Synthesis and cytotoxic evaluation of new (4,5,6,7-tetrahydro-indol-1-yl)-3-R-propionic acids and propionic acid ethyl esters generated by molecular mimicry.

Abstract Indolones 4 and 5 , and indolyl-aminoacids 6a – e , 7a – e , and 8a and 8b were designed by structural modification of lead compound 3 . These compounds were tested on six tumor cell lines to determine the role of the azepinone ring and the N -phenyl substituent in the cytotoxicity of 3 . Our results show that 4 and 5 have dramatically reduced cytotoxicity, due to the loss of the azepinone moiety of lead compound 3 . In contrast, indolyl-aminoacids 6a , 7a , and 8a ( N -( l )-cysteine ethyl ester derivatives) inhibited the proliferation of almost all cancer cell lines tested, even though they lack the azepinone ring. In addition, derivative 6c ( N -( d )-alanine methyl ester group) was selectively cytotoxic to HCT-15 cells. Preliminary structure–activity relationship (SAR) studies with these compounds revealed the importance of the ethyl ester moiety on the amino acid moiety. Compounds 6a – e , 7a – e , and 8a and 8b were obtained in good yields by a catalytic Paal–Knorr reaction carried out under microwave irradiation using commercially available chiral amino esters or amino acids and 1,4-dicarbonyl compounds.