Low-symmetry A3B-type 6H-1,4-diazepinoporphyrazines with anti-Kasha effect as promising photosensitizers.

A series of tribenzo[g,l,q]-6H-1,4-diazepino[2,3-b]porphyrazines has been synthesized. A temperature-dependent steric effect was applied in the mixed Linstead macrocyclization of phthalonitrile and 5,7-bis(2'-arylethenyl)-6-propyl-6H-1,4-diazepine-2,3-dicarbonitrile to achieve high yield of low-symmetry A3B-type Mg(II) tribenzo[g,l,q]-6H-1,4-diazepino[2,3-b]porphyrazinate. The analysis of photophysical and photochemical properties of the obtained complexes showed the anti-Kasha effect: the ultrafast spin changes successfully compete with the IC. TD-DFT calculations showed that the presence of 1,4-diazepine heterocycle in the porphyrazine structure leads to the formation of additional charge-transfer triplet state T2. We propose, it could participate in the pumping of T1x state alongside with T1y state (these states are degenerate in D4h symmetry) and, therefore, increase singlet oxygen (1Δg) generation. Stable micellar nanoparticles have been obtained based on the tribenzo[g,l,q]-6H-1,4-diazepino[2,3-b]porphyrazine Mg(II) and Zn(II) complexes using polyvinylpyrrolidone. The nanoparticles effectively interact with model biological structures (FBS and brain homogenate), leading to disaggregation of the macrocycles. They also exhibit pronounced phototoxic effects in MCF-7 cells upon red light irradiation. We propose that enhancement in PDT activity could be explained by their increased resistance to aggregation due to the presence of n-propyl substituent directly attached to the C6 position of the 1,4-diazepine moiety. The demonstrated results show the promising potential of tribenzo-6H-1,4-diazepinoporphyrazines as heavy atom-free photosensitizers.

New Spirocyclic Hydroxamic Acids as Effective Antiproliferative Agents.

AIMS: The main goal of this work is to synthesize new original spirocyclic hydroxamic acids, investigate their cytotoxicity against the panel of tumor cell lines and possible mechanism of action of these active compounds. BACKGROUND: Hydroxamic acids are one of the promising classes of chemical compounds with proven potential anticancer properties. This is manifested in the presence of metal chelating and antioxidant activities, the ability to inhibit histone deacetylase enzymes and a chemosensitizing effect against well known cytostatics. OBJECTIVE: Original spirocyclic hydroxamic acids were synthesized and spectra of their antiproliferative activities were investigated. METHODS: The cytotoxic activities on different tumor lines (SH-SY5Y, HeLa and healthy cells HEK-293) were investigated and determined possible underlying mechanisms of their activity. RESULTS: New original spirocyclic hydroxamic acids were synthesized. These compounds exhibit antiproliferative properties against various tumor cultures cells and also exhibit antioxidant activity, a depolarizing effect on the mitochondrial membrane, inhibit the activity of the histone deacetylase enzyme, and also decrease of basal glycolysis and glycolytic capacity reserve of HeLa and SH-SY5Y tumor cell lines. CONCLUSION: The most promising are compounds 5j-l containing two chlorine atoms as substituents in the quinazoline part of the molecule and hydroxamate function. Therefore, these compounds can be considered as hit compounds for the development on their basis multi-target anticancer agents.

Synthesis and Cytotoxic Activity of Azine Derivatives of 6-Hydroxyxanthanodiene.

BACKGROUND: The conjugates of the sesquiterpene lactone of the eremophilane series of 6- hydroxyxanthanodiene with hydrogenated azines (piperidines and piperazines) have been synthesized and identified by NMR spectrometer. OBJECTIVE: A lactone with an unusual skeleton "6-hydroxyxanthanodiene" was extracted from the plant Elecampane (Inula helenium L) and identified various species with NMR spectrometer. METHODS: The cytotoxic, mitochondrial, and antioxidant activities on different tumor lines such as A549, HCT116, RD and Jurkat were investigated and determined possible mechanisms. RESULTS: The results showed that the most potent compound was IIIi exhibiting highest cytotoxicity against RD cells (IC50 25.23 ± 0.04 µM), depolarized the mitochondrial membrane and was an effective antioxidant (IC50 inhibition of LP 10.68 ± 3.21 µM) without any toxic side effect on healthy cells. CONCLUSION: The conjugates of sesquiterpene lactone 6-hydroxyxanthanodiene III and hydrogenated azines may help to design potential promising anticancer drugs.

A Novel Heterocyclic System Based on Natural Epoxyalantolactone.

Natural sesquiterpene lactones which contain an exocyclic methylene group in the ß-position of the lactone ring react readily with N-nucleophiles. When studying the reaction of the natural epoxyalantolactone with the primary amines we demonstrate the formation of a new heterocyclic system-the hydrogenated benzo[g]furo[4,3,2-cd]indol-3(1H)-one. Spectral data on the characteristics of the synthesized compounds are presented. The data on the reaction mechanisms and its applicability for the preparation are discussed.

The influence of substituents on the reactivity and cytotoxicity of imidazothiazolotriazinones.

A series of tetrahydroimidazo[4,5-e]thiazolo[3,2-b]-1,2,4-triazine-2,7(1H, 6H)-diones were synthesized via the reaction of imidazotriazinethiones and bromoacetic acid followed by condensation with isatins. Amidine skeletal rearrangement of 3,3a,9,9a-tetrahydroimidazo[4,5-e]thiazolo[3,2-b]-1,2,4-triazine-2,7 (1H, 6H)-diones into 1,3a,4,9a-tetrahydroimidazo[4,5-e]thiazolo[2,3-c]-1,2,4-triazine-2,8 (3H, 7H)-diones under KOH treatment has been studied. The influence of substituents at positions 1,3,3a,6,9a of imidazothiazolotriazine on the ability to undergo rearrangement was analyzed based on experimental data and theoretical calculations. Both imidazothiazolo[3,2-b]triazines and their rearrangement products were evaluated for their cytotoxic activity against rhabdomyosarcoma, A549, HCT116 and MCF7 human cancer cell lines by MTT assay. Among the derivatives, 1,3-diethyl-6-[1-(2-propyl)-2-oxoindolin-3-ylidene]-3,3a,9,9a-tetrahydroimidazo [4,5-e]thiazolo[3,2-b]-1,2,4-triazine-2,7(1H, 6H)-dione 4i was found to have the highest antiproliferative activity toward the tested cell lines (4i: [Formula: see text], 2.29, 0.47 and [Formula: see text], respectively). The [Formula: see text] value of compound 4i against normal human embryonic kidney cells HEK293 was [Formula: see text], which appeared to be 6-41-fold higher than [Formula: see text] values of 4i against human cancer cells.

Synthesis and biological evaluation of new substituted thioglycolurils, their analogues and derivatives.

A novel series of substituted N-aminothioglycolurils was synthesized by tandem hydrazone formation - ring contraction reaction of 3-thioxoperhydroimidazo[4,5-e]-1,2,4-triazin-6-ones with (E)-3-phenyl(furan-2-yl)acrylaldehyde derivatives. S-Alkyl substituted N-aminothioglycolurils were prepared through alkylation of corresponding thioglycolurils with iodoalkane or 4-chlorobenzylchloride. Methylthio group in S-methyl derivatives can be substituted with hydroxyl group in acid medium to give N-aminoglycolurils. Representative compounds were evaluated for their cytotoxic activity against RD, A549, HCT116 and MCF7 human cancer cell lines by MTT-assay and screened for their antifungal activity against phytopathogenic fungi using the mycelium growth inhibition method in vitro. Among the derivatives, 4-((E)-((E)-3-(2-Methoxyphenyl)allylidene)amino)-3-methyl-1-phenylthioglycoluril 8i was found to have the highest antiproliferative activity toward the RD and HCT116 cell lines (8i: IC50 = 0.02 and 0.012 µM, respectively), which exceeded cytotoxicity of reference drugs. 1,3-Diethyl-4-((E)-((E)-3-(2-methoxyphenyl)allylidene)amino)thioglycoluril 8l showed the most marked activity toward A549 cells (8l: IC50 = 0.61 µM) compared to reference drugs. The IC50 values of thioglycolurils 8i,l against normal human embryonic kidney cells HEK293 were 0.23 and 86.11 µM, respectively, exceeding the IC50 values of this compound toward the RD, HCT116 (8i) and A549 cells (8l) by one-two orders of magnitude. Experiments with annexin showed that compounds 8b,i,l induced apoptosis in Jurkat cells (acute T cell leukemia). Alkylthioderivatives 12a,13a displayed the strongest antifungal action against R. solani, F. oxysporum, and F. moniliforme exceeding those of triadimefon.