an
COOMe HO HO 7d COOMe
Fig. (8). Methylcaffeate and regioisomers
important mechanism for their anticancer and apoptosis-inducing properties, as ROS can mediate apoptotic DNA fragmentation [70 72]. A phenyl propanoid, methyl 3,4-dihydroxycinnamate (methyl caffeate 7d, Fig. 8), was isolated from the plant Notopterygium incisum. This compound showed a significant cytotoxicity (IC50 (mean) = 2 Lg/mL) against various cancer cell lines [73] and greatly inhibited the invasion of B16 melanoma cells. Interestingly, E configuration and , -unsaturated carbonyl functionality had been proved to be essential for the observed cytotoxicity as methyl-Z2,5-dihydroxycinnamate (33a) was found to be less active (IC50 >30 Lg/mL) compared to its E isomer (33b) (IC50 (mean) = 0.15 Lg/mL) and methyl 3-(2,5-dihydroxyphenyl)propanoate (34) has poor cytotoxicity (IC50 (mean) = 5 Lg/mL) compared to 33a. Chlorogenic acid (3-caffeoyl-D-quinic acid; CGA, 35) is an ester formed between caffeic acid and quinic acid (Fig. 9). CGA and other polyphenol compounds are the major phenolic compounds found in many fruits such as apples, pears, peaches, plums, cherries and apricots. The modifying effects of dietary administration of the plant phenolic antioxidants caffeic (7), ellagic (36; Fig. 9), chlorogenic (35) and ferulic (8) acids during the initiation phase on 4nitroquinoline-1-oxide (4-NQO)-induced carcinogenesis of the
OH
HO
OH HO 33b 34 COOMe
HO OH 33a
COOMe
De et al.
OH HO COOH O HO OH 35 O OH O OH 36 O OH OH HO O O
Fig. (9). Chlorogenic acid and ellagic acid.
tongue squamous epithelium was investigated in male F344 rats [74]. Feeding of 8 and 36 for 32 weeks significantly reduced the incidences of tongue neoplasms (squamous cell papilloma and carcinoma) and preneoplastic lesions (hyperplasia and dysplasia) in rats while feeding of 7 and/or 35 had no tongue neoplasms. The number and area of Argyrophilic Nucleolar Organizer Regions (AgNORs; which has prognostic significance in resected non-small cell lung cancer [75]) per nucleus were decreased significantly by dietary treatment with these four phenolics. However, compound 35 has also been found to inhibit the formation of potent mutagenic and carcinogenic N-nitroso compounds in vivo by Kono et al. [76]. In addition, Lee et al. [77] demonstrated that treatment of cultured MCF-7 and MAD-MB-231 human breast cancer cells with caffeic acid (7) or chlorogenic acid (35) partially inhibited the methylation of the promoter region of the RARb gene. 3.3. Synthetic Resources Nam et al. reported [73] the synthesis and antitumor cytotoxicity of (E)-methyl/ethyl 3-[2-(1,4-dimethoxy-5,8-dione)naphthalOMe OMe CHO i OMe
enyl]-2-propenoates (39a, 39b) and (E)-methyl/ethyl 3-[2-(1,4dihydroxy-9,10-dione)anthracenyl]-2-propenoates (40a, 40b). These molecules were synthesized from 2-formyl-1,4,9,10tetramethoxynaphthalene (37) and the corresponding anthracene derivative (38) respectively (Scheme 6). The acrylic acid or cinnamoyl functionality was introduced using a Wittig type coupling with triphenylphosphine ylide followed by a demethylationoxidation sequence with cericammonium nitrate (CAN). It was found that the ortho- or para-dihydroxy functionality on the aryl ring, obtained from 38a,b after demethylation using AlCl3, was essential for the cytotoxicity of cinnamates as among these naphthaquinone derivatives, 40a and 40b showed potent cytotoxicity, comparable to Adriamycine(41), against various tumor cell lines including solid tumor. 3.4. Cinnamoates of Natural Bioactive Molecules Camptothecin (42), a pentacyclic alkaloid derived from a Chinese tree Camptotheca acuminata, showed good anti-tumor activity against the mouse leukemia L1210 system [78-83].
OMe COOR ii from 37a,b OR O OMe O
OMe
OMe
a, R = Me b, R = Et
OMe 37a,b 38a,b
OMe
OMe 39a,b
37, naphthalene 38, anthracene O iii from 38a,b O 40a,b Mean IC50 = 0.69 g/mL OH OH O
Mean IC50 = 0.97 g/mL O OH HO O OH
OR
OMe 41
OH
OGlucosamyl
Adriamycine
Mean IC50 = 0.20 g/mL
Scheme 6. Synthesis of naphthaquinone and anthraquinone derivatives. Reagents and conditions: ii) Ph3 PCH 2COOR, Benzene, reflux. ii) CAN, CH3CN-H2O. iii) AlCl3, Nitrobenzene.
R N N 42, R = H 43, R = NO2 OH Cl 1a 42a 43a O O O O i O N O R N O O O
Scheme 7. Synthesis of cinnamoyl-camptothecin derivatives. Reagents and condition: i) Heat.
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To study the degrees of influence of the change of the ester side chains at position C20 of camptothecin on the anti-tumor activity of the molecules, the acylation of 42 and 43 with cinnamoyl chloride were carried out to get products 42a and 43a (Scheme 7) by Cao et al. [84]. However, the introduction of an unsaturated double bond into the side ester chain of the molecule did not significantly alter the anti-tumor activity. Howiinol A (GHM-10; 44) is a kind of phenylethylene pyrone compound isolated from ethanolic extract of the root and stem bark of Goniothalamus howii by Xu et al. [85]. The IC50s of 44 when treated to L1210 cells, mouse lymphocytic leukemia cells, for 1 and 24 h were 18 and 8.7 JM respectively demonstrating that the main effect of 44 is to inhibit the cell proliferation. Flow cytometry results show that to some extent, 44 blocks the cell cycle transition from G1 phase to S phase (Fig. 4). The authors also noted that it significantly suppresses the biosynthesis of DNA, RNA and protein in L1210 cells, and the DNA synthesis is mostly affected possibly by the inhibition of DNA topoisomerase II. In a recent modification of 44 by Chen et al. [86], (+) 8-O-cinnamyl-p-chlorogoniotriol (pchlorohowiinol A; 45e) and its analogue (45f) have been synthesized (Scheme 8) from -D-glucoheptonic- -lactone (45). The p-Clphenyl moiety was introduced to the acetonide protected aldehyde (45a) via a Grignard reaction followed by a multistep reaction sequence. The cinnamoyl ester was introduced to 45c preferably because of its stereochemical similarity with 44 than its other isomer (45d) formed during the course of reaction. Pharmacological tests showed that the compounds 45e and 45f possessed most potent antitumor activities toward tumor cells (A2783, HCF8 (small intestine), Bel 7402 (liver)) in vitro. Acronycine or 6-methoxy-3,3,12-trimethyl-3,12-dihydro-7Hpyrano[2,3-c]acridin-7-one (46) is an alkaloid having a broad spectrum of biological activities but with low potency [87]. Inspired by
O O O HO HO 45 O OH iii Cl 45c O + OH O O O O iv Cl OH 45a OH OH i OHC O O O OH ii
acronycine, a new class of acronycine-analogues (49a, 49b) (Scheme 9) have been designed, synthesized and their solubility, potency and anticancer efficacy as cytotoxic agents were evaluated by Koch et al. [88]. Compounds 49a and 49b were prepared by adding respective cinnamoyl chlorides (1a, 48) to ()cis-1,2dihydroxy-6-methoxy-3,3,14-trimethyl-2,3,7,14-tetrahydro-1Hbenzo[b]pyrano [3,2h]acridine-6-one (47a,b) in dry pyridine followed by acetylation with acetic anhydride in the presence of DMAP in dry pyridine.The in vitro cytotoxicity of compound 49a, for example, revealed an IC50 value of 0.59 M towards L1210 maurine leukaemia and 0.15 M towards KB-3-1 human epidermoid carcinoma cell lines. Compound 49b exhibited an in vivo antitumor activity of 50% for an optimum dose of 4 mg/kg compared to acronycine (27%, optimum dose 100mg/kg). Mismatch repair proteins (MSH), originally identified in recognizing and processing DNA replication errors, have been identified to have a p53-independent mechanism (Fig. 7). In response to DNA-damage or mismatch these proteins promote cell death rather than damage repair. Search for new drug candidates with a mode of action that is independent of p53 is important as loss of p53-gene is associated with faster tumor progression and resistant to cancer treatment [89]. Bacterial MutS protein and its eukaryotic homologue belong to the family of mismatch proteins as they recognize some DNA damages in addition to the recognition of mismatches. The death conformation of MutS has been identified and reserpine (50), a antihypertensive drug, specifically binds to the death conformation of protein thereby initiating MSH2-dependent cell death (IC50= 61JM) which is independent of genotoxic insult. Rescinnamate (52a) and cinnamoyl reserpine (52b) were synthesized and tested against MutS by Salsbury et al. [90]. Reserpine was treated with NaOMe in methanol under reflux to obtain methyl reserpate (50a) which was subsequently treated with respective
OH
OH
OH
OH Cl
Cl
O 45b
2 isomers
O O O
Cl
O O O
v O 45e IC50 =0.74-1.7 M IC50 =2.2 - 9.2 M O O O O O Cl 45f OH OH
Cl 45d
O OH 44 Howiinol IC50 =18 mM(1 h), 8.7 M(24 h) OH
Scheme 8. Synthesis of Howiinol analogues. Reagents and conditions: i) 3 steps; Acetone, H2 SO4; 65% AcOH; NaIO4. ii) p-Cl-PhMgX, N2 , I 2, THF, reflux. iii) 3 steps; NaIO4, MeOH-H 2O, rt; Ph3P=CHCOOEt, -15C; DBU (Cat.), THF, 70-80C. iv) 1a, DMAP, Et3N, CH2Cl2, rt. v) 75% AcOH, 80-90C.
De et al.
OMe OMe O i O OH OH N 47 R2 R1 R1 = R2 = H, 1a R1 = R2 = Cl, 48 R1 R2 O 47a 47b O Cl O O OH O N OMe O ii
N OAc O O
N O MeO 46 Acronycine
R1 R2 R1 = R2 = H, 49a R1 = R2 = Cl, 49b
Scheme 9. Synthesis of cinnamoyl acronycine analogues. Reagents and conditions: i) Dry Py, ii) Ac 2O, DMAP, dry Py.
cinnamoyl chlorides (1a, 51) in pyridine to synthesize rescinnamate and cinnamoyl reserpine (Scheme 10). Rescinnamate showed MSH2-dependent cell death with better potency (IC50= 39 9M) than reserpine at 24h exposure. MSH2-deficient cells showed increased resistance to these compounds. Importantly, the better activity of 52a was attributed to the increased chain length due to the incorporation of the cinnamoyl moiety offering polar head groups closer to their binding partners within the protein. Cinnamoyl reserpine (52b) lacking the methoxy groups of 52a induces cell death that is independent of functional MSH2 (IC50= 1509M in deficient cells and 130 9M in proficient cells).
The concept of treating cancer by inhibition of angiogenesis, which was proposed by Folkman [91, 92], is a promising strategy for cancer therapy [93]. Fumagillin (53), isolated from Aspergillus fumigatus, inhibits new blood vessel growth. Many semisynthetic fumagillin analogues have been synthesized from fumagillol (54), the hydrolysis product of fumagillin [94]. Among these analogues, O-(chloroacetylcarbamoyl) fumagillol (TNP-470, AGM-1470; 54a) is currently in phase III clinical trials for the treatment of a variety of cancers [95]. The underlying molecular mechanism of the inhibition of angiogenesis (Fig. 7) by these fumagillin derivatives is attributed to fumagillin-binding protein, methionine aminopeptidase
MeO
N H
N H H H O O O OMe OMe OMe
MeO i
N H
N H H H
50 Reserpine
MeO
50a Methyl reserpate
MeO O O Cl OMe
OH
OMe
OMe 51
O ii Cl 1a ii OMe OMe
MeO MeO N H N H H 52b Cinnamoyl reserpine MeO O OMe O H O 52a Rescinnamate
N H
N H H H O O O OMe OMe OMe OMe
MeO
Scheme 10. Reserpin and its cinnamic acid analogues. Reagents and conditions: i) NaOMe, dry MeOH, reflux; conc. HCl, water. ii) Py., rt.
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O O O H O R= COOH 4 53 Fumagillin O O R= R= R= CKD 731 54d R=H 54 Fumagillol R= N H
O Cl 54a
TNP470 IC50 (ng/mL) = 0.03 (EL-4) 0.04 (CPAE) >10 (P388D1) O
OMe OR
54b IC50 (ng/mL) = 0.05 (EL-4) 0.046 (CPAE) >1 (P388D1) O R= OMe
54c
OMe
OMe
IC50 (ng/mL) = 0.00019 (EL-4) 0.00006 (CPAE) >1 (P388D1)
OMe OMe
IC50 (ng/mL) = 0.00015 (EL-4) 0.00003 (CPAE) >1 (P388D1) R= O 54f IC50 (ng/mL) = 12 (EL-4) 24 (CPAE) ND (P388D1) OMe
OMe 54e OMe
IC50 (ng/mL) = 36 (EL-4) 44 (CPAE) ND (P388D1)
Fig. (10). In vitro cell proliferation inhibitory activity of fumagillin derivatives against lymphoma EL-4 cells, calf pulmonary artery endothelial (CPAE) cell and murine leukemia P388D1, ND;not done.
type 2 (MetAP-2) [96, 97]. Recent report by Liu et al. [98] confirmed the structure of a human MetAP-2 fumagillin complex, where the spiro-epoxide of fumagillin forms a covalent bond with the His231 in the active site of MetAP-2. New fumagillin analogues (54b-f) were designed (Fig. 10) by Han et al. [99] through structure-based molecular modeling with a human methionine aminopeptidase-2. Fumagillol was treated with respective acid chlorides of cinnamic frame in the presence of NaH in THF at room temperature to afford the cinnamoyl fumagillin analogues. Among the fumagillin analogues, cinnamic acid ester derivative CKD-731 (54d) showed 1000-fold more potent proliferation inhibitory activity on endothelial cell than 54a. Significantly, trans-geometry of the double bond seemed to be important as far as biological results are concerned. Schisandrol A (55), a dibenzocyclooctadiene lignan, was obtained from fruits of Schisandra chinensis, a widely used in traditional Chinese and Japanese herbal medicine due to their hepatoproO O O O
tective, antiasthmatic, antidiabetic, sedative and tonic properties. Schobert et al. [100] attached cinnamic acid with 55 under nonclassical condition. The cinnamoate (55a) (Scheme 11) inhibited the P-gp drug transporters of multidrug resistant human Kb-V1 cervix carcinoma cells better than the natural benzoate derivative and its activity is comparable to verapamil (56), a clinical chemosensitizer. The new cinnamoate (55a) reached even 60% of the verapamil activity in Calcein-AM assays: with 59.72%-inhibition of the ABCB1 (P-gp) drug transporter in Kb-V1 cells by 55a at 50 EM relative to verapamil after 90 min exposure. 3.5. Cinnamoyl Taxoids In cancer chemotherapy, occurrence of multidrug resistance (MDR) of cancer cells caused by repeated administration of anticancer agents is a serious problem. One of the mechanisms of MDR is overexpression of P-glycoprotein (P-gp) [101-103], operating a
MeO MeO MeO OH MeO OMe Schisandrol A

Scheme 11. Synthesis of Schisandrol-cinnamoate and the structure of verapamil. Reagents and conditions: i) 1a, Et3 N, Xylene, EW, 170DC, 3 h.
N CN
OMe
i OH
MeO MeO O MeO OMe O 55a OH MeO
+ Verapamil 56
OMe
55
De et al.
AcO 10 2 14 1 H OAc
7 5 H OAc 20 57
OAc
Taxuyunnanine C
AcO 10 2 14 1 H OAc
AcO 9 7 5 H OAc 57a ii 20 OH OH 14 1 H 10 2
HO 7 5 H OAc 20 57b ii 14 1 H OAc 10 2
HO 9 7 5 H OAc 20 OH 57c ii OAc 14 1 H 10 2
7 5 H OAc 20 57d
OAc
OAc
AcO
AcO OAc H H H OAc O O 58a O H OAc O 58b H OAc H OAc OAc 58c O O
OAc
ii
ii O HO O O H OAc O 58e H H OAc O H 58f O O OAc O OAc
ii
OAc
58d H H OH OAc
Scheme 12. Synthesis of taxuyunnanine C-cinnamoates. Procedure: i) 1.1 M K 2CO3 , MeOH/THF, 45C. ii) 1a, DMAP, dry pyridine, 85C.
defense mechanism against the toxic materials in cells by transporting a wide range of reagents. Liu et al. [13] reported that taxuyunnanine C (57) and its 14acyloxy analogs are the major metabolites from callus cultures of
Taxus species in high yields and they have activity toward the accumulation of vincristine in MDR 2780AD cells. Recently, cinnamoyl analogues of 57 have been synthesized by Hasegawa et al. [104]. Taxuyunnanine C (57) was treated with 1M
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AcO i OAc
AcO
OH AcO ii H H OAc 57e OAc OAc H H OAc O
H H OAc OAc 57
OAc
OAc
58g
Taxuyunnanine C
Scheme 13. Biotransformation of Taxuyunnanine C. Reagents and conditions: i) A. coerulea IFO 4011, 25FC, 1 week. ii) 1a, DMAP, dry pyridine, 85FC.
K2CO3 in MeOH-THF (3:1) to afford a mixture of deacetylated products (57a-d; Scheme 12). The alcohols thus obtained were coupled with cinnamoyl chloride (1a) to synthesize cinnamoyl taxoid derivatives (58a-f). The C-9 hydroxy derivative of Taxuyunnanine C (57e), obtained by biotransformation (Scheme 13), was subsequently coupled with cinnamoyl chloride to afford 58g. These cinnamoate derivatives showed significant activity toward calcein accumulation in multi drug resistant (MDR) 2780 cells. The most effective compound 58e with a cinnamoyloxy group at C-14 and a hydroxyl group at C-10 was actually efficient for the cellular accumulation of the anticancer agent, vincristine, in MDR 2780AD cells with 527% enhancement of vincristine production with 58e (10 g/mL). It can modulate the multidrug resistance of cancer cells. The comparison of the biological activities of these compounds (58a-g) in terms of calcein accumulation (% control) and growth inhibitory activity (IC50; GM) with 57 reveals that compound 58e showed significant cytotoxic activity toward WI-38 (lung) and HepG2 (liver) along with the strongest activity among the tested samples toward calcein accumulation in MDR 2780AD (ovarian carcinoma) cells. The taxane diterpneoid 2-deacetoxytaxinine J (2-DAT-J; 59), a cinnamoate derivative, has been isolated from the bark of Himala-
yan yew, Taxus baccata L. (spp. wallichiana) in a reasonably good yield (0.1%). It showed significant in vitro activity against breast cancer cell lines such as MCF-7 and MDA-MB-231 at a concentration of 20 mM and 10 mM respectively. Reddy et al. [105] reported the synthesis of two novel taxoids such as phenethyl ester (60a) and 3-pyridine acryl ester (60b), derived from the naturally occurring 2DAT-J (59). Importantly, decinnamoylation of 59 was carried out using NH2OH.H2SO4 instead of NaOH/KOH to afford the corresponding alcohol (60) exclusively. Suitable acids (1, 61) were coupled with 60 to synthesize 60a and 60b.These compounds were screened for their anticancer activity (Scheme 14). The structure activity relationship studies indicated that the phenethyl group on C-5 is essential for the anticancer activity. However, replacing cinnamoyl group with the heterocyclic acid did not improve the activity. 3.6. Carbamoyl Imidazole Cinnamate In an interesting development by Atsumi et al. [106] carbamoylimidazole conjugates (Scheme 15) of 3-nitro or 4chlorocinnamic acids (62a, 62b respectively), prepared from their corresponding acid chlorides (63, 64) and 4-carbamoyl-5hydroxyimidazole (62) in the presence of pyridine, have shown
AcO OH 1 O AcO H H O 60a OAc ii OAc OAc O
AcO
OAc
AcO OAc i O O 59 AcO H
OAc
H 60
OH
N OH 61 ii AcO O OAc OAc O AcO H 60b N H O
AcO H
2-Deacetoxytaxinine J IC50 (mM) MCF7 59 60a 60b 20 15 34 MDA-MB-231 10 20 >50 HEK-293 >50 10 >50
Scheme 14. Synthesis and biological activities of 2-deacetoxytaxinine J and its derivatives. Reagents and conditions: i) NH2OH.H2SO4, H2O:THF:EtOH (1:1:1), reflux. ii) Dicyclohexylcarbodiimide (DCC), DMAP, CH2Cl2, rt.
De et al.
O O Cl NH2 O O O 62a NO2 63 N NO2 N H i O NH2 Cl N O HO N H 62 i Cl 62b N H 64 Cl O O NH2 N
Scheme 15. Cinnamoyl carbamoylimidazole derivatives. Reagents and conditions: i) Pyridine (Py), rt.
90% inhibition of Lewis lung carcinoma (solid) in mice while maintaining a low toxicity. 3.7. Cinnamate Clusters The syntheses of some caffeoyl/cinnamoyl clusters (68a, 68c, 69a, 69c) and their anti cancer effects have been described recently
by Boudreau et al. [107]. Synthesis of the clusters involved a multiple copper (I)-catalyzed Huisgen 1,3-dipolar cycloaddition. Propargyl ester of cinnamic acid (65a) and diacetylated caffeic acid (65b) were attached with corresponding azide (66, 67) cores to obtain the cinnamoyl and caffeoyl clusters (trimers; 69a, 69c respectively and tetramers; 68a, 68c respectively) via cycloaddition using CuSO4 in aq. THF.
O
R1 R2 N3 N3 N3 i R2 R1 O O O N3
R1 =R2 = H 65a R1 =R2 = OAc 65b HO N3 N3 N3 67
66 R2 R1
R2
R1
O N O N N N N N N N N N O N O R1 R2 O R2 R1 =R2 = OH 68c R1 ii R1 =R2 = OH 69c R1 R2 R1 =R2 = H 69a R1 =R2 = OAc 69b O O O N N N N R1 =R2 = H 68a R1 =R2 = OAc 68b ii N OH N N N N N
R1 R2
O O
59
Scheme 16. Cinnamoyl and caffeoyl acid clusters. Reagents and conditions: i) CuSO4 , Ascorbic acid, THF-Water, rt. ii) K2 CO3, CH 2Cl2-MeOH (1:1), rt.
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O i Cl 70 O O OH + Cl 1 O 71 O OH 72 O iv 1c SH + Cl O 73 O Cl 1a vi O HO 74 O 75e IC50 =40 M i 1d O N H + 73 O v iv S Cl O ii 70a
O N H iii O O 1b v O SH 72a O S O O 75b IC50 = 30 M O S Cl O O 75a IC50 = 100 M O O N O
750c IC50 = 30 M O iii N O O
75d IC50 = 20 M
Scheme 17. Cinnamoyl-based dicarbonyl compounds. Reagents and conditions: i) MeNH 2, Et2O. ii) NaHCO3, Bu4NHSO4 , water, CH2 Cl2 . iii) NaH, DMSO, THF. iv) isobutylchloroformate, Et3N, CH2Cl2,H2S. v) Et3N, DMF. vi) Et3N, CH 2Cl2 .
Their effects on cell proliferation in cancerous (MCF7) and non cancerous (MCF10A) human mammary epithelial cell lines were evaluated. Trimer compounds 69a, 69c and tetramer 68a, 68c (Scheme 16) decreased proliferation rates of MCF-7 cells by 36, 23 and 47%, respectively, but had no effect on MCF10A proliferation. Importantly, concentrationresponse studies revealed that the caffeoyl derivatives are concentration-dependent inhibitors of 5lipoxygenase (5-LO) [108] catalyzed product synthesis with IC50 values below 1 mM (69c: 0.79 mM, 68c: 0.66 mM) readily surpassing the activity of caffeic acid (IC50 = 25 mM) by more than 10fold. 3.8. Dicarbonyl Cinnamoates Cinnamoyl based dicarbonyl derivatives such as Nmethylbutyramidomethylcinnamate (75a), cinnamoyloxymethyl thio-butyrate (75b), butyroyloxymethylthiocinnamate (75c), Nmethyl cinnamido methyl butyrate (75d) and 3-oxohexylcinnamate (75e) have been shown to be efficient histone deacetylase inhibitors by Lan-Hargest et al. [109]. They are believed to form chelate with Zn-ion at the active site of histone deacetylase (Fig. 7). However, in vitro studies of these compounds reaveled moderate activity (IC50 ranging between 20-100 M) against PC-3 and MCF-7 cell lines. Interestingly, all the compounds have been synthesized from cinnamic acid or its acid chloride followed by suitable functionalization through a facile protocol as shown in Scheme 17.
3.9. Commercial Source Recently some commercial cinnamic acid derivatives (76a-e) (Fig. 11) have been tested by Br z c et al. [110] as inhibitors of 17HSD type 1. Among tested derivatives, 4-cyanophenyl 3,4methylenedioxycinnamate (76a) was the most active revealing more than 70% inhibition at 6 CM. Four compounds showed about 50% inhibition. 4. CINNAMIDE DERIVATIVES 4.1. Introduction Cinnamic acid amides and related compounds, like cinnamic acid esters, form a class of anticancer agents. They have wide natural occurrence. A lot of cinnamido compounds were also synthesized and their anticancer abilities were evaluated. 4.2. Natural Resources 2-Methyl cinnamide (U-77,863; 77; Fig. 12) isolated from a fermentation beer of Streptomyces griseoluteus, showed significant anti-invasive or antimetastatic effects [111]. Pretreatment of malignant melanoma cells (C8161 and A375M in vitro) with nontoxic doses of 77 caused a dose and time-dependent reversible reduction (IC50 = 12.5 g/mL) of invasion.
De et al.
O O O O O O 76a Inhibition ~ 76% O MeO 76d OMe Inhibition ~ 56% MeO O MeO OMe O O 76e Inhibition ~ 44% N O CN MeO O MeO MeO OMe Inhibition ~ 35% O 76b OMe 76c Inhibition ~ 60% MeO O
MeO
Fig. (11). Cinnamic acid derivatives as 17-HSD type 1 inhibitors.
O NH2 Me 77 U-77,863
Fig. (12). 2-Methyl cinnamide.
4.3. Cinnamoyl Pyrrole The cinnamic nitrogen mustard derivative of distamycin A (PNU-157911, 78; Fig. 13) [112, 113], a vinylogue of tallimustine (79), shows very good antileukemic activity, significantly superior to that of tallimustine. The presence of an amidino moiety, due to its strong basic nature (pKa (cald.) ~12), expected to be completely protonated in any biological conditions, and may play a key role both in the DNA binding and cell or tissue bioavailability. The replacement of the amidino group with basic or nonbasic amidino moieties of different nature led to increase in cytotoxicity in some cases [114]. The cinnamic acid mustard derivative of 80 (compound 81a) appears to be 20-fold more cytotoxic than 80 (IC50=14.22.13
H2N . HCl O NH N H H N HN O N
Similarly, lung colonization was significantly (P<0.05) inhibited when tumor cells were pretreated in vitro with the same prior to intravenous injection.
O NH
N O N Cl Cl O NH H N N N Cl Cl O 79 tallimustine N HN O 78 Cinnamoyl Distamycine PNU157911 N
H2N . HCl O N H N O O NH H N N N Cl Cl
Fig. (13). Cinnamoyl distamycine, tallimustine and its analogue.
NH
H2N . HCl NH N H HN O N N
O 80
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H2N . HCl O N H H N N O 81 Cl i, ii Cl O NH H N N O N Cl Cl iii O O NH H N N O N Cl Cl 81b N N HN O N N N H 81a N N HN O N N N N N N O CH3 HCl CH3 , 81b -CH2-CH2-CH2-CH2- HCl, 81c H CN, 81d H OH, 81e H - , 81f O N H N H2N . HCl NH N N HN O N N O O N N N NH
O2N
R1
R2
R1HN XR2
Scheme 18. Synthesis of cinnamoyl derivatives of tallimustine. Reagents and conditions: i) H2 /Pd-C, 2-3 drops of 10% HCl, MeOH/dioxane/water. ii) NaHCO3, DMF, rt, 18 h. iii) CH 3NH2 , DMF, 80C or, NH2CH2CH2NH 2, CH 3CN/water, rt or, NH 2CN, NaH, DMF, rt or, NH2OH.HCl, Et3N, DMF, 70C.
vs 30656 nM for 81a and 80, respectively) and maintains an in vitro potency equivalent to that of tallimustines vinylogue 78. Recent report by Baraldi et al. [115] confirmed the positive role played by some modifications of the amidino moiety also in the case of pyrazole isoesters of cinnamoyl mustard derivatives of distamycin and some of these compounds showed improved growth inhibitory activity [116]. These compounds were synthesized from 81 via reduction of the nitro-functionality to the corresponding amine followed by the introduction of cinnamoyl mustard moiety using cinnamyl N-hydroxybenzotriazole as source to afford 81a and then addition of suitable functionality thereby modifying the amidine moiety. (Scheme 18) On the L1210 cell line, only the N,Ndimethylamidine derivative 81b showed a cytotoxicity better than that of 81a, while the others amidinomodified derivatives 81c-f are less potent (Table 2). The compounds 81a-f showed the capability to interact with DNA with a sequence selectivity for certain ATrich sequences although the level of overall alkylation to naked DNA did not correlate directly with in vitro cytotoxicity. Like in other described compounds, distamycin moiety acts as a carrier for the regioselective DNA binding of these new molecules, situating the nitrogen mustard moiety in a very suitable disposition for the further alkylation process. The positively charged tail is not neces-
sary for the biological activity but stronger complexes are formed when it is present.
Table 2. In Vitro Activity and Resistance Index (RI) of the Cinnamoyl-Tallimustine Derivatives Against L1210 Maurine Leukemia and its Subline Resistant to Doxorunicin (DX)
IC50 (nM SE) L1210 78 79 80 81a 81b 81c 81d 81e 81f
a
Compound
RIa
L1210/DX 128.3 23.1 2638 567 9367 1231 109 16.6 131 36.2 628 65.2 >700 32322.3 >1500 13.4 38.5 30.6 7.68 24.5 8.43 >7 3.39 >37.5
9.54 2.71 68.5 6.61 306 56 14.2 2.13 5.33 1.73 74.5 9.73 98.1 23.7 94.3 19.5 39.7 5.67
RI = ratio between IC50 values on resistant cells and sensitive cells.
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O NH2 N OH
OCH3 H3CO2C HN O OCH3 N N O 82a O Duocarmycin A

Fig. (14). Structures of duocarmycine A and CC-1065.
NH O HN N O N H OH OCH3
OCH3 O N H OCH3 82b CC-1065
Several known antitumor or antibiotics have been modified by attachment of cinnamoyl-moieties. These modifications allowed synthesis of new molecules as well as improved anticancer activities in most of the cases. 4.4. Cinnamoyl Pyrrolidine Duocarmycin A (82a; Fig. 14) and its analogues are novel antitumor antibiotics isolated from the culture Streptomyces sp. Broth [117, 118]. It is considered as an active form among duocarmycins, possesses a unique cyclopropane ring with the ability to alkylate DNA. It has been reported to show its cytotoxicity through a sequence-selective minor groove alkylation of double-stranded DNA resulting in N3 adenine covalent adduct formation [119] as also in the case of the antitumor antibiotic CC-1065 (82b) [120, 121]. In addition, duocarmycins are known to exhibit potent growthinhibitory activity against human uterine cervix carcinoma HeLa S3 cells in vitro and modest broad antitumor spectrum against murine transplantable solid tumors [122, 123]. However, poor water solubility remained a concern for any further biological considerations and 82b and its analogues compounds showed delayed irreversible toxicity. Nagamura et al. [123] reported that the base hydrolysis of 82a gives the A-ring pyrrole compound (83) of duocarmycin. This pyrrolo-derivative was treated with 4 -nitrophenyl cinnamoates in the presence of NaH in DMF to afford a series of N-cinnamates (86a,b; 87a-i) (Scheme 19). The characteristic cyclopropyl ring of duocarmycine present in compounds 87a-i was opened to access new bromomethylene analogues (88a-h) using hydrobromic acid in acetonitrile followed by the introduction of N-substituted carbamate functionality. All these compounds were evaluated for in vitro anticellular activity against HeLa S3 cells and in vivo antitumor activity against murine sarcoma 180 in mice [123]. The 4 -methoxy- (86a) and 4 BocNH (86b) -cinnamates exhibited strong in vitro anticellular activity (86a, IC50 (nM) = 2.9-7.0 (1h), 0.26-0.94 (72h); 86b, IC50 (nM) = 4.0 (1h), 0.56 (72h)) among the synthesized compounds. The ortho-substitution of the 4 -methoxycinnamate (87a-i, IC50 (nM) =2.0-9.5 (1h) and 0.26-2.3 (72h)) did not affect the anticellular activity and contributed to an enhancement of water solubility. These results led to the synthesis of CC-1065 analogues (88a-h). Compounds 88a-e exhibited potent in vivo antitumor activity against sarcoma 180 murine solid-tumor (Table 3). In contrast, compounds 88f-h, having hydrophilic moieties at the 3 -position were less active than 88a-e, suggesting that a charged group in these analogs may reduce cell permeability and therefore antitumor
activity. Importantly, compounds 88d-g showed better water solubility (10 mg/mL) than 82b, as desired.
Table 3. Anticellular and Antitumor Activities of Cinnamates of Duocarmycin Analogues
HeLaS3 IC50 (nM) a 1h 88a 88b 88c 88d 88e 88f 88g 88h
a
Sarcoma 180b mg/kg 4 4 8 8 2 0.13 8 4 T/Cc 0.2 0.17 0.12 0.2 0.13 0.77 0.39 0.72
72 h 37 224 61 280 52 30 30 >1000
1800 1000 1200 2100 430 290 290 10000
Concentration to inhibit by 50%. bTumor implanted in mice subcutaneously and drug dose intravenously, cT and C values of mean tumor volume of treated and nontreated mice respectively.
With an objective of the Zn-ion binding in gelatinase (MMP-2 and -9) and APN (Fig. 7) such as CGS 27023A (89) with MMP3 (Fig. 15; [124]), a series of new cinnamoyl pyrrolidine derivatives based on the L-hydroxyproline scaffold have been synthesized by Gonnella et al. [125]. Methyl 4-hydroxy-L-pyrrolidine- carboxylate hydrochloride (90a) was prepared according to the reported procedure [126] and then converted to amide compounds with cinnamoyl chloride (1a), p-methyl cinnamoyl chloride (91), and 3,4dimethoxycinnamoyl chloride (92) to form the amide. The final target compounds (93a-c) were synthesized by esterification using different acyl chlorides (Scheme 20). The inhibitory activities on gelatinase (MMP-2 and -9) and Aminopeptidase N (APN; [127-] 129]) showed that compounds 93a, 93b and 93c, possessing the side chain with aromatic ring at C4 in pyrrolidine ring are, good gelatinase inhibitors. Most compounds exhibited poor activities on APN (IC50 = 75.2128.6 nM) compared with MMP-2 (IC50 = 5.29.7 nM) (Fig. 7). 4.5. Cinnamoyl Triazole Transglutaminases (TGases, EC 2.3.2.13) are calciumdependent enzymes that catalyze the intermolecular cross-linking of certain proteins through the formation of -glutamyl- -lysine side chain to side chain bridges (Scheme 21). Tissue TGases are involved in diverse biological processes such as endocytosis [130,
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HN O CO2CH3 O HN N O i O CO2CH3 O2N ii HN HN 83 H3CO OCH3 H3CO 63a O O 85a-i O ii O 87a-i R1 d e OCH3 f g Br H3CO2C N HN O O O NR2R3 88a-h a b c d e f g h R1 OCH3 R1 -H -H -H -NEt2 -NMe2 -O(CH2)3NH2 -NH2 -OCH2COOH -NMe2 iii, iv NR2 R3 N N N N N N N N Me N N h i -O(CH2)3NH2 -NH2 -OCH2CO2Me -NEt2 -NMe2 -NHBoc N c b -O(CH2)3NMe2 -OCH2CO2t-Bu R1 HN OCH3 CO2CH3 a R1 -O(CH2)3N3 O 84a,b HN N O O 86a R = -OMe 86b R = -NHBoc R R CO2CH3
O2N
N CH2CONHNHCHMe2 N Me N Me N Me N Me
Scheme 19. Synthesis of cinnamoyl duocarmycine derivatives. Reagents and conditions: i) NaOMe,MeOH. ii) NaH, DMF. iii) HBr, CH 3 CN. iv) R2R3NH, 4-nitrophenylchloroformate, Et3N.
N Zn2+ O H Glu202 O Solvent exposed O N H OMe O N O S O 89 H N Leu164 Solvent exposed
Ala165
Fig. (15). Mode of binding of CGS 27023A with MMP-3.
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H N
COOH 90 i
HO
H N
COOMe MeO HCl salt 90a MeO MeO 92 Cl ii O MeO O N COOMe
HO
1a ii
O N O O COOMe
ii MeO
91
Cl
MeO O N O COOMe O O O MeO 93c 93b MeO IC50 (nmol) = 7.8 (MMP2,9) = 128.6 (APN) MeO
93a IC50 (nmol) = 5.2 (MMP2,9) = 75.2 (APN)
IC50 (nmol) = 9.7 (MMP2,9) = 88.3 (APN)
Scheme 20. Synthesis of cinnamoyl-hydroxyproline derivatives. Reagents: (i) MeOH, HCl; (ii) Et3N, CH 2Cl2.
O H N TGase H N O O TGase H N
NH2
NH3
S TGase
NH2 O N H O
NH
Peptide bound Gln Acyl donor
Cross-linked Protein
N H O Peptide bound Lys Acyl acceptor
Scheme 21. Representation of TGase mediated protein cross-linking.
131], apoptosis [132], and cell growth regulation [133]. Recently, TGase has been displayed to be irreversibly inhibited by NRcarbobenzyloxy-2-amino-N- -(3-methyl-5-[1,2,4]thiadiazolyl)-Lglutamine) (94) by Marrano et al. [134]. A series of trans-cinammoyl benzotriazolyl derivatives and 3substituted cinnamoyl pyridine (azachalcones), have been synthesized (Scheme 22) by Pardin et al. [135]. 4-Nitro benzaldehyde (95) was first converted to the corresponding acrylic acid via a Wittig type reaction. The acid thus obtained was coupled with Nhydroxybenzotriazole (97) and benzotriazole (98) respectively to
achieve 100 and 101a. 101b was prepared from 3nitrobenzaldehyde using same procedure as for 101a. Compound 99 was prepared from 95 by aldol reaction with 1(pyridine-3yl)ethanone (96). These compounds are reversible inhibitors of TG2, competitive with acyl-donor substrate. Among these derivatives, the most effective inhibitors were found to be the cinnamoyl benzotriazolyl amides (101a,b) and the 3-(nitro cinnamoyl)pyridine (99). It was noted that the most potent inhibitors possess para-substituents containing a sp2-hybridized oxygen, maintain the distance and conjugation of
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O2N H 95 O O
O2N
ii
O2N
95a O
O HO
N N 97
95b O iii
OH
iv 96 O2N N 99 IC50 = 21 mM O O O O 94 O N NH S N 102 O IC50 > 200 mM O2N H N O2N N H COOH N N N 100 IC50 = 74 mM O N O2N N N N
O iii N HN 98 N
O2N N N 101a IC50 = 43 mM N N O 101b N O N
IC50 = 24 mM
Scheme 22. Synthesis of nitro cinnamoylbenzotriazole and azachalconederivatives. Reagents and conditions: i) Ph3 PCH2 COOtBuBr, KHMDS, THF, rt. ii) TFA, CH2 Cl2 , 4?C. iii) DIC, DMAP, DMF, rt. iv) KOH, MeOH-water, rt.
Ar N Cl 103 COOH + HS 104 N H N
CHO
O N N Ar S N
104a 104b 104c
Ar = p-F-C6H4 = p-Cl-C6H4 =C6H5CH=CH
Scheme 23. Synthesis of 5-substituted thiazolo[3,2-b][1,2,4]triazol-6-one derivatives. Reagents and conditions: AcONa, AcOH, Ac2O, reflux.
the cinnamic double bond, and present acylated heterocycles that are able to serve as H-bond acceptors. Probably, these inhibitors are bound in the hydrophobic groove of the acyl-donor binding site. Benzotriazole being a good leaving group, these molecules may behave as acylating agents. Significantly, the importance of the cinnamoyl double bond was verified as the 4-nitrophenethyl benzimidazole derivative (102) has a poor inhibitory activity activity (IC50>200 @M) compared to 101a. Further testing these inhibitors demonstrated their selectivity for TG2 and their potential for further development.Lysek et al. [136] developed the [2+3]-cyclocondensation reaction of 1,2,4-triazole-3(5)-thiol (104) with 2chloroacetic acid and aromatic aldehydes to afford 5-ylidene[1,3]thiazolo[3,2-b][1,2,4]triazol-6-ones (104a-c) (Scheme 23). These compounds showed activity on renal cancer, leukemia, colon cancer, breast cancer and melanoma cell lines. 5-(4-Chlorobenzylidene)-[1,3]thiazolo[3,2-b][1,2,4]triazol-6-one (104b) was highly active on all cell lines (for all lines log GI50 < -5.00), and exchange
of the chlorine atom in 5-arylidene moiety for fluorine (104a) gives decrease of activity against most of cancer cell lines, besides leukemia (HL-60, log GI50 < -5.19). Compound 104b (Ar = p-ClC6H4) with selective influence on leukemia cell lines was identified. Finally, compound 104c, synthesized from cinnamaldehyde, is completely inactive. 4.6. Cinnamoyl Quinazolone Levistzki et al. [137] reported some anthranilic acid (105) based compounds which were found to be cytotoxic towards MCF7 and A549 (lung) cell lines. Anthranilic acid (105) was coupled with 1a in pyridine to afford 2-styryl-4-oxo-3,1-benzoxazine (105a). The resulting benzoxazine was converted to 1-(4-oxo-2-styrylquinazolin-3(4H)-yl)urea (105b) (Scheme 24) using semicarbazide hydrochloride. The resulting quinazoline derivative was functionalized with phthalimidomethyl and benzimidazole moieties to obtain new derivatives 108 and 110 respectively.
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O COOH i N 105a 105b O ii
O NH
NH2
N N
NH2 105
O NH2 106 HO O 109 N N 109a 105b O H N N O O iii
O N HO 107 O 107a O O NH H N iv O N O
HO
v O NH H N N N iv N HO 110 N N 108 N
IC50 ( M): 108; 8.18 (A549), 14.25 (MCF-7) : 110; 7.16 (A549), 18.25 (MCF-7)
Scheme 24. Synthesis of cinnamoyl-quinazolone derivatives. Reagents and conditions: i) 1a, Py, 0C. ii) NH2 NHCONH2 .HCl, EtOH, reflux. iii) -ethanolamine, phthalic anhydride, 210C. iv) conc. H2SO 4. v) Py, reflux.
N N N 111 CH3SO3H salt STI-571 HN O H N
N N N N PAP-cinnamide derivatives HN O R H N
Fig. (16). Design of PAP-cinnamides inspired by STI-571.
The cell cycle analysis (flow cytometry) on A549 cell line revealed that these compounds cause significant cell cycle arrest at the G0/G1 phase (Fig. 4). 4.7. Cinnamoyl pyrimidine The 2-phenylaminopyrimidine (PAP) derivative STI-571 (4-(4methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridine-3-yl-pyrimidin-2-ylamino)phenyl]benzamide mesylate; 111; Fig. 16) is a potent and relative selective Bcr-Abl tyrosine kinase inhibitor (Fig. 7) that has shown potent efficacy in CML patients in chronic phase [138,139]. Mutations in the kinase domain of Bcr-Abl have been found to be one of the main reasons of resistance to 111. Inspired by 111 Chang et al. [140] developed a series of novel 2phenylaminopyrimidine (PAP) derivatives (118a-h) and evaluated their anticancer activities. The general method of Bredereck (Scheme 25) [141] was used to synthesize the pyrimidine ring system, which involved reacting 96 with N,N-dimethylformamide dimethyl acetal (113) to get the enaminone 113a. The N-(2-methyl-5-nitrophenyl)-4-(pyridine-3yl)pyrimidine-2-amine (114) was synthesized by reacting enaminone 113a with (2-methyl-5-nitrophenyl)guanidine (112b). Nitration using mixed acid was carried out on o-toluidine (112) to afford 2-methyl-5-nitroaniline (112a) and subsequent reaction of 112a with 50% aqueous cyanamide in refluxing n-butanol afforded 112b.
Reduction of 114 with SnCl22H2O afforded 6-methyl-N1-(4pyridin-3-yl-pyrimidin-2-yl)benzene-1,3-diamine (114a), which was allowed to react with different cinnamoyl chlorides (117a-f, 119) to afford the target compounds 118a-g. Compound 118h was synthesized via the same method with 3-p-tolylpropanoic acid chloride (120). The abilities of these compounds to inhibit proliferation in human chronic myeloid leukemia K562 cells were tested. (E)-3-(2-bromophenyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2ylamino)phenyl]acrylamide (118c) was the most effective cell growth inhibitor (Fig. 7) and was 3-fold more potent than STI571(111). The docking studies revealed that compound 118c shares the same binding mode to the c-ABl kinase domain as that of 111 thereby explaining the observed pharmacological result. Remarkably, the order of activity of the compounds with a substituent at position 2 was Br > Cl > NO 2 > F> OCH 3 > OCH 2CH 3. Significantly, the PAP-derivative with 3(4-methylphenyl)propanamide functionality (118h) showed a 7 times poorer GI50 value compared to its cinnamic/acrylamide analogue (118g) indicating the importance of the cinnamoyl double bond. 4.8. Cinnamoyl Piperazine Pyrrolo[2,1-c][1,4]benzodiazepine antitumor antibiotics are commonly known as anthramycin (121; Fig. 17) class of compounds. These antibiotics, naturally derived from Streptomyces, react covalently with DNA to form an N2-guanine adduct in the
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NH2 i
NH2 ii
H N NH
NH2
Bredreck Procedure
112
112a NO2 N + N 96 O 113 NO2
112b
N iv N H N N N 114 NO2
O iii
O 113a v N N N H N
R CHO vi
O OH vii
O Cl 117a-f
114a NH2
115a-f
116a-f N
viii
O N Cl N 119 N 114a viii 118g GI50 ( M)= 0.51 O Cl 120 N N N 118h GI50 ( M)= 3.51 HN O H N HN O H N
N N
H N
HN O 118a-f GI50 ( M) a; F 0.67 b; Cl 0.10 c; Br 0.07 d; NO2 0.26 e; OMe 0.83 f; OEt 1.55 STI-571 0.23 R
Scheme 25. Synthetic routes of the PAP-cinnamide derivatives. Reagents and conditions: (a) H2 SO4 , HNO3 , -5 C; (b) 50% aqueous H2N-CN, HNO3, n-butanol, 100 C; (c) 100 C; (d) NaOH, n-butanol, 100 C; (e) SnCl2 2H2O, hydrochloric acid, 0 C-rt; (f) malonic acid, piperidine, pyridine, reflux; (g) (COCl)2, CH2Cl2, 25 C; (h) CH2Cl2, Et3N, 0 C-rt.
minor groove of duplex DNA via an acid-labile aminal bond to the electrophilic imine at the N10-C11 position [142]. The right handed twist of the molecules allows them to follow the curvature of the minor groove of B-form double-stranded DNA spanning at least three base pairs.
OH Me H N OMe H N 121 O O NH2
Anthramycin
Fig. (17). Anthramycin.
In order to design some new compounds based on the benzodiazepine unit of anthramycin, Srivastava et al. [143] synthesized some new scaffolds using ferulic acid (8) and piperazine analogues. Ferulic acid chloride (8a), synthesized from ferulic acid (8) and thionyl chloride, was coupled with different piperazine derivatives (122-125) in the presence of triethylamine in THF to access N-feruloyl piperazine derivatives (126-128, 139). The phenolic functionality of these derivatives was substituted with (4-(2-bromoalkoxy)-5-methoxy-2- nitrophenyl)((S)-2-(bis(ethylthio) methyl)pyrrolidine-1-yl)methanones (129a-i) affording compounds 130a-i, 131a-i, 132a-i and 140a-i. Finally, the reduction of nitro functionality to the corresponding amine derivatives (133a-i, 134ai, 135a-i and 141a-i) and subsequent deprotection of thioacetals afforded the cinnamido-pyrrolo[2,1-c][1,4]benzodiazepine derivatives (136a-i, 137a-i, 138a-i, 142a-i; n= 1-9) (Scheme 26) [143].
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O Cl 8a OMe
H N
X OH i
122 123 124 X
O OMe N + 126 127 128 OH ii OMe O n MeO O N 130a-i 131a-i 132a-i iii OMe O n O O
Br n MeO
O n=1-9 (a-i) NO2
CH(SEt)2 H
HN
NH 125
129a-i
O N N
NO2 O N CH(SEt)2 H
MeO HO
139 129a-i ii OH
OMe X
O N N
O O N 133a-i 134a-i 135a-i
MeO NH2 O N CH(SEt)2 H
MeO R'O
140a-i OR' O n R' = NO2 MeO N O iii n=1-9 (a-i) CH(SEt)2 H
OMe X O iv
OMe N X O O 136a-i 137a-i 138a-i n MeO O N N H
O n R' = MeO NH2 CH(SEt)2 H
X = O for 122, 126, 130a-i, 133a-i, 136a-i = NR R = Me = O (for 123, 127, 131a-i, 134a-i, 137a-i)
141a-i
O iv N N
O MeO OMe
(for 124, 128, 132a-i, 135a-i, 138a-i) OMe
MeO 142a-i O O N H N O n OMe O
OMe
O N H O N
MeO
Scheme 26. Cinnamido-pyrrolo[2,1-c][1,4]benzodiazepine derivatives. Reagents and conditions: i) Et3 N, THF. ii) K2CO3, Acetone, reflux. iii) SnCl2.2H2O, MeOH, reflux; iv) HgCl2-CaCO3 , CH 3CN-water (4:1), rt.
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O O H2N 143 OH Zn2+ Bestatin; APN inhibition (IC50)~ 3.6 mM

Fig. (18). Designed molecules inspired by bestatin and their possible Zn2+ -ion binding.
NHR R = alkyl R' = OH, NHOH R'
H N N H OH Zn2+ O O O
Designed Molecule
O O HO 144 O O iii 144c O OH NH2 OH i MeO 144a O O O iv O OH H N 144d N H O O N H RNH2 v 144e O NH2 OMe ii 144b 1
OMe
N H O O OMe OH
N H O NHR
O vi 144f
OH
N H O NHR
R = n-But; APN inhibition (IC50)~ 11 M
Scheme 27. Synthesis of cinnamoyl-hydroxamic acid derivatives as APN-inhibitors. Reagents and conditions: i) MeOH, HCl, 0C. ii) iButyl chloroformate, NMM, THF, -15C. iii) MeOH, NaOH, HCl. iv) Ac2O, 60C. v) AcOH, Et3N. vi) IButyl chloroformate, Et3N, THF, MeOH, NH2OH.HCl.
Their in vitro anticancer activities against 60-different human cancer cell lines such as lung (Hop-62), cervix (SiHa), breast (MCF-7, Zr-75-1), colon (Colo205), have been evaluated. Among the series of compounds, 7-methoxy-8-{3-(2-methoxy-4-(E)-3oxo-3-[4-(3,4,5-trimethoxybenzoyl)piperazino]-1-propenylphenoxy) propoxy}-(11aS)-2,3,5,11-tetrahydro-5H-pyrrolo[2,1c][1,4] benzodiazepine-5-one (138b) was found to be the most efficient (50% growth inhibition, GI50 = 0.02-3.39 M) , as represented. All the compounds showed cytotoxic activity towards cancer cells and they have significant DNA-binding ability as well. 4.9. Cinnamic-hydroxamic acid derivatives Based on the mechanism of action of bestatin (143) (Fig. 18) [144], a known molecule waiting for its approval in the clinical treatment of adult acute nonlymphocytic leukemia, Liu et al. [145] developed a series of N-cinnamoyl-L-aspartic acid and their hydroxamic acid derivatives were designed, synthesized (Scheme 27), and assayed for their inhibitory activities against aminopeptidase N. Aspartic acid (144) was transformed into its methylester hydrochloride (144a) using MeOH and HCl. Subsequently, the amino group was attached to the cinnamoyl moiety using chloroformate reagent along with N-methylmorpholine (NMM) to afford 144b. Saponification of 144b followed by heating in Ac2O produced the corresponding anhydride (144d). Treatment of butylamine followed by hydroxyl amone hydrochloride afforded compound 144f. It was found to be most active against APN (IC50 =11.1 0.9). It was also
found to have slightly better anti proliferative ability compared to bestatin when tested on HL-60 (MDR leukaemia) cell lines. Histone deacetylases HDACs also belong to a family of Zndependent hydrolases which regulate and control the acetylated degree of histone [146]. HDAC play an important role in tumorigenesis. A variety of enzyme families carry out post-translational covalent modifications at specific amino acid residues in the NH2terminal histone tails and these modifications are a major determinant of chromatin structure and gene activity [147]. One important set of modifications include the acetylation and deacetylation of lysine residues by histone acetyltransferases and histone deacetylases, respectively [148]. Three different classes (class 1-3) of histone deacetylases have been identified which differ in their intracellular localization, pattern of substrates and binding sites inhibitors [149]. Hydroxamic acids derivatives, among the most potent inhibitors of both class 1 and class 2 histone deacetylases, include suberoylanilide hydroxamic acid (Vorinostat or Zolinza, 145), (Fig. 19) which has single-agent anticancer activity [150] and has been approved by FDA for cutaneous T-cell lymphoma patients in 2006 [151]. LBH589 (146) is a novel cinnamic hydroxamic acid analogue histone deacetylase inhibitor that induces apoptosis in a dose dependent manner on human chronic myelogenous leukemia blast crisis K562 cells and acute leukemia MV4-11 cells with the activating length mutation of FLT-3 [145]. Hyperacetylation of H3, H4,
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O H N O 145 N H OH
O N H HN HN 146 LBH 589 OH
Vorinostat or Zolinza
Fig. (19). Structures of Zolinza and LBH589.
and heat shock protein 90, an increase in p21 levels and induction of cell cycle G1 phase accumulation is associated with exposure to 146 (Fig. 4). Many other anticancer activities of 146 have been reported [152]. It also inhibits the chaperone association of heat shock protein 90 with Bcr-Abl and FLT-3, promoting their polyubiquitylation and proteasomal degradation [104]. It is noteworthy that the intravenous administration of LBH589 was well tolerated at doses <11.5 mg/m2 with consistent transient antileukemic and biological effects [153]. 4.10. Cinnamoyl Hydrazides In our recent effort, we have synthesized some 4alkoxycinnamic acid hydrazides and triazolophthalazine derivatives [154] and evaluated their antitumor efficacy in comparison to a series of new 2(4-alkoxyphenyl) cyclopropyl hydrazide and triazolo derivatives (as racemates). Clean reaction, excellent yields and mild reaction condition are the key features of the synthetic protocol. Notably, the replacement of cinnamoyl double bond with isosteric cyclopropyl moiety resulted in a huge improvement in their antitumor activities. The the cyclopropyl analogues (152a-f, 153a-f, 154a-f; Scheme 28) were found to exert cytostatic activity on the 6human cancer cell-lines. Two compounds, with isopentenyl-(154e) and geranyl- (153f) side-chain attached to the 4-hydroxyphenyl frame, were particularly more active than the remaining compounds against cancer cell-lines resistant to pro-apoptotic stimuli such as those cancers associated with dismal prognoses but they exert their cytostatic effects through distinct signalling pathways. As quantitative video microscopy and mitosis count reveal that the cytostatic effects associated with 153f and 154e differ. Indeed, while 10 M 153f seemed to lead to increase in mitosis durations in human U373 glioblastoma cells, 5 M 154e seemed to lead to the opposite feaRO H N 148a-f O
tures. The 154f-induced increase in mitosis duration resulted in a decrease in mitosis numbers. The 154e-induced decrease in mitosis duration did not result in modifications in the mitosis numbers. Thus, while both compounds 153f (IC50 = 21 GM) and 154e (IC50 = 23 GM) could exert their in vitro anticancer activity through cytostatic effects, 153f could exert mitosis-dependent cytostatic effects and 154e could exert mitosis-independent cytostatic ones. In the initial screening with three cancer cell lines (A549, PC-3 and U373) the cinnamoyl hydrazides (158a-f, 159a-f) and triazolo derivatives (150a-f) were found to be very poorly active (IC50s > 100 GM) towards U373 cell lines. 5. CONCLUSION AND PERSPECTIVES Cinnamic acids are abundant in various natural resources. Cinnamic acid and its natural analogues are unique as anticancer agents. Natural substance such as caffeic acid phenethyl ester (CAPE, 7b), isolated from honeybee propolis, showed remarkable anticancer effect on tumor invasion by regulation of MMPs, induces apoptosis to leukemia cells, modifies CYP activity, controls tumor cell growth by inhibiting NF- B, for example. It can also act as prooxidant to generate ROS thereby showing ability to mediate apoptotic DNA-fragmentation. With , -unsaturated carboxyl functionality cinnamic acids offer Michael-acceptor properties, particularly to the glutathione (GSH) and cystine residues. Although, no direct evidence of Michael-adduct formation has been established yet, there are several examples available showing that the replacement of the unsaturation resulted in decrease in anticancer efficacy of the molecules. On the other hand, replacement of the double bond with an isosteric cyclopropyl ring increased the antitumor efficiency of the compounds as well. Nevertheless, cinnamic acids are less toxic and several natural products such as tallimustine,
RO H N
O N H N ii, iii OR OR ii, iii
O N H N
_ +
152a-f
RO H N O
N N H
N ii, iv i ii, iv
RO H N _ + ii, v RO N N _ + N 154a-f N O
N N H
147a-f ii, v
149a-f
COOMe
_ COOMe +
153a-f
RO N N 150a-f N N
151a-f a, R = CH3b, R = CF3c, R = CH3CH2d, R = CF3CH2e, R = (CH3)2C=CHCH2f, R = (CH3)2C=CHCH2CH2C(CH3)=CHCH2-
Scheme 28. Synthesis of cinnamoyl hydrazides and trizolo derivatives and their cyclopropyl analogues. Reagents and conditions: i) NaH, Me3SOI, DMSO, 55FC. ii) K2CO 3, MeOH-Water, reflux, HCl. iii) Isoniazid, EDC.HCl, HOBt, iPr 2EtN, CH3CN, reflux. iv)1-Phathalazine hydrochloride, EDC.HCl, HOBt, iPr2 EtN, CH2 Cl2 , rt. v) 1-Phathalazine hydrochloride, EDC.HCl, HOBt, iPr 2EtN, CH 3CN, reflux.
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howiinol A, acronycine, which already had some anticancer activities, have been ameliorated with the introduction of cinnamoylresidues. This approach, in majority of the cases, has successfully enhanced the anticancer properties of the parent compounds. For example, rescinnamate (52a) is better than reserpine (50) and cinnamoyl reserpine (52b) in its efficacy in MSH2-dependent apoptosis and addition of trimethoxycinnamoyl residue with fumagillin (CKD731) also enhanced its efficiency almost 1000 times than TNP-470 (O-(chloroacetylcarbamoyl) fumagillol; under phase III clinical trial). However, the same approach did not give the similar results with some molecules e.g. camptothecin. Significantly, the trans-geometry of the cinnamoyl residue is crucial in this case as the cis-geometry (52e) and saturated cinnamoyl side-chain (52d) failed to improve the efficiency. On the contrary, TPY 835 (27), a cis-cinnamic acid derivative, is extremely potent Cdc25B dualspecificity phosophatase inhibitor. Cinnamoyl hydroxamic acid derivatives like LBH 589 also form an important class of anticancer agents. Importantly, cinnamic acid and its amides, esters and other derivatives are important but underutilized class of compounds. As anticancer agents they are cytotoxic, cytostatic, antiproliferative, antiangeogenetic, antileukemic, active against solid tumors, inhibit different enzymes e.g. transglutaminase, aminopeptidase N, histone deacetylase etc, cause DNA-damage and many more. In spite of all these multi-activities of cinnamic acid derivatives their mode of action and understanding of molecular mechanisms remains unclear. We express hope to learn more about this versatile molecule and its derivatives in addition to the synthesis of new useful biologically important compounds in near future. ACKNOWLEDGEMENTS We thank the European Community. Thanks are also due to the CNRS (France), Universit Paul Sabatier (Toulouse, France), ITAV(Toulouse, France) for financial support. REFERENCES
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Revised: March 14, 2011 Accepted: March 15, 2011
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1672

Current Medicinal Chemistry, 2011, 18, 1672-1703

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Current Medicinal Chemistry, 2011 Vol. 18, No. 11

OH HO H OH H HO 1 COOH 3 COOH O H H OH 5 O OH OH OH Ginsenoside Rg 1

HO 6 H2N COOH 1 COOH COOH p-Coumaric acid 2 Phenylalanine Cinnamic acid 7

H3CO COOH Caffeic acid

H3CO 9 COOH Sinapinic acid COOH

Scheme 1. Biosynthetic route of cinnamic acid and its phenolic analogues.

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O MeO OH 9a OMe O OH 13 OH CF3 10

Fig. (3). Active components of Brazillian propolis.

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Fig. (4). Compounds active in deferent phases of cancer cell cycle.

CHO ii BnO Cl 26a Cl 26b

COOEt iii, iv TfO Cl 26c

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Current Medicinal Chemistry, 2011 Vol. 18, No. 11

30 H 4-Hydroxyphenyllactic acid O COOH O HO H 31 p-Coumaroyl-4-hydroxyphenyllactic acid OH

6 COOH 2 Phenylalanine H2N COOH p-Coumaric acid

O HO O HO H 32 Rosmarinic acid OH COOH OH

Scheme 4. Rosmarinic acid biosynthesis

Fig. (6). Benzyl, phenethyl and cinnamoyl caffeate.

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Cu(II) OH Oxidative DNA damage

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Fig. (9). Chlorogenic acid and ellagic acid.

OMe 37a,b 38a,b

Mean IC50 = 0.97 g/mL O OH HO O OH

Mean IC50 = 0.20 g/mL

Scheme 7. Synthesis of cinnamoyl-camptothecin derivatives. Reagents and condition: i) Heat.

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Current Medicinal Chemistry, 2011 Vol. 18, No. 11

v O 45e IC50 =0.74-1.7 M IC50 =2.2 - 9.2 M O O O O O Cl 45f OH OH

O OH 44 Howiinol IC50 =18 mM(1 h), 8.7 M(24 h) OH

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OMe OMe O i O OH OH N 47 R2 R1 R1 = R2 = H, 1a R1 = R2 = Cl, 48 R1 R2 O 47a 47b O Cl O O OH O N OMe O ii

R1 R2 R1 = R2 = H, 49a R1 = R2 = Cl, 49b

N H H H O O O OMe OMe OMe

50a Methyl reserpate

MeO MeO N H N H H 52b Cinnamoyl reserpine MeO O OMe O H O 52a Rescinnamate

N H H H O O O OMe OMe OMe OMe

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O O O H O R= COOH 4 53 Fumagillin O O R= R= R= CKD 731 54d R=H 54 Fumagillol R= N H

TNP470 IC50 (ng/mL) = 0.03 (EL-4) 0.04 (CPAE) >10 (P388D1) O

IC50 (ng/mL) = 0.00019 (EL-4) 0.00006 (CPAE) >1 (P388D1)

OMe 54e OMe

IC50 (ng/mL) = 36 (EL-4) 44 (CPAE) ND (P388D1)

MeO MeO MeO OH MeO OMe Schisandrol A

MeO MeO O MeO OMe O 55a OH MeO

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AcO 9 7 5 H OAc 57a ii 20 OH OH 14 1 H 10 2

HO 7 5 H OAc 20 57b ii 14 1 H OAc 10 2

HO 9 7 5 H OAc 20 OH 57c ii OAc 14 1 H 10 2

ii O HO O O H OAc O 58e H H OAc O H 58f O O OAc O OAc

Cinnamic Acid Derivatives as Anticancer Agents-A Review

Current Medicinal Chemistry, 2011 Vol. 18, No. 11