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

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 (IC 50 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.

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

“…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.…”

“…[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.…”

Cytotoxic and Antitumoral Activity of N-(9H-purin-6-yl) Benzamide Derivatives and Related Water-soluble Prodrugs

“…Three compounds (2, 3, and 8) out of nine clearly showed the best cytotoxicity in MTT assay with IC50 values below 15 µM, and compounds 3 and 8 exhibited significant cytotoxic activity against all three cell lines tested. For comparison, IC50 values on RL cells are approximately 40 nM for clofarabine, 100 nM for cladribine, 7 µM for fludarabine, 0.8 µM for 6-mercaptopurine and 1.2 µM for 6-thioguanine (raw data from [13]), whereas other chemically related compounds had IC50 of around 5 µM on liver cancer cells [8]. In addition, these compounds were also able to induce apoptosis in RL cells at comparable levels as with fludarabine (more than 50% dead cells at 50 µM).…”

“…Purine nucleobases, such as 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) are well known drugs used in the treatment of childhood ALL [3,4], and fludarabine, cladribine and clofarabine among others are purine containing nucleoside analogues commonly used in clinic [5]. In addition, N-6-benzoyl adenine derivatives and some substituted 6phenyl purine analogues (Figure 2) have recently been identified as potential anticancer agents, respectively as BRD4 inhibitors [6,7] and as cytotoxic agents on a panel of hepatocellular cancer lines [8].…”

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

“…Purine and purine nucleoside analogs exhibit a variety of biological activities. These analogs have been extensively studied as enzyme inhibitors, [2][3][4][5] cytotoxic, [6][7][8][9][10] antiviral, [11][12][13][14] antihyperglycemic, 15 immunostimulatory, 16 antifungal, and antibacterial [17][18][19][20][21][22] agents due to their potential activities, even though their antiviral and anticancer effects are more commonly known. 5-Fluorouracil (5-FU), a well known fluorinated nucleobase analogue, is highly preferred for the treatment of various cancers in clinics.…”