Design, Synthesis and In Vitro Cytotoxic Activity of New 6,9-Disubstituted Purine Analogues

Abstract

A series of new 6,9-disubstituted purine analogs with 4-substituted piperazine at C-6 and 4-substituted benzyl at N-9 were designed and synthesized in four steps. All synthesized compounds (7-26) were screened initially for their in vitro anticancer activity on Huh7 liver, HCT116 colon and MCF7 breast carcinoma cell lines. Cytotoxic bioactivity studies revealed that all compounds screened, with compound 19 being the exception, were found to have promising cytotoxic activities at IC 50 range of 0.05-21.8 μM against cancer cells Huh7, HCT116 and MCF7. Among the prepared purine analogs, two of them (12 and 22) exhibited excellent cytotoxic activities, with IC 50 0.08-0.13 μM, on Huh7 cells comparable to camptothecin (CPT) and better than cladribine, fludarabine and 5-FU. Afterwards, the evaluation of cytotoxicity of the most potent purine analogs was screened against further hepatocellular cancer (HCC) cell lines. The 6-(4-(4-trifluoromethylphenyl)piperazine (12) and 6-(4-(3,4-dichlorophenyl)piperazine analogs (25) displayed a significant IC 50 values (IC 50 < 0.1-0.13 μM) comparable to CPT and better cytotoxic bioactivity when compared with 5-FU, cladribine and fludarabine on HCC cells (Huh7 and HepG2).

Newly synthesized 6-substituted piperazine/phenyl-9-cyclopentyl containing purine nucleobase analogs act as potent anticancer agents and induce apoptosis via inhibiting Src in hepatocellular carcinoma cells

“…Therefore, we synthesized 6-(4-substituted phenyl piperazine)-9-cyclopentyl purine derivatives (19-24) from compound 2. Thus, purines substituted with phenyl piperazines at position C-6 (19)(20)(21)(22)(23)(24) were prepared with the nucleophilic aromatic substitution reaction of 2 with the appropriate piperazines using triethylamine in ethanol (Scheme 1).…”

“…The in vitro cytotoxic activities of the newly synthesized compounds (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24) and (47)(48)(49)(50)(51)(52)(53)(54)(55)(56) were initially evaluated against human liver (Huh7), colon (HCT116), and breast (MCF7) cancer cell lines using NCI-sulforhodamine B (SRB) colorimetric assay. Time-dependent IC 50 values for each compound were calculated in comparison with 5-fluorouracil (5-FU), cladribine, fludarabine, and pentostatine as reference anticancer agents.…”

“…Consequently, these results suggested that cytotoxic activity increases remarkably when a directly substituted phenyl group replaces the phenyl sulfonyl substitution to the 4th position of the piperazine ring. Among all the synthesized molecules, the most active group corresponds to the group with substituted phenyl piperazine (19)(20)(21)(22)(23)(24). Moreover, the most active compounds accommodated electrons attracting 4-CF 3 , Cl, and 3,4-diCl substitutes in the phenyl ring.…”

“…[20][21][22][23] In the present work, we report the synthesis of new derivatives of purines (I), (II), (III), (IV), and 36 as 9-cyclopentyl-purines (11-24 and 47-56) and evaluate their cytotoxic effects against human epithelial cancer cells: liver (Huh7), colon (HCT116), and breast (MCF7) (Tables 2 and 3). With the potent analogs 15, (17)(18)(19)(20)(21)(22)(23)(24), (49), and (56), further screening was done against hepatocellular carcinoma (HCC) cell lines Huh7, Hep3B, HepG2, PLC, Mahlavu, FOCUS, Snu475, Snu182, Snu387, Snu398, Snu423, and Snu449 (Table 4). This analysis sheds light on the pathway leading liver cancer cells to apoptosis.…”

“…In vitro cytotoxicity of 6-(4-substituted phenyl piperazine)-9-cyclopentyl purine analogs(19)(20)(21)(22)(23)(24) on different human cancer cell lines (Huh7, HCT116, and MCF7)…”