Synthesis and in vitro screening of novel N-benzyl aplysinopsin analogs as potential anticancer agents.

Abstract A series of novel substituted ( Z )-5-((1-benzyl-1 H -indol-3-yl)methylene)imidazolidin-2,4-diones ( 3a – f ) and ( Z )-5-((1-benzyl-1 H -indol-3-yl)methylene)-2-iminothiazolidin-4-ones ( 3g – o ) have been synthesized utilizing microwave irradiation. These analogs were evaluated for in vitro cytotoxicity against a panel of 60 human tumor cell lines . Compound 3i exhibits potent growth inhibition against melanoma UACC-257 (GI 50  = 13.3 nM) and OVCAR-8 ovarian (GI 50  = 19.5 nM) cancer cells while possessing significant cytotoxicity (LC 50  = 308 nM and LC 50  = 851 nM, respectively) against the same cell lines within this series of compounds. A second analog, 3a , had GI 50 values of 307 and 557 nM against SK-MEL-2 melanoma and A498 renal cancer cell lines, and exhibited GI 50 values ranging from 0.30 to 6 μM against 98% of all cancer cell lines in the 60-cell panel. Thus, ( Z )-5-((5-chloro-1-(4-fluorobenzyl)-1 H -indol-3-yl)methylene)-2-iminothiazolidin-4-one ( 3i ) and ( Z )-methyl 1-(4-cyanobenzyl)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)-1 H -indole-6-carboxylate ( 3a ) can be regarded as useful lead compounds for further structural optimization as antitumor agents.