Structure–Activity Relationship of Tumor‐Selective 5‐Substituted 2‐Amino‐3‐carboxymethylthiophene Derivatives |
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Authors: | Dr. Joice Thomas Dr. Alenka Jejcic Peter Vervaeke Prof. Romeo Romagnoli Prof. Sandra Liekens Prof. Jan Balzarini Prof. Wim Dehaen |
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Affiliation: | 1. Department of Chemistry, KU Leuven, 3001Heverlee (Belgium);2. Rega Institute for Medical Research, KU Leuven, 3000 Leuven (Belgium);3. Dipartimento di ScienzeChimiche e Farmaceutiche, Università di Ferrara, 44121 Ferrara (Italy) |
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Abstract: | 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. |
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Keywords: | 2‐amino‐3‐carboxymethylthiophene analogues antitumor agents lymphoma/leukemia structure– activity relationships tumor selectivity |
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