Aldehyde dehydrogenase inhibitors: α,β-Acetylenic N-substituted aminothiolesters are reversible growth inhibitors of normal epithelial but irreversible apoptogens for cancer epithelial cells from human prostate in culture

• Published in: European journal of medicinal chemistry 2008-05, Vol.43 (5), p.906-916
• Main Authors: Quash, Gerard, Fournet, Guy, Courvoisier, Charlotte, Martinez, Rosa M., Chantepie, Jacqueline, Paret, Marie Julie, Pharaboz, Julie, Joly-Pharaboz, Marie Odile, Goré, Jacques, André, Jean, Reichert, Uwe
• Format: Article
• Language: English
• Subjects: Acetylenic aminothiolesters; Aldehyde Dehydrogenase - antagonists & inhibitors; ALDH1 and ALDH3 inhibitors; Animals; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Biological and medical sciences; Cell Line, Tumor; Cell Proliferation - drug effects; Drug Screening Assays, Antitumor; Epithelial Cells - cytology; Epithelial Cells - drug effects; Esters; General aspects; Human prostate cancer cells; Human prostate epithelial normal cells; Humans; Isoenzymes - antagonists & inhibitors; Male; Medical sciences; Mice; Mitochondria - drug effects; Mitochondria - metabolism; Oxidation-Reduction; Pharmacology. Drug treatments; Prostatic Neoplasms; Structure-Activity Relationship; Sulfhydryl Compounds - chemical synthesis; Sulfhydryl Compounds - chemistry; Sulfhydryl Compounds - pharmacology; Superoxides - metabolism; Transplantation, Heterologous
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2007.06.004

The pharmacomodulation of the N atom of α,β-acetylenic aminothiolesters or the replacement of the thiolester moiety by more electrophilic groups did not permit any clear rationale to be established for improving the selective growth-inhibitory activity of this family of compounds over that of the previously synthesized α,β-acetylenic aminothiolesters DIMATE and MATE [G. Quash, G. Fournet, J. Chantepie, J. Goré, C. Ardiet, D. Ardail, Y. Michal, U. Reichert, Biochem Pharmacol 64 (2002) 1279–92]. Hence DIMATE and MATE were investigated more thoroughly for selectivity and growth-inhibitory activity using human prostate epithelial normal cells (HPENC) on the one hand and human prostate epithelial cancer cells (DU145) on the other. Unequivocal evidence was obtained showing that both compounds were reversible growth inhibitors of HPENC but irreversible growth inhibitors of DU145. Growth-inhibition of DU145 was due to the induction of early apoptosis as revealed by the flow cytometric analytical profile of inhibitor-treated cells, of the decrease in the redox potential and increase in superoxide anion content of their mitochondria. Of the two intracellular enzymes: aldehyde dehydrogenases 1 and 3 (ALDH1 and ALDH3) targeted by DIMATE and MATE, ALDH3 was inhibited to the same extent by both compounds whereas ALDH1 was less susceptible to inhibition by MATE. As the induction of ALDH3 by xenobiotics is hormone-dependent, MATE, the more selective of the two inhibitors, is a useful tool not only for examining the role of the ALDH3 isoform in hormone-sensitive and resistant prostate cancer cells in culture but also for investigating if it can inhibit the growth of xenografts of prostate cancer in immunodeficient mice. [Display omitted] Growth-inhibitory efficacy and selectivity of α,β-acetylenic N-substituted aminothiolesters obtained by the pharmacomodulation of the N atom have been addressed. Dimethylamino and morpholino compounds are reversible inhibitors of the growth of human prostate epithelial normal cells (HPENC) but irreversible inhibitors of the growth of human prostate epithelial cancer cells (DU145).