Synthesis, photochemical synthesis and antitumor evaluation of novel derivatives of thieno[3′,2′:4,5]thieno[2,3-c]quinolones

Abstract

The novel derivatives of thieno[3′,2′:4,5]thieno[2,3-c] quinolones 6a, 6b, 7, 10a and 10b were synthesized in multistep synthesis starting from thiophene-3-carboxaldehyde and malonic acid reacting in aldol condensation or from 3-bromothiophenes or methyl 4-bromothiophene-2-carboxylate reacting in Heck reaction. They resulted in corresponding substituted thienylacrylic acids 3a - c, which were cyclized into thieno[2,3-c]thiophene-2- carbonyl chlorides 4a - c and converted into thieno[2,3-c]thiophene-2- carboxamides 5a - d. Prepared carboxamides were photochemically dehydrohalogenated into corresponding substituted thieno[3′,2′:4,5] thieno[2,3-c]-quinolones 6a-d. Compound 7 was prepared from 6d by alkylation with N-[3-(dimethylamino)propyl]chloride hydrochloride in the presence of NaH. Compounds 10a and 10b were prepared from 6c in the multistep synthesis over acid 8 and acid chloride 9. Compounds 6a, 6b, 7, 10a and 10b were found to exert cytostatic activities against malignant cell lines: pancreatic carcinoma (MiaPaCa2), breast carcinoma (MCF7), cervical carcinoma (HeLa), laryngeal carcinoma (Hep2), colon carcinoma (CaCo-2), melanoma (HBL), and human fibroblast cell lines (WI-38). The compound 6b, which bears the 3-dimethylaminopropyl substituent on quinolone nitrogen and methoxycarbonyl substituent on position 9, exhibiedt marked antitumor activity. On the contrary, compound 7, which also bears the 3-dimethylaminopropyl substituent on the quinolone nitrogen but anilido substituent on position 9, exhibited less antitumor activity than the others. © 2002 Pharmaceutical Society of Japan.