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Current Developments in the Discovery and Design of New Drug Candidates from Plant Natural Product Leads

Current Developments in the Discovery and Design of New Drug Candidates from Plant Natural Product Leads

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Current Developments in the Discovery and Design of New Drug Candidatesfrom Plant Natural Product Leads
†,‡
Kuo-Hsiung Lee*
 Natural Products Laboratory, School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599-7360 Received August 14, 2003
This review article will emphasize recent research in the Natural Products Laboratory, School of Pharmacy,University of North Carolina at Chapel Hill, on various classes of plant-derived compounds that possesspotent antitumor or anti-HIV activity. These compounds were obtained by bioactivity- and mechanismof action-directed isolation and characterization coupled with rational drug design-based modificationand analogue synthesis. Structural modification, SAR, and mechanism of action studies are discussed.From ancient to modern times, herbs and other plantshave been used as medicinal agents, first only on a folkloricbasis and later developed on a scientific basis into singleagent drugs, such as the antiasthmatic drug ephedrinefrom
Ephedra sinica
.
1
The drug discovery and developmentprogram in the author’s Natural Products Laboratory(NPL) and those of other researchers worldwide use plantsas an essential route to new pharmaceutical leads.
2
A major objective of the NPL is the preclinical develop-ment of bioactive natural products and their analogues aschemotherapeutic agents, including plant-derived antitu-mor agents, particularly novel etoposide analogues, anti-HIV compounds and analogues, as well as antimalarial,antifungal, antiviral, and anti-inflammatory agents. Chi-nese herbal medicine is the primary, although not sole,source of new leads. The three main research approachesare (a) bioactivity- or mechanism of action-directed isolationand characterization of active compounds, (b) rational drugdesign-based modification and analogue synthesis, and (c)mechanism of action studies. Drug discovery is an iterativeprocess of lead discovery (i.e., isolation of bioactive leadcompound(s) from these natural sources) coupled with leadimprovement (rational design and synthesis of new ana-logues to improve pharmacological profiles). After selectionof a new lead, drug development continues outside of theacademic laboratories through preclinical studies (toxicol-ogy, formulation, and production) followed by clinical trials.In the academic laboratory, drug design/structure modifi-cation employs several tools to identify the optimumchemotherapeutic agent:(a) structure
-
activity relationship (SAR) studies includ-ing both qualitative and quantitative SAR,(b) mechanism of action studies including drug receptorinteractions and specific enzyme inhibitions,(c) drug metabolism studies including identification of bioactive metabolites and blocking of metabolic inactiva-tion,(d) molecular modeling studies including determinationof 3D pharmacophores,(e) combinatorial chemistry, including creation of peptideand nonpeptide libraries to generate new leads.The discussion below will present several of these agentsas well as prior and new lead identification and researchperformed in the NPL.
Plant-Derived Antineoplastic Agents and TheirAnalogues as Clinical Anticancer Drugs (Figures1
-
3)
Many plant antitumor agents are used as clinicalanticancer drugs: in the United States (in chronologicalorder) vinblastine (Velban,
1
), vincristine (Oncovin,
2
),vinorelbine (Navelbine,
3
), etoposide (VP-16,
4
), teniposide(VM-26,
5
), paclitaxel (Taxol,
6
), docetaxel (Taxotere,
7
),topotecan (Hycamtin,
8
), and irinotecan (Camptosar,
9
) andmany others in China, including 10-hydroxycamptothecin(
10
) and homoharringtonine (
11
) (Figure 1).Vinblastine (
1
) and vincristine (
2
) are major drugs usedto treat Hodgkin’s lymphoma and acute childhood leuke-mia. They are natural alkaloids isolated from
Catharan-thus roseus
(L.) G. Don (Apocynaceae) or
Vinca rosea
L.(Chinese medicine: Chang Chung Hua).
3
Among numer-ous synthetic analogues designed to have activity againstother tumor types or fewer side effects, Navelbine (
3
)(vinorelbine) was developed by Burroughs Wellcome andis used against non-small cell lung and advanced breastcancers.
4,5
This compound is a synthetic analogue of 
1
, buthas a nine-membered rather than an eight-membered Cring and a dehydrated D ring.
4,6,7
The Chinese tree
Camptotheca acuminata
Decne. (Nys-saceae)
8
contains the natural anticancer alkaloids camp-tothecin (
12
) (Figure 2) and 10-hydroxycamptothecin (
10
),
8
which are used to treat gastric, rectal, colon, bladder, liver,and head and neck cancers in the Peoples Republic of China. However, synthetic derivatives, including topotecan(
8
)
9,10
and irinotecan (
9
, CPT-11),
11
-
13
were developed toanswer water solubility problems of the natural alkaloids.They contain amino groups that can form more solublehydrochloride salts; for example, compound
8
is 100-foldmore water-soluble than
10
. All natural and syntheticcamptothecins exert their anticancer activity by inhibitingthe enzyme topoisomerase I (topo I). The NPL synthesizeda series of water-soluble 7-(acylhydrazono)formyl camp-tothecins.
14
Compound
13
with a 7-(
l
-tyrosylhydrazono)group and four others were more potent than
12
ininhibiting DNA topo I and causing protein-linked DNAbreaks, but were less toxic in several cancer cell lines.Similarly, the NPL also chemically linked camptothecin(
12
) with paclitaxel (
6
), a natural antimitotic anticanceragent, through a variable length
ω
-aminocarboxylic acid
Dedicated to the late Dr. Monroe E. Wall and to Dr. Mansukh C. Waniof Research Triangle Institute for their pioneering work on bioactive naturalproducts.
Antitumor Agents 231 and Anti-AIDS Agents 59. Presented, in part,at the 43rd Annual Meeting of the American Society of Pharmacognosy andthe 3rd Monroe E. Wall Symposium on July 28, 2002, in New Brunswick,NJ.* To whom correspondence should be addressed. Tel: 919-962-0066.Fax: 919-966-3893. E-mail: khlee@unc.edu.
273
 J. Nat. Prod.
2004,
67,
273
-
283
10.1021/np030373o CCC: $27.50 © 2004 American Chemical Society and American Society of PharmacognosyPublished on Web 12/03/2003
 
(imine bond to 7-formylcamptothecin and ester bond topaclitaxel’s C-7 hydroxyl).
15
The resulting compounds (
14
-
16
) were less active than camptothecin against topo I, butstill were potent inhibitors of tumor cell replication. In mostcell lines, the conjugate compounds were more active thancamptothecin, but less active than paclitaxel. However,
Figure 1.
Clinical anticancer drugs (
1
-
11
).
Figure 2.
Camptothecin and paclitaxel analogues.
274
Journal of Natural Products, 2004, Vol. 67, No. 2 Reviews
 
they were more active than either natural compoundagainst HCT-8 cells, implying a possible novel mechanismof action.
15
Paclitaxel (
6
) (Taxol), which is found naturally in thebark of 
Taxus brevifolia
Nutt. (Taxaceae),
16
has a uniquemode of anticancer action (it promotes the assembly of microtubules and consequently inhibits mitosis) and isactive against breast, brain, tongue, endometrial, andovarian cancers.
17
-
19
Because the natural source wasnonrenewable and in scarce supply, analogue syntheseswere widely pursued.
20
-
22
The clinically used docetaxel (
7
)is synthesized from the more readily available 10-deacetyl-baccatin III (
17
), which is found in the needles of theEuropean yew tree (
Taxus baccata
L.).
23
The NPL alsoconjugated paclitaxel with 4-aminoepipodophyllotoxin (seenext section), using 4-carboxybenzaldehyde as the linkerbetween the two compounds (imine bond to the 4-amino oepipodophyllotoxin and ester bond to the C-2
-hydroxyl of paclitaxel).
24
Compared with epipodophyllotoxin, the con- jugate (
18
) showed comparable or better activity in severaltumor cell lines and resulted in a lower-fold resistance inpaclitaxel-resistant cell lines.
Etoposide Analogues.
Podophyllotoxin (
19
) (Figure 3)is a natural lignan found in
Podophyllum pelatum
L.(Berberidaceae),
P. emodi
Wall, and
P. pleianthum
Hance.Like paclitaxel, podophyllotoxin is a mitotic inhibitor actingon tubulin; however, unlike paclitaxel, podophyllotoxininhibits the assembly of microtubules. The clinical anti-cancer drugs etoposide (
4
) and its thiophene analogueteniposide (
5
) are semisynthetic analogues of podophyllo-toxin. In these analogues, a
β
-C-4 glycosyl group hasreplaced the
R
-C-4 hydroxyl of podophyllotoxin and ahydroxyl has replaced the C-4
methoxy group. Etoposideand teniposide do not affect mitosis, but instead inhibit theessential enzyme DNA topo II and, subsequently, increaseDNA cleavage.
18
Although they are used clinically to treatsmall-cell lung cancer, testicular cancer, leukemias, lym-phomas, and other cancers,
25
-
28
problems include poorbioavailability, myelosuppression, and drug resistance.
29
Consequently, the NPL, as well as other groups, hascontinued to explore structural modifications geared atimproving pharmaceutical properties of the etoposide class,and the descriptions below illustrate many aspects of thedrug development process, highlighted by the clinical trials(Phase II) with the semisynthetic analogue GL331 (
20
).
4-Amino-epipodophyllotoxin Derivatives IncludingGL331.
On the basis of computer-modeling studies (seemore details and studies below) and the possibility oforming water-soluble salts, the NPL synthesized numer-ous 4-alkylamino and 4-arylamino epipodophyllotoxin ana-logues from podophyllotoxin using a simple two-step reac-tion sequence.
30,31
Variously substituted arylamino analogues
Figure 3.
Etoposide analogues.
 Reviews Journal of Natural Products, 2004, Vol. 67, No. 2
275

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