Design And Synthesis Of Novel Purine And N-(3,4,5-trimethoxybiphenyl-2-yl) Benzamide Derivatives With Antitumor Activity

Cancer is one of modern diseases that are increasingly threatening the public health.According to WHO reports,cancer is a leading cause of death worldwide and accounted for 8.2 million deaths(around 13%of all deaths)in 2012.Deaths attributed to cancer are expected to rise to more than 13.1 million in 2030.However,cancer is diverse and can follow different paths,not all of which develop to metastates and deaths,and include lethargic disease that causes negligible harm during the patient’s lifetime.Therefore,the development of new active drugs is necessary to improve the outcome for patients with cancer.In this paper,novel purine and N-(3,4,5-trimethoxybiphenyI-2-yl)benzamide derivatives were designed and synthesized.And their antitumor activity and mechanism were also evaluated.Part Ⅰ Design and synthesis of purine derivatives with antitumor activitiesPurine is an important heterocyclic scaffold in the field of medicinal and pesticidal chemistry since its derivatives are well known for their diverse biological activities.In addition.purines are a class of important cellular components,which involves in metabolic,energy transactions,nucleic acid synthesis and a multiplicity of biochemical reactions.And its derivatives have attracted considerable attention for their important chemopreventive and chemotherapeutic effects on cancer,and are potent inhibitors of heat shock protein 90(Hsp90),cyclin dependent kinase(CDK),Histone deacetylase(HDAC),C-Src,PDK1,and vascular endothelial growth factor receptor(VEGFR)and tubulin.In this paper,6-chloro-9-multimethoxylbenzyl-9H-purines(87a-h),6-chloro-7-multimethoxylbenzyl-9H-purines(99a-b).9-multimethoxylbenzy 1-N-(4-methoxyphenyl)-N-methyl-9H-purin-6-amines(88a-f and 89a-f),2-(6-chloro-9H-purine-9-yl)-1-multimethoxyl-phenylethanone(90a-c)and 2-(theophyllinum-9-yl)-1-multimethoxylphenylethanone(91a-d)were synthesized and evaluated for their antiproliferative effects on four human tumor cell lines,and for their effect on cell cycle distribution,and for their inhibitor activities to tubulin,CDK2 and HSP-α.Among these compounds,compounds 87a-d,90a-c and 91a-d dispalyed weak antiproliferative activities.However,compounds 87e-h and 99a-b showed higher activities than 5-Fu,and GC50 in the range of 1.7 μM-36.2 μM.And N-(4-methoxyphenyl)-N-methyl-9H-purin-6-amines bearing a multimethoxylbenzyl group at 9-position(88a-f and 89a-f)shown good to moderate activities against K562,SY5Y and AGS cells.Moreover,compounds 88d,88g,89d and 89g showed higher inhibitory activities(their GI50 are 0.43 μM,0.26 μM,7.3 μM and 3.0μM respectively)against SY5Y cells than 5-FU(GI50＝11.9μM).More interesting,compounds 88d and 88g displayed preference for SY5Y cells with a higher selectivity of about 165 and 653-fold over AGS cells,and about 382 and 738-fold over K562 cells respectively.In addtion,compound 89b showed good inhibitory activities against K562(GI50 = 2.3μM),SY5Y(GI50 = 3.4 μM)and AGS cells(GI50=0.26μM).A careful analysis of the SAR of these compounds demonstrate that the substituents in 2-position of purine derivatives has large influence on its antitumor activity.Purine derivatives(87e-h and 89a-f)bearing a chloride atom at 2-position diasplayed higher activities against K562 and AGS cells than their corresponding purine derivatives(87a-d and 88a-f)bearing a hydrogen atom at 2-position.In additon,compound 87g arrested the cellular cycle in the S phase,however compound 89b arrested the cellular cycle in the G2/M phase.And Compounds 88d,88g and 89b showed weak inhibitor activities to CDK2 and HSP90-α,but can significantly induce neuroblastoma SH-SY5Y cell apoptosism at low concentrations,and exert some inhibitory activity on tubulin polymerization at 10μM.Part Ⅱ Design and synthesis of N-(3,4,5-trimethoxybiphenyl-2-yl)amide derivatives with antitumor activitiesBiphenyl derivatives widely present in nature,and exhibit a broad spectrum of biological activities.And the phenyl benzene is an important scaffold in the field of medicine.In addition,many biphenyl derivatives bearing 3,4,5-trimethoxy phenyl group display wonderful antitumor activities.Therefore,a series of N-(3,4,5-trimethoxybiphenyl-2-yl)amide derivatives(105a-o)bearing a amide side chain was designed and synthesized.Their antiproliferative effects on human tumor cell lines(AGS)and the inhibitory against tubulin polymerization were also evaluated.The results indicated compoounds 105b,105c,105d and 105m displayed comparative activity against AGS cells with 5-FU.In addition,compound 105d and 1051 exert some inhibitory activity on tubulin polymerization.In summary,a total of thirty-one new purines and fifteen N-(3,4,5-trimethoxybiphenyl-2-yl)amide derivatives were synthesized and evaluated for antitumor activities.All new compounds were identified with NMR and MS.The preliminary biological evaluation founds some active compounds with good antitumor acitivites,which could be used as the lead compounds.Moreover,compounds 105d and 5m arrested the cellular cycle in the G2/M phase.