Novel Derivatives of Benzo[b]thieno[2,3-c]quinolones:  Synthesis, Photochemical Synthesis, and Antitumor Evaluation

Abstract

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.

Accepting the Invitation to Open Innovation in Malaria Drug Discovery: Synthesis, Biological Evaluation, and Investigation on the Structure–Activity Relationships of Benzo[b]thiophene-2-carboxamides as Antimalarial Agents

“…Freshly distilled thionyl chloride (2 equiv) and pyridine (0.1 equiv) were added to a solution of the suitable cinnamic acid (1 equiv) in anhydrous chlorobenzene (0.5 mL/mmol) and the stirred reaction mixture was heated at 130 °C for 2 h. Residual thionyl chloride was distilled and the crude was treated with hexane at reflux to afford the respective acyl chloride as pale yellow needles that were collected and used for the following reaction without further purification. Analytical data for compounds 6 – 9 matched the data already published. ,, …”

“…Analytical data for compounds 6−9 matched the data already published. 24,50,51 General Procedure for the Synthesis of Compounds 11−25. A mixture of the suitable 3-chlorobenzothiophene-2-carbonyl chloride (1 equiv) and the proper amine (1 equiv) was refluxed in anhydrous dioxane until consumption of the reacting agents according to TLC.…”

Synthesis of Quinolines: A Green Perspective

“…Few methods have been described for the photocatalytic synthesis of quinolines, mainly due to the low yields and high quantity of side-products normally achieved. Two studies reported C–N bond formation through activation with a leaving group and UV (Scheme , route 1) or white light (Scheme , route 2) promoted cyclization and elimination. , In the second, Jiang et al described an iridium catalyst for the cyclization of acyl oximes in dry DMF and using white LED lights. Even though the reaction proceeded during 10 h, low energy consumption could still be achieved due to LED technology (5 W lamps).…”

Comparison of Antitumor Activity of Some Benzothiophene and Thienothiophene Carboxanilides and Quinolones in 2D and 3D Cell Culture System

“…[9] More specifically, substituted heterocyclic benzo [b]thiophenes, quinolones and carboxamides as very important organic structural motifs, have therefore recently attracted considerable attention from medicinal and synthetic organic chemists due to their spectra of diverse pharmacological features. [10][11][12][13] Furthermore, abovementioned structural units could be found in a variety of bioactive natural products and numerous of synthetic medical and biochemical agents. As a part of our continuing search for potential anticancer agents structurally related to heterocyclic quinolones, we have previously reported synthesis and strong inhibitory activities on several human tumor cell lines of versatile benzothiophene and thienothiophene carboxanilides and quinolones, thus confirming the anticancer potential of this class of compounds.…”