UV-vis absorption spectra of 1,4-dialkoxy-2,5-bis[2-(thien-2-yl)ethenyl]benzenes.

Complex theoretical and experimental studies and quantum-chemical calculations were applied to study the UV-vis spectroscopic features of the novel compounds: three stereoisomers of 1,4-diethoxy-2,5-bis[2-(5-methylthien-2-yl)ethenyl]benzene (A-C) and E,E isomer of 1,4-diisopropoxy-2,5-bis[2-(thien-2-yl)ethenyl]benzene (D). These structures are the derivatives of 2,5-bis[2-(thien-2-yl)ethenyl]benzene, and belong to a group of thienyl-PPV family that are able to polymerize due to the presence of pi-conjugated bonding system. It was established that such compounds during electropolymerization are strongly dependent on their stereochemistry and on the eventual presence of substituents in alpha-positions of the tiophene ring. We have obtained a good agreement between the theoretically simulated optical within a framework of TDDFT approach and experimentally measured data. Influence of PMMA polymer matrices on the UV-vis spectra is explored. It is shown that a red wavelength spectral shift is observed only for D compounds and agreement between calculated and experimental spectral data is sufficiently good. This may indicate on different influence of local polymer matrix field on the spectral behaviors of the chromophores with different stereochemistry.

Multinuclear magnetic resonance and theoretical calculations in the study of structure and tautomerism of some 2-amino-N'-(aryl)-benzamidines.

1H, 13C and 15N NMR spectra of eight 2-amino-N'-(aryl)-benzamidines and of the parent compound were recorded, and unequivocal chemical shift assignments through the use of COSY, 1H-J resolved, HETCOR and COLOC sequences were performed. 1H and 13C chemical shifts for the nuclei of the benzamidine aromatic ring were not affected by the substituents present at N'-phenyl group, while the substituent effects in the chemical shifts of the same nuclei of N'-phenyl ring were very similar to the ones reported for the corresponding monosubstituted benzenes, indicating that there is no interaction between the two aromatic rings. 15N NMR spectra (DEPT sequence) show just two hydrogenated nitrogen atoms, which confirm that the amino form is the most stable tautomer, but the observation of a sharp signal and two broad signals (15N decoupled spectra), and the corresponding broad signal for the =C-NH(2) protons (in the 1H spectra), indicates the occurrence of tautomerism between the amino and imino forms, observable for some of the studied benzamidines. Theoretical calculations lead to the conclusion that these compounds occur mostly as the amino tautomer with Z configuration, which is stabilized by hydrogen bonding.

Two 1-substituted 4-nitroimidazoles.

Crystalline 4-nitro-1-phenylimidazole, C9H7N3O2, (I), and 4'-nitro-1-phenyl-4,1'-biiimidazole, C12H9N5O2, (II), contain C-H...O and C-H...N hydrogen bonds, connecting the molecules into infinite chains. The aromatic fragments in both compounds are nearly planar. The dihedral angles between the benzene and imidazole rings are 26.78 (5) degrees in (I) and 29.36 (8) degrees in (II).

Nitroimidazoles, XIV: Synthesis of 4-nitroimidazoles with 1-substituents containing acid, ester or phenol functions, and radiosensitizing efficiency of some of these compounds.

1,4-Dinitroimidazole and 1,4-dinitro-2-methylimidazole were reacted with aminocarboxylic acids and their esters, aminosulfonic acids, and aminophenol to obtain the corresponding 1-substituted-4-nitroimidazoles. The radiosensitizing efficiency of some esters of 2-(4-nitro-1-imidazolyl)alkanecarboxylic acids was tested.

Mutagenic and clastogenic activity of the chloro-nitroimidazole radiosensitizer P40 in vitro and in vivo.

The hypoxic radiosensitizer 1-(2-hydroxy-3-methoxypropyl)-2-chloro-4-nitroimidazole [P40] was investigated for its mutagenic activity in bacterial Ames test as well as for genotoxic activity in micronucleus assay in vivo. This nitroimidazole showed the weak mutagenicity towards TA100 strain (base pair substitution) and towards TA98 strain (frameshift) only in the highest concentration. P40 induced also a significant increase in the frequency of micronucleated polychromatic erythrocytes (PCEs) at the doses of 0.6 mg/g and 1.2 mg/g. The maximum time response was at 48 h. The decrease of percentage of PCEs suggested the possible cytotoxicity on bone marrow cells after treatment with P40. Positive results in this battery short-term tests provide evidence of clastogenic activity of P40.

Synthesis of 3'-(4-nitroimidazol-1-yl)-2',3'-dideoxynucleosides of pyrimidine analogues and their biological evaluation against HIV.

Reaction of 1,5-di-O-acetyl-2,3-dideoxy-3-phthalimido-beta-D-erythro-pento-fur anose (1) with silylated pyrimidinediones 2a-c using the Lewis acid trimethylsilyl triflate as catalyst afforded nucleosides 3a-c and 4a,c which were deprotected with 33% methylamine/ethanol to give the corresponding 3-aminonucleosides 5a-c and 6. These were reacted with 1,4-dinitroimidazoles 7a,b to give the 3-imidazolyldideoxynucleosides 8a,b and 9a-f. At sub-toxic concentrations these compounds were ineffective against HIV-1.

Radiosensitization of the rats' rhabdomyosarcoma R 1 by chloronitroimidazole compound--P40 dependent on radiation dose in fractionated radiotherapy.

The radiosensitizing effectiveness of 1-(2-hydroxy-3-methoxy-propyl)-2-chloro-4-nitroimidazole (P40) dependent on various fractionated schedules was tested in the rat solid tumor, rhabdomyosarcoma R 1. P40 combined conventional fractionation of gamma rays exerted no radiosensitizing effect measured as local control and growth delay as well. In contrary, the significant sensitization has been noticed when nontoxic doses of the nitroimidazole were combined with higher (3.7 Gy) doses of radiation. Low toxicity of P40 is encouraging for further experimental studies.

Chloronitroimidazoles as radiosensitizers of hypoxic cells in vitro.

Some results of the first more complex studies in vitro on radio-sensitizing efficiency, cytotoxicity and reactivity with blood-thiols of a series of 4- or 5-nitroimidazoles substituted in the 5, 4 or 2 position with chlorine are presented. The derivatives of 4-nitroimidazole substituted in 5 position ("ortho" position) with Cl show higher radiosensitizing efficiency than one may expect from their reduction potential, E1/2. At the same time they are extremely toxic, especially for aerobic cells. It is considered that high biological activity of ortho-substituted 4-nitroimidazoles is connected with their considerable chemical reactivity towards thiols and suppression of those natural protective compounds in the cells. The corresponding 5-nitro isomers are about tenfold weaker sensitizers, and simultaneously much less cytotoxic, either in aerobic or in hypoxic conditions. The chloro-4(5)-nitroimidazoles nonsubstituted at N-1 and ionizable in aqueous solution are relatively weaker at the same time less toxic radiosensitizers. It is evaluated that potential application in radiotherapy may have those chloronitroimidazoles which show low aerobic cytotoxicity, moderate radiosensitizing ability and no reactivity towards thiols. On the basis of the study in vitro, we have selected such a compound: 1-methyl-2-chloro-4-nitroimidazole (P13) for screening in vivo.

2-Chloro-4-nitroimidazole radiosensitizers of hypoxic tumor cells in vivo.

The transplantable rhabdomyosarcoma in WAG/Rij rats was used to test the in vivo effectiveness of 1-methyl-2-chloro-4-nitroimidazole (P13) and its analog 1-(2-hydroxy-3-methoxy-propyl)-2-chloro-4-nitroimidazole (P40) as tumor-cell radiosensitizers after their i.p. administration at low doses. The results indicate that both compounds administered repeatedly at nontoxic concentrations (70-150 mg/kg body wt.) in combination with moderate fractional doses of irradiation (3.7 Gy) enhance the radiation effect on tumors. The local control of tumors on the 210th day in all experimental groups has been higher than in the control ones. In the case of P40 administered in the maximal dose, the increment in local control is statistically significant (p less than 0.05). The regrowth delay has also been longer after treatment with radiosensitizers. In the course of treatment we did not observe any symptoms of neurotoxicity of the compounds. The mean body weight of rats during the administration of compounds remained on the level of control rats whose tumors were irradiated only.

Radiosensitizing ability and cytotoxicity of some 5(4)-substituted 2-methyl-4(5)-nitroimidazoles.

Radiosensitizing efficiency and cytotoxicity of three 2-methyl-4(5)-nitroimidazoles substituted with electron-withdrawal groups -NO2, -Cl and -OCH3 in 5(4)-position ("ortho" position) have been evaluated in vitro on V 79-379 A cells under aerobic as well as under hypoxic conditions. It has been established that 2-h incubation of cells at 37 degrees C in the presence of increasing (up to 2 mM) concentration of the compounds causes a moderate cytotoxicity for P7(2-methyl-5(4)-chloro-4(5)-nitroimidazole) and P5(2-methyl-4,5-dinitroimidazole). Cytotoxicities of these compounds are much stronger under hypoxic than under aerobic conditions. The compound P9(2-methyl-5(4)-methoxy-4(5)-nitroimidazole) is practically completely nontoxic. The radiosensitizing efficiency of P5, P7, and P9 at 2 mM concentration expressed by ER (enhancement ratio) equals 1.75, 1.57 and 1.14 respectively. A discussion regarding the features of electron-affinity, cytotoxicity and radiosensitizing ability of the compounds studied is presented.

Response of the solid Guerin epitheliomas of rats to fractionated irradiation and a new 4-nitroimidazole.

The transplantable Guerin epithelioma in Wistar rats was used to test the in vivo effectiveness of 1-(2-hydroxy-3-methoxypropyl)-2-methyl-4-nitroimidazole (P1) as a tumour-cell radiosensitizer after its oral administration at relatively low doses. The radiosensitizing ability of P1 was compared with that of metronidazole. The results indicate that P1 is less toxic than metronidazole, and greater concentrations of P1 in blood and tumour tissues are obtained for the same administered dose of the compounds. The radiosensitizing ability of P1, determined from tumour-regression rates and local-control percentage at 130 days, was higher than that of metronidazole.