title: Pronounced anti-proliferative activity and tumor cell selectivity of 5-alkyl-2-amino-3-methylcarboxylate thiophenes.
abstract: 5-(2-(4-Methoxyphenyl)ethyl)-2-amino-3-methylcarboxylate thiophene (TR560) is the prototype drug of a recently discovered novel class of tumor-selective compounds that preferentially inhibit the proliferation of specific tumor cell types (e.g. leukemia/lymphoma). Here, we further increased tumor selectivity by simplification of the molecule through replacing the 4-methoxyphenyl moiety by an alkyl chain. Several 2-amino-3-methylcarboxylate thiophene derivatives containing at C-5 an alkyl group consisting of at least 6 (hexyl) to 9 (nonyl) carbon units showed pronounced anti-proliferative activity in the mid-nanomolar range with 500- to 1000-fold tumor cell selectivity. The compounds preferentially inhibited the proliferation of T-lymphoma CEM and Molt/4, prostate PC-3, kidney Caki-1 and hepatoma Huh-7 tumor cells, but were virtually inactive against other tumor cell lines including B-lymphoma Raji and cervix carcinoma HeLa cells. The novel prototype drug 3j (containing a 5-heptyl chain) elicited a cytotoxic, rather than cytostatic activity, already after 4 h of exposure. The unusual tumor selectivity could not be explained by a differential uptake (or efflux) of the drug by sensitive versus resistant tumor cells. Exposure of a fluorescent derivative of 3j revealed pronounced uptake of the drug in the cytoplasm, no visible appearance in the nucleus, and a predominant localization in the endoplasmic reticulum. These observations may be helpful to narrow down the intracellular localization and identification of the molecular target of the 5-substituted thiophene derivatives.
authors.affiliation: KU Leuven, Department of Chemistry, Celestijnenlaan 200f, B-3001 Leuven, Belgium.
authors.forename: Joice
authors.initials: J
authors.lastname: Thomas
authors.affiliation: KU Leuven, Rega Institute for Medical Research, Herestraat 49, Postbus 1043, B-3000 Leuven, Belgium.
authors.forename: Alenka
authors.initials: A
authors.lastname: Jecic
authors.affiliation: KU Leuven, Rega Institute for Medical Research, Herestraat 49, Postbus 1043, B-3000 Leuven, Belgium.
authors.forename: Els
authors.initials: E
authors.lastname: Vanstreels
authors.affiliation: KU Leuven, Rega Institute for Medical Research, Herestraat 49, Postbus 1043, B-3000 Leuven, Belgium.
authors.forename: Lizette
authors.initials: L
authors.lastname: van Berckelaer
authors.affiliation: Dipartimento di Scienze Chimiche e Farmaceutiche, Università di Ferrara, 44121 Ferrara, Italy.
authors.forename: Romeo
authors.initials: R
authors.lastname: Romagnoli
authors.affiliation: KU Leuven, Department of Chemistry, Celestijnenlaan 200f, B-3001 Leuven, Belgium. Electronic address: wim.dehaen@kuleuven.be.
authors.forename: Wim
authors.initials: W
authors.lastname: Dehaen
authors.affiliation: KU Leuven, Rega Institute for Medical Research, Herestraat 49, Postbus 1043, B-3000 Leuven, Belgium. Electronic address: Sandra.liekens@kuleuven.be.
authors.forename: Sandra
authors.initials: S
authors.lastname: Liekens
authors.affiliation: KU Leuven, Rega Institute for Medical Research, Herestraat 49, Postbus 1043, B-3000 Leuven, Belgium. Electronic address: jan.balzarini@kuleuven.be.
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
mesh_terms: D000478:Alkylation; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006801:Humans; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D013876:Thiophenes
keywords: 5-Alkyl-2-aminothiophenes; Anti-proliferative activity; Gewald reaction; Intracellular uptake; Tumor selectivity