Synthesis and biological activity of hydrazones of 5α-steroids.

Condensation reactions catalyzed by acetic acid of severalarylhydrazine (2,4-dinitrophenyl hydrazine) and hydrazides (hydrazides of bromobenzoic and salicylic acid, benzofuran-2- and indol-2-carboxylicacid) with 3β-acetoxy- and 3β-hydroxy-5α-pregn-16-en-20-one (1 and 2), epiandrosterone (6) and 5α-androst-2-en-17- one (9) were studied for the purpose of synthesizing potentially bioactive 5-steroidal hydrazones. The starting ketones (1,2,6,9) were synthesized on the bases of aglicon of steroidal saponine - tigogenin isolated from plant “Yucca gloriosa” introduced in Georgia. The structures of synthesized new hydrazones (3-5,7,8,10,11) were established by NMR 1H, 13C and mass-spectral data. The antiviral activity some of them (7,8,10,11) were studied

Synthesis of some novel nitrogen-containing 5α-steroids based on tigogenin

A number of nitrogen-containing compounds were obtained using a condensation reaction catalyzed by acetic acid to investigate structure-chemical reactivity and structure-biological activity relationships in the search for potential biologically active steroids within ketones of the 5α-pregnane and 5α-androstane series. Novel steroidal hydrazones were synthesized from 5α-pregnan-3β-ol-20-one and 5α-pregna-9(11),16-dien-3α-ol-20-one, which, in turn, were obtained by a multistep transformation of 3β-acetoxy-5α-pregn-16-en-20-one. All of the starting steroid ketones were synthesized on the basis of a convenient domestic raw material – tigogenin, isolated from the Yucca gloriosa plant introduced in Georgia. Acetic acid catalyzed condensation reaction was carried out in ethanol using various reagents with pharmacophoric features – arylhydrazides, arylhydrazines, hydroxylamine, and semicarbazide. The structure of the newly obtained steroids was confirmed by1 H,13 C NMR, mass spectra and investigation of their biological activity is in process. The cytotoxic and antiviral activity of the previously synthesized steroid oximes, amines and hydrazones was assessed

Synthesis of some 5α-androstano[17,16-d]pyrazoles from tigogenin

Condensation reaction of several arylhydrazines with 16α, 17α-epoxy-5α-pregnan-3β-ol-20-one synthesized from 5α-pregn-16-en-3β-ol-20-one–intermediate product of tigogenin transformation – were studied for the purpose of synthesizing potentially bioactive 5α-androstano [17,16-d] pyrazoles. Despite various conditions (different temperature, in protic and aprotic solvents) of the reaction, a complex mixture was obtained and then separated by column chromatography (eluent-hexane-ethylacetate). Two main products of intermolecular cyclization: 5α-androstano [17,16-d] pyrazole and its hydrogenated analogue – 5α-androstano [17,16-d]pyrazolines were isolated by substitution of electron-donating group (phenylhydrazine, p-methyl-, p-bromophenylhydrazine) at the hydrazine amine atom. In the presence of electron-withdrawing group (p-nitrophenylhydrazine) at the hydrazine amine atom cis-opening product of epoxygroup – 16α-acetoxy-5α-pregnan-3β, 17α-diol-20-one hydrazine – was obtained. The structures of synthesized compounds were established by NMR1H,13C and mass-spectral data. Structures of 3β-hydroxy-1/-phenyl-3/-methyl-5α-androstano [17,16-d] pyrazoles were confirmed by IR, NMR1H,13C, DEPT-135, HMBC and mass-spectral data. Synthesis of 5α-androstano [17,16-d] pyrazolines with 5α-androstano [17,16-d] pyrazoles by condensation reactions in the mentioned conditions was not described previously

Synthesis of New 5α-Steroidal Hydrazones from Tigogenin

In the present study potentially biologically active steroids, new hydrazones, semicarbazones, and 20O-methyloxime have been synthesized from ketones of the 5α-pregnene, 5α-pregnane, and 5αandrostane series. The condensation reaction of ketones – 5α-pregn-16-en-3β-ol-20-one, 5α-pregnan3β-ol-20-one and 5α-androstan-3β-ol-17-one – with various arylhydrazides, semicarbazide, and methoxyamine was carried out in ethanol with a catalytic amount of acetic acid. The starting ketones were made from tigogenin, an aglycone of steroidal saponins that is a domestic raw material for the synthesis of 5α-series steroids. Tigogenin was isolated from the Yucca gloriosa plant, which was introduced in Georgia.1H,13C NMR and mass spectra were used to confirm the structure of the newly obtained steroids. The cytotoxicity of these and previously synthesized hydrazones was investigated in vitro using the Rezazurin reduction test and Hoechst test aginst lung carcinoma (A549), colorectal adenocarcinoma (DLD-1) and normal skin fibroblasts (WS-1) cell lines in comparison to etoposide. The results show that, of all the compounds studied, only p-methyl-and pmethoxybenzoylhydrazone 5α-pregnan-3β-ol-20-one are of particular interest since, unlike the others, they demonstrate activity comparable to etoposide

Ring-opening polymerization of a 2,3-disubstituted oxirane leading to a polyether having a carbonyl-aromatic pi-stacked structure

2-Methoxycarbonyl-3-(3,4-dimethoxyphenyl) oxirane was synthesized and polymerized using a cationic initiator to afford a polymer having a rather stiff, stretched conformation. The side-chain methoxycarbonyl group and 3,4-dimethoxyphenyl group of neighboring monomeric units may form a hetero pi-stacked structure between side-chain carbonyl and aromatic groups which leads to intramolecular charge transfer (ICT) interactions. 2-Ethoxy-carbonyl- 3-phenyloxirane failed in polymerization, leading only to small molecules including cyclic compounds

Synthesis and cytotoxicity of epiandrosterone hydrazones

Two series of hydrazones were synthesized from 3β-hydroxy- and 3β-(1-adamantoate)-5α-androstan-17- one, respectively, to study the structure–activity relationship. Cytotoxicity studies showed that 5α-androstan3β-ol-17-one m-nitrobenzoylhydrazone exhibited pronounced specific activity in a Hoechst experiment against lung carcinoma (A-549) and colorectal adenocarcinoma cell lines (DLD-1)

Stereochemical characterization of methyl trans-3-(3,4-dimethoxyphenyl)glycidate by enantioselective HPLC-CD analysis and TD-DFT calculations

Enantiomerically pure oxiranes are valuable electrophilic, chiral synthons [1] and have been introduced into pharmaceutical applications for the synthesis of biologically active polyethers. Stereochemical characterization plays an important role in medicinal chemistry, since chirality is fundamental in the definition of the activity of several biologically active compounds. Consequently, analytical techniques allowing for the stereochemistry to be fully characterized are receiving increasing attention. The absolute configuration of methyl trans-3-(3,4- dimethoxyphenyl)glycidate (trans-1), a recently synthesized building block for the synthesis of methylated analogues of biologically active polymers from different species of comfrey and bugloss [2], was investigated by means of enantioselective high-performance liquid chromatography hyphenated with a circular dichroism detection system (eHPLC-CD) [3]. A Lux Cellulose-4 and a Lux Cellulose-2 columns were successfully employed for the preparative and analytical enantioresolution of racemic trans-1 [4]. The CD spectra of the enantiomeric fractions of trans-1 were then measured both by off-line analysis after preparative chromatographic separation and by stopped-flow measurements during the eHPLC-CD analysis [3]. This last strategy resulted more reliable, because the risk of degradation of the analyte was drastically reduced. The absolute configuration of each enantiomeric fraction was finally determined by comparison of the experimental CD spectra with quantum mechanical (QM) calculations based on time-dependent density functional theory (TD-DFT). The conformationally-averaged theoretical CD spectrum of (2S,3R)-1 reproduced with a reasonable degree of accuracy the CD spectrum of the first-eluted fraction of trans-1 on the Lux Cellulose-2 column: consequently, a full stereochemical characterization of the enantiomers of trans-1 was achieved and the elution order on Lux Cellulose-2 was determined. [1] H.C. Kolb, M.S. VanNieuwenhze, K.B. Sharpless, Catalytic asymmetric dihydroxylation, Chem. Rev. 94 (1994) 2483\u20132547. [2] V. Barbakadze, L. Gogilashvili, L. Amiranashvili, M. Merlani, K. Mulkijanyan, Novel biologically active phenolic polymers from different species of genera Symphytum and Anchusa (Boraginaceae), J. Chem. Eng. Chem. Res. 1 (2014) 47\u201353. [3] C. Bertucci, D. Tedesco, Advantages of electronic circular dichroism detection for the stereochemical analysis and characterization of drugs and natural products by liquid chromatography, J. Chromatogr. A 1269 (2012) 69\u201381. [4] K. Lomsadze, M. Merlani, V. Barbakadze, T. Farkas, B. Chankvetadze, Enantioseparation of chiral epoxides with polysaccharide-based chiral columns in HPLC, Chromatographia 75 (2012) 839\u2013845

Synthesis and biological activity of steroidal tigogenin hydrazones and pyrazolines

Steroidal hydrazones and pyrazolines were synthesized via condensation of a series of 5α-steroidal ketones with several hydrazines. Their cytotoxic activity against cancer cultures (A549 lung cancer, DLD-1 colorectal cancer, and WS1 normal skin fibroblasts) and antibacterial activity against E. coli and S. aureus strains were studied. The structures of the synthesized compounds were elucidated using PMR, 13C NMR, and mass spectra