Preparation of substituted N'-(arylcarbonyl)benzhydrazides and N'-(benzylidene)benzhydrazides and analogs as activators of caspases and inducers of apoptosis for use as antitumor agents.

Abstract

The present invention is directed to substituted N'-(arylcarbonyl)benzhydrazides, N'-(arylcarbonyl)benzylidene hydrazides and analogs thereof, represented by Ar1C(O)NR2NR1C(O)Ar2 and Ar1C(O)NR2N:CR1Ar2 (e.g. N'-(2-phenoxypyridine-3-carbonyl)-3-(trifluoromethyl)benzhydrazide (1)): wherein Ar1 is optionally substituted pyridyl, pyrimidinyl or phenyl; Ar2 is optionally substituted aryl or heteroaryl; and R1 and R2 are independently H, alkyl or cycloalkyl; with the proviso that said compd. is other than 4-hydroxybenzoic acid (2-hydroxybenzylidene)hydrazide. The present invention also relates to the discovery that these compds. are activators of caspases and inducers of apoptosis and therefore may be used to induce cell death in a variety of clin. conditions in which uncontrolled growth and spread of abnormal cells occurs. Although the methods of prepn. are not claimed, 42 example prepns. are included. Compd. 1 and analogs were identified as caspase cascade activators and inducers of apoptosis in solid tumor cells and as antineoplastic compd. that inhibits cell proliferation (GI50). Treatment with 1 leads to cell cycle arrest and apoptosis in T-47D cells. Compd. 1 and analogs were identified as antineoplastic compd. that selectively inhibits the proliferation of breast cancer cells (GI50). Compd. 1 was also found to inhibit the clonogenic survival of T47D and MX-1 solid tumor cell lines. [on SciFinder(R)]