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    United States Patent ‘US009855280B2 a2) (a0) Patent No. US 9,855,280 B2 Lin et al. (a5) Date of Patent: Jan, 2, 2018 (54) NANOPARTICLES CONTAINING AZOLIUM NHC comple: I vito anticancer sts" Chany Cena AND NTETEROCYCLIC CARBENE Sowa 2013, 72, p. 117. (Year 2013)" COMPOUNDS AND USE THEREOF (Costin) (7) Applicant: National Dong Hwa University Primary Examiner —Tiwothy P Thomas Shoufeng (TW) “Assistant Examiner — Andee S Rosenthal (72) Inventor: Ivan Jyh Blaw Lin Shoufeng (FW); 4) Attorney, Agent, or Fem — Coen Yoshinura LLP Tine HT. Hsu, Shouteng CW): Shlu-Huey Chou, Taper (1W) 6 ABSTRACT The pesca policalion provides a compostion compeising (7) Assgnce: NATIONAL DONG HWA a cove formed by gold nanparice«conpotud of Fonnila UNIVERSITY, Shoufens (1W) hs (#1) Notice: Subjeto any dstaimer, he term af this Palen is extended or ased under 35, » USC. 1540) by O dys 21) Appl Now t8784.889 x (22) ied: Now 42016 (65) Prior Publication Data US 201710129007 AI May 11,2017 ‘ Data wherein dake tines in Formula (represent (with or (60). Provisional application No. 62252350, led on Nov. Thou Se mackonas of bene goose Ge cet 6.2018. bead wire thowa within a ag Re is hydrogen or Tagen: iv inker selected rom C2. ali o pobyeth (state t - lene hyo Ry Chay alll C, subst aly, AOIKAUSSS (200601) : z Bern tees | eal hexarceanyl amido, pyidiny, bey or pyrimidinyl and 8 oman? —aveo1) compoued of Forme ‘tik 1709 Gora) re © AGIK 31335 (2013.01), AOIK 31/4700 % ‘Gotsoty werk 470923 (2017 08) 467K $6029 201708), COPD 401/12 (201301) (58) Pek of Clasitcation Search 0 cre NeIK 318709; AGIK 31/555; ASIK 4116029, CO7D 401/12, COOB 4416 pplication fie for compos serch histo 6) References Cited US. PATENT DOCUMENTS 2ooroosso1s At 22007 Wage eta pba ZNy7 Zuo At Fann Ae x i Solanowons? AL aoe Pouole at 20160331727 AD 11/2016 Zhuo etal X FOREIGN PATENT DOCUMENTS (OTHER PUBLICATIONS sancer(oyathess, characterization and etal stires of 291 (Ondo, ca, & Pa) Linke bishencimidarotim salts an At wherein dashed Fines, R,, Ry and Ry are defined as Formula (I1), and Mis # metal Inhibition ability against a cancer The composition has an 28 Claims, 14 Drawing Sheets US 9,855,280 B2 Page 2 66) References Cited (OTHER PUBLICATIONS Paloque, Ea. “Symthesis,chantsization, and antilishaxial setviien of gold) complenes involving cuisline functionalized "tctroyelc carbons" Europea Jounal of Meisaal Chemistry 9 2015) 22229 (Year 2015) Roa et al, "Phamacokitetic an toxicological evaluation of mui {unetional thiol-6boro-Sdeoxy-D-lucose gold anopartiles ia ‘ve, Nanotechnology 2012, 25, 375101 ‘Murphy eal, "God Nanopatces ia Biology: Beyond Toxicity 19 Cetluia raging" Accounts of Chemical Rescarch, De, 2008, vl. 41, No. 2, pp 1721-1730. Applications of Nanopaictes in Biology” Kim etal, “Entrapment of Hyckopbobic Drugs in Nanoparticle “Monolayer with Econ Releae int Cancer Cs Jornal tbe American Chemical Society. 2000, 0131, No. pp. 1360-136 Dylon etal, “Uptake of Enginered Gold Nanoparticles into ‘Manmulian Cas, Chemical Reviews, 2014, 1, pp. 12581288 Wan ct aly “Real-Time Light Searing Tracking of Gold ‘Nanopartles—biocoajugated Respiratory Syneyeal Vis Ineet- ing HEp-2 Cells, Seiemiie Reports, Mar 2014, #: 4829, pp. 7 Fghiedan eal, “High Seasivity of In Vivo Detection of Gold Nanorads Using a Laser Opescoustc Imaging Systm", Nano Teter, 2007, v7, No.7 pp 1918-1918, Advanced ijohtan el, “Gold Nanos for Biology and Moticine” ‘Sngem Chem in Hl, 2010 4, pp. 5280-398 Otter a. "Nanoelses in foie Luis idence fr N-Hetero tgelie Catbene Formation ffm sizlitBased lose Ligds Desc 211 NMI Jal ofthe Amerian Chemical Soe, 2008, 127 pp, 5788-535), Coesp eal Uleasmall NHC-coatel gold nanopsicls cain Through solvent tee thermolysis of rganomeie Aull) com plexet" Daim Tranacons, 201445, pp 137118718 Baquero et alu “ilghly Sale’ WaterSolble Pariun ‘Nanoparticles Stabilized by ype N-Heteroejee Carbone, !Sngem Chem, 2014, 126, pp. 136-1340. Tie a, "Mallamaciocylesmodied gold nop new pals sefacefuntonaltin™ Cher. Commun, 2014 80 p.o71974 Crake eal, “Ulta table velasembled mooolyer of Nhe tvceylic eabnes on gol, Nae Chemisty. May 2014 vol 6, pp too SGiell i, “Halouuate and halpaadte inant: strictures, properties, and use as precursors for cate metal tanopaicle",Daton Transactions. 2013, 42, pp. 13851593, {ing eta. "Sopracrstals of Nlecrcyche Caheneonted At Nanocrystals", Chemisty of Materials. 2018, 27, pp 414423 Hurd ot a, NCHletroeelceatbene cost etal nope” [New Journal of Chemistry, 2009, 38. pp. 37-1840, Vigonolle et aly "NHetroeyele” caene-stabized gold suopacles and Weis assonblyialo 3D supelatices". Chem. Comma 2009, pp. 7250-7232 * cited by examiner U.S. Patent Jan, 2, 2018 KANO ee KO, CHIEN, coon 48h wayen Feet 100°, so rf Hen Ag, CHSCN, Sain een Sheet 1 of 14 US 9,855,280 B2 we WAAL TEGaCI ce Pro [C4 TEGO-Imjct oy neared Heal Cras wn [(Cie,TEGOAmy),AuIC Fig. 1 U.S. Patent Jan, 2, 2018 Sheet 2 of 14 US 9,855,280 B2 (A) o Naot vases + yt ccamo MN 2eq AUP eA tea Seq Aun s-6 (B) © (D) 2 z 2 é ar ar ar er) wavelength (nm) Fig.2 U.S. Patent Jan, 2, 2018 Sheet 3 of 14 US 9,855,280 B2 (A) Ov 2(C16,TEGO-Imjct CORN, =1016, TEGOmy)2aujCt Fig.3 U.S. Patent Jan, 2, 2018 Sheet 4 of 14 US 9,855,280 B2 Fig. 4 U.S. Patent Jan, 2, 2018 Sheet 5 of 14 US 9,855,280 B2 (At) 1D cisplatin K562 8 [ceTEGQImja. @ [(GTEGOAmy), Auer wm Auli 10 09. os 07 06 1g = 0.090 £ 0.013 pg/ml 20s os 03 02 a4 00 0 Vehicle 0.099 0078 0.156 03125 0.625 128 25 $10 pg/ml (42) K562 tio ¢ Cisplatin © [CTEGQImICI J 10 Fw eres) Aua = oo bw auts-e a) = m0 s = 0 2 50 2 a £20 zn 2 0 0.039 0.078 0.156 03128 06 Hei Fig. 5 U.S. Patent Jan, 2, 2018 Sheet 6 of 14 US 9,855,280 B2 (B-1) THP-1 on 8 ic,.TEGQimic a 1B (6.TE60Imy.Au}t os tale fT A ca - Tiel | Iu = 0.42 £ 0.0237 pgiml om Tay | oo HT | oo UH ~ © vehicle 0039 007R O86 8213 06S 128 28 5 10 git (B-2) THP-1 100 © Cisplatin © [C,,TEGO-Imjct °0 80 70 B [(GysTEGQImy), AIC = AuNps-8 0.039 0.078 0.156 (eo oo ug/ml Fig. 5 (cont'd) U.S. Patent Jan, 2, 2018 Sheet 7 of 14 US 9,855,280 B2 (C-1) o te.766aime . ® e.70:myas : 8 atrs 7 Ig" 0338 £0087 ug ts os re w i “1 | Li oo hel (C2) CEM Leal O Cisplat 8 tems eaten Auta Anes / » | | fs | : V0 067s 186 08K OHS 128 28S ng/ml Fig. 5 (cont'd) U.S. Patent Jan, 2, 2018 Sheet 8 of 14 US 9,855,280 B2 HepG2 -y 2 Osplotin . © (GTEGCAIm|e a 1 (GTQ, AvIe % mune 0 % 144 0.739 + 0,060pg/m1 os fo S 06 os a4 ry a ote oo UE 0 Vehicle 039 0078 0456 03125 0625 125 25 8 1 g/ml (2) HepG2 nd O Cisplatin B [c,TEG-Imct {{Cj.TEGOAmy) Aue = 60 Ea Fi 3 ° Taw (all fb i g/m Fig. 5 (cont'd) U.S. Patent Jan, 2, 2018 Sheet 9 of 14 US 9,855,280 B2 HT29 © splat w 2 (cue6a4m 1 {(¢,1€604my, Au} os IC, 0.394+ 00Stp g/ml a ar ao Lil 13 vehicle 039 00TH 186 OHS US 128 2S Sw ial (E2) HT29 g 8 Gspiatin = 8 Ie Feeaima 2 1 ((¢,,1EGO-Imy) Aue 2 2 vay eoT wise aS MwS SSS et Fig. 5 (cont'd) U.S. Patent Jan, 2, 2018 Sheet 10 of 14 US 9,855,280 B2 ey 460 © Cisplatin 10 0 [eFEeainie w (86, Auk unre as a 1g = 0258 £ 0.077 44/1 20 L Al Bos Ball 2 7 “ WU a 03 wu ® Lay ot MRL a tn | | og LL eh 0 seh 0839 0078 0156 0312 OMS 125 28 $10 g/ml ce 460 0 © cipatn 10 Fa tereeauime 8 (6, Teoc-imy) Aut suns ° 0039 OWT 04S ARE 082 1382S SD s/ml Fig. 5 (cont'd) U.S. Patent Jan, 2, 2018 Cn itary rate of Vehicle (%) ir 0 ow or as oy oo 100 Gt Sheet 11 of 14 SAS US 9,855,280 B2 Byetsrecaim (c157ESOAmyeA¥}O manne 386 40.086 pg’ Vehicle 00391 00742 G2 splat Blasrecaame ‘B{(c16, 7.60: 2Aw}a mares 04863 OSS 0405 ml AS gmt Fig. 5 (cont'd) 125 U.S. Patent Jan, 2, 2018 Sheet 12 of 14 US 9,855,280 B2 Z 3 as a (Hay Hs578T iexerecaimiet ‘8c16 ecasyaaute 1Cyy=0.28 £0.05 git niedlom vehile 003 00TH O56 0313 068 125-288 g/ml (Hay Hs578T ‘8(c16 eCaAmIC) ‘ai(cu6re6amyi2nsie mane we Fig, 5 (cont'd) U.S. Patent Viability (%) 100 Vehicle Jan, 2, 2018 oas Sheet 13 of 14 0.628 1 AuNPsB (ng/ml) Fig. 6 US 9,855,280 B2 -o-12h eons eon U.S. Patent Jan, 2, 2018 Sheet 14 of 14 US 9,855,280 B2 ) PL Annexin ¥ (B) AUNPS-B (ig/ml) Ven 4 025 4 Cospees oe = - 17 kda Cleaved Caspase 3 hes Be Actin 42 kde US 9,855,280 B2 1 NANOPARTICLES CONTAINING AZOLIUM. "AND N-HETEROCYCLIC COMPOUNDS AND US! ‘CROSS-REFERENCE TO RELATED APPLICATIONS, ‘This application claims priority to U.S, Provisional Patent Application No. 62/252350 filed on Nov. 6, 2015, the Uisclosuies of which are incorporated ersin by reference BACKGROUND OF THE INVENTION 1, Field ofthe Invention Tie present invention relates toa nanoparticle composi Gon, and more particularly to a nanoparticle composition containing szolium and N-heteroeyeic carbene compounds 2. Deserption of the Related Art Cancers area arg family of diseases that involve abnor smal cell growth with the potential to invade oF spread 10 thee parts of the tod): Cancer is & major public health 3 problem in dhe world. In dhe United States its expected 10 ‘come the leading eause of death inthe next few Yeas, On the other hand, the survival rate for those suffered from jeaneerinereases in recent years, This could be atsbuted ‘nly to the advancement of new chemotherapeutic agents Cisplatin is one of the chemotherapeutic agents that have ben widely applied to treat cancers, However, eeause ots high toxicity and drug resistance, cisplatin is not an ideal anticancer daig. Therefore, there is a need 10 find new fnticancer drugs having low toxicity and high theeapeutic elects. “Theresa sure of interest in the medicinal application of gold nanoparices (AuNPs) because of thei lg toxicity." biocompattility” and high drug accumulation.” In order to disperse AUNPS in. phospbate-bulleed. saline ‘or other ‘medium solutions for medical applications, capping agents fre neces." For this purpose, AuNPs capped with oligo ucleotides, peptides, pids, antibodies, ammonium sls, famines, and citvate are used as drug cariers, imsging ‘qents* ora photo-responsve therapeutic agents.” TIidazolium salts are a widely studied family of com. plications including, infections, cancers, ‘brtie diseases and so on (US 2007/0043016, US 20147 (0142307, WO 20091096008). Imidazotium salts have boon used to prepare metal NPs. Thus prepared NPs often have imidazolium salts asthe capping or stabilizing agents. In few ceases N-heteroeyele earbenes (NHICS) derived fom imida- ‘olin sats have also been fond on the NP mrface, NHC fare good o-donor ligands, able to form strong bonds with ttals of diferent cidation states, The fst proposition of | possible NHC formation on 1x0) nano cluster surface was evidenced by the observation of H-D exchange of imidazo- Tium ring protons.” Up To now, diferent approaches have boon developed to prepre NHC-coated meal NPs," Inone case, eduction of metal NHC complexes has been employed to produce metal NPs.®" As a diferent approach, dsplace- ment of capping gent on metal NPs by preformed NHC has been reported" S* Altematively, azolium salt with mtallate anions as precursors have been utilized 0 foam [NHC capped metal NPs via deprotonation and reduction processes 7 SUMMARY ‘The present application provides novel sxolium com- pounds, In some embodiments,» compound having a sruc- ‘ure of Formula (1) is provide: o In some embodiments, a compound having a structure of| orm (I) is provide In Formulae (1) and (ID, dashed lines respectively repre sent (i) ith oF without an atachment of benzol grovp, al (i) & delocalized bond where showa within «ing, Ry is hydrogen or a halogen: Ry iso linker selected from C25 aly or polyetiyleneplyeol:R, is Cay alkyl Cy. substi= tuted allyl hexadeeanyl amido, pyidiny, benzyl or pyri ‘inyl In Formula (11, Misa metal selected from gold (Au), silver (Ag), palladium (Pa), platinum (P), iridium (lr) or hom (Rb), The present application also provides a composition com: prising the compound of Fommils (Il) and 2 compound of | Forma (). The present application further provides 4 composition comprising a gold nanoparticle, the compound of Formula ((), and the compound of Fouls (1). In some embodiments, the present application provides a ‘method for preparing the composition comprising a gold ‘nanoparticle with a compound of Formula (I) alone or in dition with a compound of Formla (2). The metho ‘comprises mixing an aqueous solution of metal jon with an onganic or aqueous solution of compound of Formula (Dj Stering the mixed solution; adding a redueing agent to this Solution; and isolating the composition from the aqueous solution In some embodiments, the present application further provides a method for eating a cancer comprising adi string an effective amount of a compound of Forma () Insome embodiments, dhe present application also provides meted for eating. cancer comprising administering an effective amount ofa composition comprising tbe compound of Formula (ll) and a compound of Formula (). In some tmbodiments, the present application “also provides a tethod for treating @ cancer comprising administering an US 9,855,280 B2 3 eectve amon of composition comprising gold nano- particle, the compound of Fomula (Il) and a compound of | Forma (). [BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 isa Rowshar illustrating the process for preparing ‘a imidazolium compound FIG, 2 shows (A) syntheti scheme for AUNPS-A and -B, (8) a TEM image of AUNPS-A, (C) a TEM image of AuNPs-B and (D) UV-vis absorption specta of AuNPs-Ain (CH,CL,, and AuNPS-B in 1.0. FIG. 3 shows the proposed structure of AuNPS FIG. 4 shows TEM images of K562 cells after tating with AUNPS-B for 3h. (A) KS62 cells without AuNPS ‘weatment; (B) cells tearing, with 06 pg/ml of AUNPS, showing AUNPS entered in the cytosol and organelle, the location of AUNPS-B boing marked with open artow bead; (C) eating with 1 ygiml of AuNPS-B, the red box indicating AAUNPS inthe vesicle, with magnification given in the white box; and (D) treating with 1 ppiml of AUNPS-B, showing AuNPs-B in the nucleus. Seale bars on panels (A), (B), and (€) 200 om, panel (D) $00 nm FIG. § shows the dose response for various cancer cells, prosented as the mean of ODsza of inhibitory rate (% of | conte), FIG. 6 shows Cell viability of £562 incubated with blank, 0.15, 0.63, 1.00, 1.25, or 1.50 yim of AUNPS-B, was assessed at different ime interval IG. 7 shows apoptosis of K502 cells induced by AUNPS- B. (A) Flow eytometry analysis of FITC and PL stained 562 cells upon treating with AUNPS-—B for 60 h, Plas are green PI vs, red annexin V-PITC stained emissions. Num bers on the graph represent the percentages of live cells ower-left_quadrand, early apoptotic cells (lower-ight quadrant), latephase apopttie eels (upperrght quadrant) ‘ordead cells (upper-left quadrant in different quadrants. (B) \Westem blot evaluation of caspasc-3 activation upon tcat- 9, ing with AuNPs at diferent concenirations after 60 (top) unactivated caspase-3 enzymes (35 kDa), (middle) cleaved caspase 3 (17 kDa and 19 kDa), and (botlom) BeActin as an internal contol DETAILED DESCRIPTION OF THE EMBODIMENTS ‘The present application provides novel azolium sats NHC compounds and gold nanoparticles. Most of them show excelent selectivity against cancer cells and are less ‘oxie to normal coll. In some embodiments, compound having a stueture of Formula (Ds provided: In some embodiments, compound having a strcture of Formula (I) is provide In Formulae (1) and (UD, the dashed lines respectively represent () with of without sn attachment of benzol group, and (i) 2 dojecalized bond where shown within a ring. In some embodiments, th dashed lines in Formula (1) repre feat @ without an atachatent of beazol group. In some embodiments, the dashed lines in Formula (11) represent () without an attachment of benzol group. In Formulae (1) and (I) R, can be respectively selected fom hydrogen or a halogen such as fluorine (F), chlorine (Cb, bromine (3) or iodine (D, In one profered embod iment, Ry is hydrogen In Formulae (1) and (ID, R, can be a Tinker respectively Selected from Cy. 39 alkyl or polyethylene glycol. The C, x5 alkyl ean be unstbstitted ally or substituted alkyl In some embodiments, R, is polyethylene plyeol. In one prefered temodiment, Ris tnethvlene givok In Formulae {1) and (Il), Ry ean be respectively selected fiom Chay alkyl Cap substituted alkyl, hexadscanyl amido, pytiinyl, benzyl or pyrimidiny, In some embodi- mens, Ry is Cy a alk In Formula (i), M is a metal selected fom gold (Au), silver (Ag), palladium (Pa), platinum (PD), iridium (ir) or rhodium (Rb). In one preferred embodiment, M is gold. Tn some embodiments, the present application provides a fist composition comprising compounds of Formula 0) and Foro (I) Tn some embodiments, the present application provides a second composition comprising a core formed By gold nanoparticle, and stabilizers consisting compounds of For ‘mula (1) and Formula (). In some embodiments, the present application further provides «third composition comprising «core formed by Bold nanoparticle stabilized by compounds of Form (I. The compositions of the present applications can further comprise a solvent, @ pharinacetically acceptable caerie, tndior a pharmaceutically acceptable excipient. In some embodiments, the solvent can be water, saline and the like The compositions of the present applications can he in a {orm of solution with colloidal particles of nanoscale size. In some embodiments, the composition in a form of particle has an average particle diameter of between 1 nm and 100 1m. In some embodiments, the composition hasan average particle diameter of 1-75 am. In some embodiments, the ‘nas an average particle diameter of 5-50 nn. In ‘ome embodiments, the composition hae an average particle diameter of 1-20 am. US 9,855,280 B2 5 In embodinents the second composition has a multi luyer-like and sphere-like structure. In particular, the mul tikyerlike sicture has a core of geld nanoparticles, a plualty of the compound of Formula (I) suround the Surface of the core to form a layertike structure, and a plurality ofthe compound of Formula (I) covers the outer Surface of the particle. The term “mullyer-like stracture” sed berein is merely 10 describe the location and the distribution of each componeat easly it does not mean real layer formation, Tn some embodiments, the second composition compris: fing a gold nanoparticle core stabilized by compounds of Formula (I) and Formula (I) can be prepared by a method comprising the following steps: mixing an aqueous solution fof metal ton with an organte solution of a compound of formula (1 ‘wherein dashed Iines in Fomanta (1) represent () with or ‘without an attachment of beazol group, bond where shown within a ring; Ry is hydrogen of a halogen: Ry isa linker selected fom Cy, pally ox polyeth- lene giveol; Ry is Cy alkyl, C.np substituted alkyl, inexadeeanyl amie, pyrdiny], benzyl ee pyrimidingl: X CI, Br, 1, NO, PFy, SO,, PO, CIO, BE, BPhys string the two-phase solution; ‘adding a reducing agent to the two-phase solution; and ‘obisining the aqueous layer of the two-phase soTulion 0 isolate the composition In some embodiments, the second composition ean be prepared by: mixing agucous solutions of metal ion and a compound of formula (Dy string the mixture; adding a reducing agent to the mixed solution; and isolating the ‘composition from the mixed solution in some embodiments, the aqusous solution contains a ‘metal ion selected from a group consisting of gold (An), silver Ag), palladium (Pa, platinum (P%), iridium (Br) and sodium (Rb). Ina prefered embodiment, the metal ion is gold (Au). Ina preferred embodiment, the agueous solution fomprises HAUCL, a delocalized, 6 Insome embodiments, the reducing agent ean be NaBH, H, ascorbic acid, other borohydride derivatives andthe like Tithe method, the metal ion and the compound of forma () have a molar ratio of I: atleast 3, namely, equal to or ‘more than 3 mole of the compound of formula (0 is used 10 react with T mole of the metal ion. In some embodiments, the meta ion and the compound of formula () have a molar ratio oF about 1:3 to about 1:20, For example, the mola ratio can be 1:3, 1, 135, 1:6, £7, 1:8, 1:9, 1:10, 1:15 and any Jintermodiate values filling in any ranges defined between any of the aforementioned values In some embodiments, the composition obtained by the above method is in a form of nanoparticles having an average diameter of between J nm and 100 nm. In some embodiments, the composition hasan average particle diam: ‘er of 1-75 nm, In some embodiaents, the composition has fn average particle diameter of 5-50 nim. In sme embod tents, the composition hasan average particle diameter of 1-20 nm, Inthe presem application, the compound of Formula (1), the compound of Formula (I) the fist composition, the sccond composition and the thir! composition respectively has the ability to inhibit against a cancer, Therefore, the compounds andthe compositions can be applied wo cancer treatment or amelioration. In some embodiments, the present application further provides « method for treating a cancer comprising admin string an effective amount of the compound of Formula (1), the compound of Formula (ID, the first composition, the second composition andor the third composition. ‘The ‘alministation includes, but not limited to, oral adminis tion, injection, inhalation, local administration of skin, nose, rectum, of vagina andthe Tike “These compounds or compostios can be administered with a solvent, a pharmaceutically acceptable carr, andlor { pharmaceutically acceptable excipient. In some embod ‘menls, the solvent ean be water, saline and the like. These compounds of compositions may be administered in con- binsion with an anticancer dng The cancer may inelude, but not limited to, leukemia, liver cancer, colon cancer, lung cancer, gastric cancer, breast cancer, head and neck cancers, gynaecological cancers, prostate cancer, malignant lymphoma, tongue squamous fareinoms, neuroblastoma and the hike. Tn some embodiments, the method for treating a cancer comprising administering an effective amount of the com- pound of Formula (Di provided. The compound of Formula (0) includes, but not limited to, the following composinds US 9,855,280 B2 continued and the Hike. EXAMPLES, Atypical example to prepare one of these imidazolium salts is shown in FIG. 1 84(0-Chloro-1,47-rioxanon--yl)guinoline_(CITEGQ) was frst synthesized by treating S-hydroxyguinoine wilh 1.2-bis(2-chloroethoxy ethane in CH,CN in the presence of potassium carbonate. This was then reacted with N-hexade- 0 Cflimidazole to afford 3-hexadeey!-1-(2-2-(quinoi yloxy) ethoxyethoxy)ethyD}imidazolium chloride, [Cy4, TEGQ-ImjCt. Following the procedures developed by one of te inven: tors, the Au())—NHC complex [C,,, TEGQ-Imy),AulCl, 65 where CyqcTEGQimy stands for Shexadeeyll-G-2-2- (qvinotin-8-yloxy ethoxy ethoxy ethy-imide yldene, was prepared.

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