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.

There is little literature data describing the antitumor activity of heterocyclic quinolones. Some new analogs of 4-quinolinones and 1,7 naphthyridin-4-ones were synthesized and their in vitro antitumor activity against central nervous system (CNS) (SNB-75), breast (T-47D) and lung (NCI-H 522) cancer cell lines was tested.2) One of the first quinolinequinones, streptonigrin (SN) is an antitumor antibiotic, which has activity against a broad range of tumors.3-5) SN was studied clinically as an antitumor agent, but its use was limited because of reports of delayed myelotoxicity.6,7) Nevertheless, positive results were reported for SN either as a single agent 8,9) or in combination chemotherap, 10,11) SN is an excellent substrate for oxidoreductase (NQ01). 12)Pyranoquinoline-2-ones were synthesized and evaluated for their in vitro cytotoxicity against a panel of human tumor cell lines, 13) while 2-arylquinazolinones displayed significant growth inhibitory action against tumor cell lines and some of them were potent inhibitor of tubulin polymerization. Some of them displayed selective activity against P-gp-expressing epidermoid carcinoma of the nasopharynx.14) Recently trifluoromethyl substituted pyranoquinolinone was tested for its ability to modulate the transcriptional activity of the human androgen receptor (HAR). 15)Searching for compounds related to these classes of biologically and pharmacologically active compounds, we prepared new substituted thieno[3Ј,2Ј:4,5]thieno[2,3-c]-quinolones containing N- [3-(dimethyamino)propyl] substituent on the quinolone nitrogen (6a, 6b, and 7) and those containing N- [3-(dimethyamino)propyl] substituent in the amide part of the molecule (10a and 10b). Results and DiscussionChemistry Compounds 6a and 6b were prepared in multistep synthesis according to Chart 1. Starting from thiophene-3-carboxaldehyde and malonic acid by already known aldol condensation reaction, 16) or from 3-bromothiophene by Heck reaction, 17) or from 4-bromothiophene-2-carboxaldehyde by oxidation of carboxaldehyde group 18) and esterification of carboxylic acid, 19) followed by Heck reaction, 5-substituted 3-thienyl-acrylic acids 3a-c were prepared. Cyclisation of 3a-c with thionyl chloride and a catalytic amount of pyridine, by the known method 20,21) gave substituted 3-chlorothieno[2,3-b]thiophene-2-carbonyl chlorides 4a-c. By refluxing of chlorides 4b and 4c with aniline in toluene corresponding 3-chlorothieno[2,3-b]thiophene-2-carboxamides 5c and 5d were obtained.On the other hand, corresponding substituted 3-chlorothieno[2,3-b]thiophene-2-carboxamides 5a and 5b were obtained from chlorides 4a-c by the Shotten-Baumann method 22) with N- [3-(dimethyamino)propyl]aniline at 0°C. All prepared anilides 5a-d were converted by photochemical dehydrohalogenation reaction into corresponding quinolones 6a-d. 20) Better yields were achieved in cases where N-atom on the anilide part of the molecule was not substituted with N- [3-(dimethyamino)propyl] substituent. Quinolone 7 was obtained by alkylation of 6d with N-...

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