Novel derivatives of benzo[b]thieno[2,3-c]quinolones: synthesis, photochemical synthesis, and antitumor evaluation.
Novel derivatives of benzo[b]thieno[2,3-c]quinolones 3a-j were synthesized in a multistep synthesis starting from substituted benzo[b]thiophene-2-carbonyl chlorides, to their corresponding benzo[b]thiophene-2-carboxamides, which were photochemically dehydrohalogenated to their corresponding substituted benzo[b]thieno[2,3-c]quinolones. Compound 4 was prepared from 3i by alkylation with 3-dimethylaminopropyl chloride in the presence of NaH. Compounds 7a,b were prepared from 3g in the multistep synthesis from compounds 5 and 6. Compounds 3b, 3c-f, 3h, 7a, and 7b were found to exert cytostatic activity against malignant cell lines: pancreatic carcinoma (MiaPaCa2), breast carcinoma (MCF7), cervical carcinoma (HeLa), laryngeal carcinoma (Hep2), colon carcinoma (CaCo-2), melanoma (HBL), human fibroblast cell lines (WI-38). The compounds that bear a 3-dimethylaminopropyl substituent on the quinolone nitrogen (3b, 3c-f, 3h) showed higher antitumor activity than compounds bearing the same substituent on the amidic nitrogen (7a and 7b). The compound 3h, which has a 3-dimethylaminopropyl substituent on the quinolone nitrogen and a methoxycarbonyl substituent at position 9, had marked antitumor activity. Because of strong cytotoxic effect of compound 4 on melanoma cells (HBL, ME 67.3, and ME 67.1), a potential mechanism of action was examined. Analysis of DNA and Annexin-V-FLUOS staining indicated that compound 4 causes cell death by apoptosis.
Dogan Koruznjak
Jasna
J
Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 20, P.O. Box 177, HR-10000 Zagreb, Croatia.
Grdisa
Mira
M
Slade
Neda
N
Zamola
Branimir
B
Pavelić
Kresimir
K
Karminski-Zamola
Grace
G
D000478:Alkylation; D017304:Annexin A5 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D004273:DNA, Neoplasm / Q000737:chemistry / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005434:Flow Cytometry; D006801:Humans; D006868:Hydrolysis; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D010777:Photochemistry; D015363:Quinolones / Q000138:chemical synthesis* / Q000494:pharmacology*; D013055:Spectrophotometry, Infrared; D013056:Spectrophotometry, Ultraviolet; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000494:pharmacology*
D017304:Annexin A5; D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D007202:Indicators and Reagents; D015363:Quinolones; D013876:Thiophenes