Structure-activity relationship of tumor-selective 5-substituted 2-amino-3-carboxymethylthiophene derivatives.

Methyl-2-amino-5-[2-(4-methoxyphenethyl)]thiophene-3-carboxylate (8 c) is the prototype of a well-defined class of tumor-selective agents. Compound 8 c preferentially inhibited the proliferation of a number of tumor cell lines including many human T-lymphoma/leukemia cells, but also several prostate, renal, central nervous system and liver tumor cell types. Instead, a broad variety of other tumor cell lines including B-lymphomas and HeLa cells were not affected. The tumor selectivity (TS; selectivity index or preferential suppression of CEM lymphoma (IC50 =0.90 µM) versus HeLa tumor cell carcinoma (IC50 =39 µM)) amounted up to ~43 for 8 c. At higher concentrations, the compound proved cytotoxic rather than cytostatic. The antiproliferative potency and selectivity of 8 c could be preserved by replacing the ethyl linker between the 2-amino-3-carboxymethylthiophene and the substituted aryl by a thioalkyl but not by an oxyalkyl nor an aminoalkyl. Among >50 novel 8 c derivatives, the 5-(4-ethyl- and 4-isopropylarylmethylthio)thiophene analogues, methyl-2-amino-5-((4-ethylphenylthio)methyl)thiophene-3-carboxylate (13 m) and methyl-2-amino-5-((4-isopropylphenylthio)methyl)thiophene-3-carboxylate (13 n), were more potent (IC50 : 0.3-0.4 µM) and selective (TS: 100-144) anti-T-lymphoma/leukemia agents than the prototype compound.