A novel thiazolidine compound induces caspase-9 dependent apoptosis in cancer cells

• Published in: Bioorganic & medicinal chemistry Vol. 20; no. 17; pp. 5094 - 5102
• Main Authors: Onen-Bayram, F. Esra, Durmaz, Irem, Scherman, Daniel, Herscovici, Jean, Cetin-Atalay, Rengul
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.09.2012; Elsevier
• Subjects: anticarcinogenic activity; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Biochemistry & Molecular Biology; Biological and medical sciences; Cancer; Caspase 9 - metabolism; Caspase-9; Cell cycle; Cell Line, Tumor; chemical structure; Chemistry; Chemistry, Medicinal; Chemistry, Organic; chemogenomics; Colon; Colon cancer; Cytotoxic; Cytotoxicity; death; death receptors; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Endometrium; Hepatocytes; Humans; inhibitory concentration 50; Life Sciences & Biomedicine; Liver; Medical sciences; Neoplasms - enzymology; Neoplasms - pathology; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Physical Sciences; Science & Technology; Structure-Activity Relationship; Terminal alkyne; Thiazolidine; Thiazolidines - chemical synthesis; Thiazolidines - chemistry; Thiazolidines - pharmacology; Tumor cell lines; uterine neoplasms; Terminal alkyne; Cytotoxic; Caspase-9; Cancer; Thiazolidine; Apoptosis; CHEMICAL GENETICS; DRUG DISCOVERY; HIGH-AFFINITY; 2-ARYLTHIAZOLIDINE-4-CARBOXYLIC ACID-AMIDES; BREAST-CANCER; ANTICANCER ACTIVITY; PROSTATE-CANCER; IN-VIVO; CYTOTOXIC AGENTS; FEEDBACK AMPLIFICATION LOOP; Acetylenic compound; Enzyme; Cysteine endopeptidases; Caspase; Cytotoxicity; Malignant tumor; Peptidases; Cell death; Hydrolases; Tumor cell; Alkyne; Thiazolidine derivatives
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2012.07.016

The forward chemogenomics strategy allowed us to identify a potent cytotoxic thiazolidine compound as an apoptosis-inducing agent. Chemical structures were designed around a thiazolidine ring, a structure already noted for its anticancer properties. Initially, we evaluated these novel compounds on liver, breast, colon and endometrial cancer cell lines. The compound 3 (ALC67) showed the strongest cytotoxic activity (IC50 ∼5μM). Cell cycle analysis with ALC67 on liver cells revealed SubG1/G1 arrest bearing apoptosis. Furthermore we demonstrated that cytotoxicity of this compound was due to the activation of caspase-9 involved apoptotic pathway, which is death receptor independent.