Synthesis of Some Substituted 6-Phenyl Purine Analogues and Their Biological Evaluation as Cytotoxic Agents.

Asligul Kucukdumlu,Ebru Bilget Guven,Meral Tuncbilek,Rengul Cetin Atalay

doi:10.17344/acsi.2017.3419

Asligul Kucukdumlu, Ebru Bilget Guven + Show 2 more

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https://doi.org/10.17344/acsi.2017.3419

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Abstract

A series of 6-(4-substituted phenyl)-9-(tetrahydropyran-2-yl)purines 3-9, 6-(4-substituted phenyl)purines 10-16, 9-((4-substituted phenyl)sulfonyl)-6-(4-substituted phenyl)purines 17-32 were prepared and screened initially for their in vitro anticancer activity against selected human cancer cells (liver Huh7, colon HCT116, breast MCF7). 6-(4-Phenoxyphenyl) purine analogues 9, 16, 30-32, had potent cytotoxic activities. The most active purine derivatives 5-9, 14, 16, 18, 28-32 were further screened for their cytotoxic activity in hepatocellular cancer cells. 6-(4-Phenoxyphenyl)-9-(tetrahydropyran-2-yl)-9H-purine (9) had better cytotoxic activity (IC50 5.4 μM) than the well-known nucleobase analogue 5-FU and known nucleoside drug fludarabine on Huh7 cells. The structure-activity relationship studies reported that the substitution at C-6 positions in purine nucleus with the 4-phenoxyphenyl group is responsible for the anti-cancer activity.

Highlights

Cancer is a major human health problem and one of the principal reasons of death in both developing and industrialized countries
The 6-(4-substituted phenyl)-9-[(4-substituted phenyl)sulfonyl]purine derivatives 17–32 were prepared as shown in Scheme 1
The N-9 position in the starting compound 6-chloropurine [1] was protected as the tetrahydropyran-2-yl (THP) derivative 230 by reacting 1 with the carbocation formed in situ from 3,4-dihydro-2H-pyran and catalytic amount of p-TSA in refluxing THF

Summary

Introduction

Cancer is a major human health problem and one of the principal reasons of death in both developing and industrialized countries. Purine and purine nucleoside analogues are important anti-cancer drugs used for the treatment of both hematological malignancies and solid tumors in chemotherapy. In 1953 and 1966, among the first anticancer drugs 6-mercaptopurine and 6-thioguanine (Fig. 1) were used as an inhibitor of nucleic acid metabolism in childhood acute lymphoblastic leukemia, respectively.1–4 6-Mercaptopurine 6-Thioguanine. Potent purine-based cyclin-dependent kinase inhibitors olomoucine, roscovitine, purvalanol A, B, amino-purvalanol (Fig. 2) and heterocyclic analogues of these compounds imidazo-pyrazines, pyrazolo-pyrida- Olomoucine Roscovitine. Zines, imidazo-pyridines, thieno-pyridines, pyrrolo-pyrimidines, pyrazolo-pyrimidines and triazolopyrimidines have been investigated as anticancer agents. Purine nucleosides such as fludarabine, cladribine, and pentostatine (Fig. 3) were approved in FDA for the therapy of hematologic disorders between 1991 and 1992.18,19

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