Fascaplysin-based CDK4 Inhibitors With Non-planar Structure:Design,Synthesis And Antitumor Activity

Fascaplysin,a natural pigment isolated from the Fijian sponge Fascaplysinopsis Bergquist sp.,is a broadly known specific CDK4 inhibitor which has broad biological activity such as anticancer,antibiotic and so on.However,fascaplysin is hardly clinically applied due to the high toxicity resulting from its planar structure intercalating with DNA.In this study,twenty one derivatives of ?-carboline,2-(1H-indol-3-yl)carboxylic acid,and 2-(1N-indol-2-yl)carboxylic acid with the specific hydrogen bonding sites with CDK4 and the non-planar structure like fascaplysin were designed via opening ring and bioisostere based on fascaplysin.They were expected to be novel specific CDK4 inhibitors not only cuting down the intercalation with DNA,but also removing the unwanted effect.These compounds were synthesized,and confirmed by the 13CNMR,1HNMR,HRMS and elemental analysis.In vitro proliferation inhibition assay of the target compounds by MTT with fascaplyisn as the positive control in five human tumor cell lines of A549,LS174T,Hela,MCF,and BeL-7402 indicated that the derivatives of ?-carboline and 2-(1H-indol-3-yl)carboxylic acid prohibited tumor cell proliferation significantly.Their IC50S were all at the micromolar level,among which a3(3 ?M<IC50<16 ?M)served as a prospective antitumor agent owing to the broad spectrum proliferation inhibition of all five cancer cell lines and the activity only about five times decreeased than the positive control fascaplysin.The derivatives of 2-(1H-indol-3-yl)carboxylic acid with amide bond reversed did two times more than the ones with amide bond unreversed,though they(40 ?M<IC50<350 ?M)all did less than?-carboline derivatives,such as b6(IC50=40 ?M).2-(1H-indol-2-yl)carboxylic acid derivatives performed the dramatically interesting concentration-depending double regulation to cancer cell proliferation in which there was the substantial dose-effect relationship with the weak inhibition at low concentrations while the significant cytoproliferation at the high concentration.