Livio Racane

Novel diamidino-substituted derivatives of phenyl benzothiazolyl and dibenzothiazolyl furans and thiophenes: synthesis, antiproliferative and DNA binding properties.

A series of new diamidino-, diisopropylamidino-, and diimidazolinyl-substituted derivatives of phenyl benzothiazolyl and dibenzothiazolyl furans and thiophenes were successfully prepared and evaluated for their antiproliferative activity on tumor cell lines in vitro, DNA binding propensity, and sequence selectivity as well as cellular distribution. A strong antiproliferative effect of the tested compounds was observed on all tested cell lines in a concentration-dependent response pattern. In general, imidazolinyl-substituted derivatives and/or the thiophene core were in correlation with increased antiproliferative activity. Two compounds (2b and 3b) were chosen for biological studies due to their differential antiproliferative properties. The DNA binding properties of this new series of compounds were assessed and evidenced their efficient minor groove binding properties with preferential interaction at AT-rich sites. Both compounds also present nuclear subcellular localization, suggesting that their cellular mode of action implies localization in the DNA compartment and direct inhibition of DNA replication and induction of apoptosis.

Novel amidino substituted 2-phenylbenzothiazoles: Synthesis, antitumor evaluation in vitro and acute toxicity testing in vivo

The efficient synthesis of new bis-substituted nitro-amidino, amino-amidino (10a, 10b-13a, 13b) and previously prepared diamidino 2-phenyl-benzothiazoles (9a, 9b) is described. The compounds 11a and 11b were prepared by recently developed methodology of the key precursors in zwitterionic form 8a and 8b with 4-nitrobenzoylchloride in a very good yield (70%). All compounds except diamidino-substituted 2-phenylbenzothiazole 9a show exceptionally prominent tumor cell-growth inhibitory activity and cytotoxicity, whereby the special selectivity of amino-amidine 2-phenylbenzothiazole 12a towards MCF-7 and H 460 cells makes this compound a prospective lead compound that should be further evaluated in animal models. All in vivo tested compounds (12a, 12b, 13a and 13b) are absorbed from mice gastrointestinal system. LD(50) are between 67.33 and 696.2mg/kg body weight (OECD/EPA toxicity categories 2-3).

Synthesis of New Cyano-Substituted bis-Benzothiazolyl Arylfurans and Arylthiophenes

The new compounds 2-[4-(6-cyanobenzothiazol-2-yl)phenyl]-5-(6-cyano- benzothiazol-2-yl)furan (6a) and 2-[4-(6-Cyanobenzothiazol-2-yl)phenyl]-5-(6-cyano- benzothiazol-2-yl)thiophene (6b) were synthesized by multi-step reactions from the corresponding 2-furan and 2-thiophene carboxaldehydes (route A), as well as from 2- furan and 2- thiophene carboxylic acids (route B). Route B involves one less step than route A, but the overall yields of the reactions are considerably lower.

Synthesis and antitumor evaluation of novel derivatives of 6-amino-2-phenylbenzothiazoles.

Novel derivatives of 6-amino-2-phenylbenzothiazole bearing different substituents (amino, dimethylamino or fluoro) on the phenyl ring were prepared as the corresponding hydrochloride salts. 6-Nitro-2-(substituted-phenyl)benzothiazoles (1-6) were synthesized by condensation reactions of substituted benzaldehydes with 2-amino-5-nitrothiophenol. Nitro derivatives were reduced to the amino derivatives with SnCl(2)/HCl. Water soluble hydrochloride salts of 6-amino-2-(substituted-phenyl)benzothiazole (13-19)were prepared using concentrated or gaseous HCl. Compounds 13-19 were found to exert cytostatic activities against malignant human cell lines: cervical (HeLa), breast (MCF-7),colon (CaCo-2), laryngeal carcinoma (Hep-2), and normal human fibroblast cell lines (WI-38).

Synthesis and antiproliferative evaluation of some new amidino-substituted bis-benzothiazolyl-pyridines and pyrazine

Novel diamidino substituted conformationally restricted derivatives of bis-benzothiazolyl-pyridines and pyrazine were synthesized and their antiproliferative activity against several human cancer cell lines were determinated. The synthetic approach used for preparation of isomeric amidinobenzotiazolyl disubstituted pyridines 3a-3k and pyrazine 3l was achieved by condenzation reaction of commercially available pyridine and pyrazine dicarboxylic acids with amidino- 2a and 2-imidazolinyl-substituted 2-aminothiophenol 2b in polyphosphoric acid in moderate to good yield. The condenzation reaction was greatly optimized. The targeted compounds were converted in the desired water soluble dihydrochloride salts by reaction of appropriate free base with concd HCl in ethanol or acetic acid. Antiproliferative assays revealed significant differences in antiproliferative activities of diamidino- and diimidazolinyl-derivatives, the latter exerting stronger concentration-dependent antiproliferative effects on tested tumor cell lines and thus being a prominent compound class for further chemical optimization and biological studies. Biological studies on SW620 cell line and BJ fibroblasts performed for the diimidazolinyl-derivative 3b revealed oxidative stress as a possible mechanism of antiproliferative action and predicted antineoplastic properties for this class of compounds.

New anticancer active and selective phenylene-bisbenzothiazoles: synthesis, antiproliferative evaluation and DNA binding.

Novel amidino-derivatives of phenylene-bisbenzothiazoles were synthesized and tested for their antiproliferative activity against several human cancer cell lines, as well as DNA-binding properties. The synthetic approach used for preparation of isomeric amidino substituted-phenylene-bis-benzothyazoles 3a-3f was achieved by condensation reaction of isophthaloyl dichloride 1a and terephthaloyl dichloride 1b or with phthalic acid 1c with 5-amidinium-2-aminobenzothiolate 2a and 5-(imidazolinium-2-yl)-2-aminobenzothiolate 2b in good yields. The targeted compounds were converted in the desired water soluble dihydrochloride salts by reaction of appropriate free base with concd HCl in ethanol or acetic acid. All tested compounds (3a-3f) showed antiproliferative effects on tumour cells in a concentration-dependant manner. The strongest activity and cytotoxicity was observed for diimidazolinyl substituted phenylene-bisbenzothiazole compound 3b. These effects were shown to be related to DNA-binding properties, topoisomerase I and II poisoning effects and apoptosis induction. The highest tested selectivity towards tumour cells was observed for the imidazolyl substituted phenylene-benzothiazole 3d that showed no cytotoxic effects on normal fibroblasts making it an excellent candidate for further chemical optimization and preclinical evaluation.

Synthesis and fluorescent properties of some new unsymmetricbis-benzothiazolyl furans and thiophenes

SummarySome newmono- andbis-benzothiazolyl compounds with furan or thiophene nuclei were synthesized by multistep reactions from the corresponding furan and thiophene aldehydes. The data obtained from emission spectra show a large influence of the benzothiazole rings on the relative quantum efficiency of the compounds under investigation.ZusammenfassungEinige neuebis-Benzothiazolylverbindungen mit einem Furan- bzw. Thiophenenring wurden in einer mehrstufigen Reaktion dargestellt. Die Fluoreszenzdaten der untersuchten Verbindungen zeigen einen großen Einfluß der Benzothiazolringe auf die relative Fluoreszenzquantenausbeute.

1,3-Benzothiazole-6-carboxamidinium chloride dihydrate

The title compound, C(8)H(8)N(3)S(+).Cl(-).2H(2)O, has been synthesized and characterized both spectroscopically and structurally. The structure consists of 1,3-benzothiazole-6-carboxamidinium cations, chloride anions and water molecules, all interconnected by hydrogen bonds into a three-dimensional network. The 1,3-benzothiazole moiety is inclined to the 6-amidine group by 36.71 (9) degrees.

Absorption and Fluorescence Properties of Some Substituted 2‐Furylbenzothiazoles and Their Vinylogues in Various Solvents

Absorption and fluorescence emission spectra of six substituted 2‐(2‐furyl) benzothiazoles and their vinylogues have been studied in different solvents at room temperature. It was found that both the kind of the substituent and the solvent polarity influenced the spectral properties. The ethylenic double bond between the furyl and benzothiazolyl moiety caused a bathochromic shift in the longwave absorption maxima of 1927–3182 cm− 1 as well as a bathochromic shift in the fluorescence maxima of 2646–3338 cm− 1. For substituted 2‐(2‐furyl)benzothiazoles a linear relationship between solvent polarity and Stokes shift was observed. This group of compounds exhibited higher relative fluorescence quantum efficiency than their vinylogues. The most fluorescent compound among them was 2‐(5‐phenyl‐2‐furyl)benzothiazole.

Bis(7-amino-1,3-benzothiazole-κn3)-dichlorozinc(II)

The title complex, [ZnCl(2)(C(7)H(6)N(2)S)(2)], contains a Zn centre with a distorted tetrahedral coordination sphere, involving two Cl(-) ligands and two endocyclic N atoms from the thiazole moiety [Zn-Cl = 2.2284 (7) and 2.2236 (7) A, and Zn-N = 2.081 (2) and 2.041 (2) A]. The interplanar angle between the two ligands is 79.32 (6) degrees. The amino groups participate in intermolecular N-H.Cl hydrogen bonds, with N.Cl distances in the range 3.463 (2)-3.519 (2) A.