ANTITUMOR ACTIVITY OF SOME DERIVATIVES OF INDOLO[2,3-A]CARBAZOLES N-GLYCOSIDES WITH XYLOSE CARBOHYDRATE RESIDUE

Introduction. The search for new antineoplastic agents in a series of indolo[2,3-a]-carbazole derivatives is an urgent and promising direction, since compounds with antitumor activity have been found in this class. In the chemical fusion laboratory, N.N. Blokhin National Medical Research Center оf the Ministry of Health of Russia has developed an original and effective method for the synthesis of glycosides of indolo[2,3-a]-pyrrolo[3,4-c]carbazoles, which makes it possible to synthesize derivatives of N-glycosides of indolo[2,3-a]carbazoles with different substituents in the heterocyclic parts including at the maleimide nitrogen atom and with different carbohydrate residues.The purpose of the study – the primary assessment of the antitumor activity of new derivatives of indolocarbazoles with a carbohydrate residue xylose in models of tumor growth mice.Materials and methods. The compounds studied at transplanted tumors of mice: the Lewis epidermoid carcinoma (LLC), colon cancer ACATOL, cervical cancer RSHM-5, breast adenocarcinoma CA-755. Studies were performed on immunocompetent mice: males and females of BDF1 hybrids (C57Bl/6 × DBA/2), females CBA/Lac and Balb/c. Compound solutions were prepared ex tempore and administered to the mice intraperitoneally at a dose of 60 mg/kg daily for five days. The antitumor effect was evaluated as to of tumor growth inhibition and increase of life span of the treated animals as compared with the control ones.Results. Eight compounds studied, containing D-xylose as a carbohydrate component and various substituents at the maleimide nitrogen atom, showed different degrees of antitumor activity. Two derivatives have been identified: N-[5,7-dioxo-12-(β-D-xylopyranosyl)-indole[2,3-a]pyrrolo[3,4-c]carbazol-6-il]benzamide (compound 4) and N-[5,7-dioxo-12-(β-D-xylopyranosyl)-5,7,12,13-tetrahydro-6H-indole[2,3-a]pyrrolo[3,4-c]carbazole-6-il]pyridin-2-carboxamide (compound 8), which showed high antitumor activity on 4 solid tumors of mice with a duration of effect of 12 days or more. The most pronounced antitumor effect was obtained in compounds 4 and 8 in RSHM-5 and Ca-755, tumor growth inhibition was amounted, respectively: in RSHM-5 – 68–82 % and 80–72 %; for Ca-755 – 57–62 % and 86–68 % (p <0.05).Conclusion. For further research, we chose the compound (N-[5,7-dioxo-12-(β-D-xilopiranosil)-5,7,12,13-tetrahydro-6H-indole[2,3-a] pyrrolo[3,4-c]carbazol-6-il]pyridin-2-carboxamide).

Evaluation of fungicidal, bactericidal and anti-tumor activities of lactones of medium and large sizes of cycles obtained from levoglucosenone

Medium and large lactones attract the attention of chemists by the uniqueness of their structure, versatile biological activity and limited availability. Among the secondary metabolites of this group, β-lactones are more common, then γ- and δ-lactones, classical and non-classical macrolides, polyene antibiotics, spiro-macrolides and macrolactones. On the basis of many lactones, important preparations of the most diverse pharmacological action have been obtained. Earlier, we proposed a 3-stage scheme for the synthesis of chiral lactones of medium and large size based on levoglucosenone. The lactones obtained according to this scheme contain the carbohydrate residue annelated at the ,γ -positions relative to the hydroxy group. To study the structure-activity relationship, it is necessary to establish the biological role of this carbohydrate residue in reference lactones. For this purpose, a number of lactones were obtained on the basis of levoglucosenone and their in vitro bioscreening of antifungal, antimicrobial, and antitumor activity was performed. It was found that the methyl substituent in the ω-position in the lactone and the benzene ring annulated with the lactone cycle exhibit a slight fungistatic activity towards the fungi: Bipolaris sorokiniana, Fusarium oxysporum, Rhizoctonia solani. Macrocyclic lactone and lactone annelated benzene ring showed weak cytotoxic properties against cells of LOX IMVI (melanoma) and A498, UO-31 (kidney cancer).

Programmable Synthesis of 2-Deoxyglycosides

Control of glycoside bond stereochemistry is the central challenge in the synthesis of oligosaccharides. 2-Deoxyglycosides, which lack a C2 substituent to guide stereoselectivity, are among the most difficult classes of glycoside bond constructions. Here we present a method to synthesize 2-deoxysaccharides with specified glycoside bond stereochemistry using a nucleophilic carbohydrate residue and the synthetic equivalent of an alcohol electrophile. Because the configuration of the nucleophile can be precisely controlled, both α- and β-glycosides can be synthesized from the same starting material in nearly all cases examined. Stereoselectivities in these reactions are often greater than 50:1 and yields typically exceed 70%. This strategy is amenable to the stereocontrolled syntheses of trisaccharide diastereomers, and a tetrasaccharide. Our method offers a fundamentally new approach to O-glycoside synthesis to enable downstream biochemical and natural product applications.

Programmable Synthesis of 2-Deoxyglycosides

Control of glycoside bond stereochemistry is the central challenge in the synthesis of oligosaccharides. 2-Deoxyglycosides, which lack a C2 substituent to guide stereoselectivity, are among the most difficult classes of glycoside bond constructions. Here we present a method to synthesize 2-deoxysaccharides with specified glycoside bond stereochemistry using a nucleophilic carbohydrate residue and the synthetic equivalent of an alcohol electrophile. Because the configuration of the nucleophile can be precisely controlled, both α- and β-glycosides can be synthesized from the same starting material in nearly all cases examined. Stereoselectivities in these reactions are often greater than 50:1 and yields typically exceed 70%. This strategy is amenable to the stereocontrolled syntheses of trisaccharide diastereomers, and a tetrasaccharide. Our method offers a fundamentally new approach to O-glycoside synthesis to enable downstream biochemical and natural product applications.

Reductive fractionation of woody biomass into lignin monomers and cellulose by tandem metal triflate and Pd/C catalysis

A catalytic process for the upgrading of woody biomass into mono-aromatics, hemi-cellulose sugars and a solid cellulose-rich carbohydrate residue is presented.

The Effects of Addition of Mononucleotides on Sma nuc Endonuclease Activity

Examination of the effects of mononucleotides on Sma nuc endonuclease originated from Gram negative bacteriumSerratia marcescensdisplayed that any mononucleotide produced by Sma nuc during hydrolysis of DNA or RNA may regulate the enzyme activity affecting the RNase activity without pronounced influence on the activity towards DNA. The type of carbohydrate residue in mononucleotides does not affect the regulation. In contrast, the effects depend on the type of bases in nucleotides. AMP or dAMP was classified as a competitive inhibitor of partial type. GMP, UMP, and CMP were found to be uncompetitive inhibitors that suggest a specific site(s) for the nucleotide(s) binding in Sma nuc endonuclease.