title: Structure-activity relationship of tumor-selective 5-substituted 2-amino-3-carboxymethylthiophene derivatives.
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.
authors.affiliation: Department of Chemistry, KU Leuven, 3001Heverlee (Belgium).
authors.forename: Joice
authors.initials: J
authors.lastname: Thomas
authors.forename: Alenka
authors.initials: A
authors.lastname: Jejcic
authors.forename: Peter
authors.initials: P
authors.lastname: Vervaeke
authors.forename: Romeo
authors.initials: R
authors.lastname: Romagnoli
authors.forename: Sandra
authors.initials: S
authors.lastname: Liekens
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.forename: Wim
authors.initials: W
authors.lastname: Dehaen
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity
chemical_list: D000970:Antineoplastic Agents; D013876:Thiophenes; C000599663:methyl 2-amino-5-((4-ethylphenylthio)methyl)thiophene-3-carboxylate; C000599664:methyl 2-amino-5-((4-isopropylphenylthio)methyl)thiophene-3-carboxylate; C000599662:methyl 2-amino-5-(2-(4-methoxyphenethyl))thiophene-3-carboxylate
keywords: 2-amino-3-carboxymethylthiophene analogues; antitumor agents; lymphoma/leukemia; structure-activity relationships; tumor selectivity