Synthesis, antitumor activities and functional mechanism of purine derivatives harboring phenyl moieties through three carbon bridges

A series of 2,6-diamine-9H-purine derivatives substituted with phenyl groups at the 8-position through three carbon bridges were synthesized as nonclassical antifolates. The anti-proliferative activities of these compounds against HL60, HeLa and A549 cells were tested. The inhibitory activities against rhDHFR and behavior towards thymine synthase (TS) and aminoimidazole carbonamide ribonucleotide transformylase (AICARFT) of our target compounds were determined. Compound 4e displayed the best inhibitory activity against HL-60 and HeLa cells. Flow cytometry studies indicated that HL-60 cells treated with 4e displayed S-phase arrest and induction of apoptosis. The effect of 4e on lysosomes and mitochondria were confirmed which indicated that the induction of apoptosis of 4e was acting through a lysosome-nonmitochondrial pathway. The results suggested that compound 4e, containing an m-methoxyphenyl side chain substituent linked by an alpha,beta-unsaturated carbonyl group as a three-carbon bridge, is worth to be further investigated as a novel potent anticancer agent.

Automated summary

A series of 2,6-diamine-9H-purine derivatives substituted with phenyl groups at the 8-position through three carbon bridges were synthesized and tested for their anti-proliferative activities against HL60, HeLa, and A549 cells. Compound 4e showed the best inhibitory activity against HL-60 and HeLa cells. Flow cytometry studies revealed that 4e induced S-phase arrest and apoptosis in HL-60 cells, acting through a lysosome-nonmitochondrial pathway. These findings suggest that compound 4e has potential as a novel potent anticancer agent.