Structure–Activity Relationship of Tumor‐Selective 5‐Substituted 2‐Amino‐3‐carboxymethylthiophene Derivatives

doi:10.1002/cmdc.201402274

Paper

Structure–Activity Relationship of Tumor‐Selective 5‐Substituted 2‐Amino‐3‐carboxymethylthiophene Derivatives

Published Dec 1, 2014 · Joice Thomas, A. Jejcic, P. Vervaeke

ChemMedChem

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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.

In Vitro Study

Study Snapshot

Methyl-2-amino-5-((4-methoxyphenethyl))thiophene-3-carboxylate (8 c) is a potent and selective anti-T-lymphoma/leukemia agent, with potential for further development in cancer therapy.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

Structure–Activity Relationship of Tumor‐Selective 5‐Substituted 2‐Amino‐3‐carboxymethylthiophene Derivatives

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