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.