Antitumor efficiency of novel fluoro-substituted 6-amino-2-phenylbenzothiazole hydrochloride salts in vitro and in vivo.

The purpose of this study was to investigate antitumor activity of novel fluoro-substituted 6-amino-2-phenylbenzothiazole hydrochloride salts in vitro and in vivo. A novel series of hydrochloride or dihydrochloride salts of the novel 2-(fluoro-substituted phenyl)-6-aminobenzothiazoles (5-7) have been prepared in multistep synthesis starting from 3- or 4-fluorobenzaldehydes and 2-amino-5-nitrothiophenol and evaluated for their antiproliferative activity against human cervical (HeLa), breast (MCF-7), colon (CaCO-2), and laryngeal (Hep-2) carcinomas and against fibroblast cell lines (WI-38). Also, antitumor activity of these compounds was evaluated in vitro and in vivo against murine melanoma (B16-F10), fibrosarcoma (FsaR), and squamous cell carcinoma (SCCVII). The tested compounds were found to exert good cytotoxic activity in vitro. The cytotoxic effect was selective, cell specific, and dose dependent, between 33 microM for MCF-7 and 110 microM for WI-38. Benzothiazoles reduced de novo protein and DNA synthesis up to 75%. All examined benzothiazoles had significant antitumor activity in vivo against melanoma B16-F10, fibrosarcoma, and squamous cell carcinoma. The best therapeutic results were achieved when therapy started 7 days after tumor cell implantation and when benzothiazoles were given repeatedly five times every 2 days, i.e., on day 7, 9, 11, 13, and 15 after transplantation of tumor cells.

Synthesis, crystal structure and antiproliferative evaluation of some new substituted benzothiazoles and styrylbenzothiazoles.

The multistep synthesis of a series of new substituted-benzothiazoles as hydrochloride or quaternary salts is described. 6-Amidino substituted 2-aminobenzothiazoles (5, 6), N-methyl-2-(4-cyanostyryl)benzothiazolium iodide (8), cyano-substituted-2-styrylbenzothiazoles (9-11) and amidino and bis-amidino-substituted 2-styrylbenzothiazoles (12-17) were prepared. The crystal structure of amidino derivative (6) was determined by single crystal X-ray analysis. All new prepared compounds were tested on the cytostatic activities against malignant cell lines: (SW620, colon carcinoma; Hep2, laryngeal carcinoma; HBL, melanoma; HeLa, cervical carcinoma and WI38, human normal fibroblasts). The compounds exerted a different inhibitory effect, depended on concentration and type of the cells. The best inhibitory effect was achieved with compounds (12-15), with slight differences among them. All of them inhibited the growth of examined tumor cell lines and also normal fibroblasts. Other examined compounds exhibited a moderate inhibitory effect, depending on type of the cells. Majority of them inhibited the growth of HeLa cells and WI38.

Synthesis and antitumor evaluation of some new substituted amidino-benzimidazolyl-furyl-phenyl-acrylates and naphtho[2,1-b]furan-carboxylates.

The multistep synthesis of a series of substituted amidino-benzimidazolyl-furyl-phenyl-acrylic acid's esters and substituted amidino-benzimidazolyl-naphtho[2,1-b]furan-carboxylic acid's esters is described starting from corresponding 3-(2-furyl)-2-phenyl-acrylic acids. The new compounds were tested on the cytostatic activities against malignant cell lines: pancreatic carcinoma (MiaPaCa2), breast carcinoma (MCF7), cervical carcinoma (HeLa), laryngeal carcinoma (Hep2), colon carcinoma (HT 29), melanoma (HBL), and human fibroblasts cell line (WI38). All compounds inhibited the proliferation of tumor cell lines. Inhibitory effect of examined compounds depended on concentration, but without significant difference among the type of tumor cells. The compounds 2 and 5 exerted very low inhibitory effect on the growth of human fibroblasts. Unsubstituted derivative 8 has not inhibited any tested cell lines.

Electron impact mass spectra of some bis-(2-benzothiazolyl)furans and bis-(2-benzothiazolyl)thiophenes.

The electron impact mass spectra of some bis-(2-benzothiazolyl)furans and bis-(2-benzothiazolyl)thiophenes have been recorded and the identity of various ions in the mass spectra established. Compounds 1 and 2 present model substances and it is found that their fragmentation pathway is similar to the mono-(2-benzothiazoles). Compounds where the benzothiazolyl groups are directly substituted on the furan nuclei, but in different positions, exhibit two main pathways of fragmentation: fragmentation of the furan nucleus and fragmentation of the benzothiazole nucleus. Other compounds studied show specific fragmentation characteristic for divinyl furan compounds and for compounds with a phenyl substituent between two heterocyclic nuclei.

Mass spectral fragmentation patterns of some 2-methyl-3-furancarboxanilides and 2-methyl-3-furancarbothioanilides. II.

The electron impact mass spectra of some 2-methyl-3-furancarboxanilides and 2-methyl-3-furancarbothioanilides are discussed. Dominant peaks are formed by simple cleavage of a C-N bond in the anilides as well as in the thioanilides. Thioanilides show some additional fragmentation pathways recently reported which are not seen in the anilides. (T. Jagodzinski and M. Stobiecki, Org. Mass Spectrom., Vol. 25, p. 333 (1990)).

Mass spectral fragmentation patterns of some new 3,7-dichloro-benzo[1,2-b:4,5-b']dithiophene-2,6-dicarboxylic acid dianilides and 3,5-dichloro-dithieno[3,2-b:2',3'-d]thiophene-2,6-dicarboxylic acid dianilides. II.

The electron impact mass spectra of some benzo[1,2-b:4,5-b']dithiophene-2,6-dicarboxylic acid dianilides and dithieno[3,2-b:2',3'-d]thiophene-2,6-dicarboxylic acid dianilides are discussed. Dominant peaks in these dianilides are formed by the cleavage of a C-N bond on one side of an anilino group. These ions fragment further by the cleavage of a C-C bond on the other side of an anilino group and a CONRPhR' group may be lost directly. After loss of CO, the characteristic benzodithiophene radical cation, C10H2S2Cl2[symbol: see text], at m/z 256 and the dithienothiophene radical cation, C8S3Cl2[symbol: see text], at m/z 262 are formed from their respective precursor compounds.

Electron impact mass spectra of some 1-(2-furyl)- and 1-(2-thienyl)-2-(2-benzothiazolyl)ethenes.

The electron impact mass spectra of some 1-(2-furyl)- and 1-(2-thienyl)-2-(2-benzothiazolyl) ethenes have been recorded and the identity of various ions in the mass spectra established. The compounds examined (1-10) exhibit two main fragmentation routes. On one hand, fragmentation of the furan and thiophene nuclei and the formation of cyclopropenylethyne cations with very significant abundance and on the other hand, fragmentation of the benzothiazole nuclei on characteristic pathways. Compounds 6-10 also show two additional fragmentation routes.

Mass spectral fragmentation patterns of some new benzo[b]thiophene- and thieno[2,3-b]thiophene-2,5-dicarbonyldichlorides and -dicarbonyldianilides and anilidoquinolones.

The electron impact mass spectra of some benzo[b]thiophene- and thieno[2,3-b]thiophene-2,5-dicarbonyldichlorides, 2,5-dicarbonyldianalides, 9-anilido-benzo[b]thienyl[2,3-c]quinolones and 9-anilidothieno[4,5-b']thienyl[2,3-c]quinolones are discussed. Dominant peaks in dianilides are formed by cleavage of the C-N bond on one side of the anilido group, as well as on the anilido group itself in anilidoquinolones. These ions fragment further by the cleavage of a C-C bond in dianilides and the CONRPh group is lost directly, while the quinolonic part of the molecule in quinolones fragments with low probability. Characteristic fragment ions of dicarbonyldichlorides arise by the cleavage of the C-C1 bond.