Alexander V. Baranovsky

Synthetic cannabinoids as designer drugs: New representatives of indol-3-carboxylates series and indazole-3-carboxylates as novel group of cannabinoids. Identification and analytical data

By means of gas chromatography with mass spectrometry detection (GC-MS), including high resolution mass spectrometry (GC-HRMS) together with ultra-high performance liquid chromatography in combination with high resolution tandem mass spectrometry (UHPLC-HRMS), nuclear magnetic resonance spectroscopy (NMR) and Fourier transform infrared spectroscopy (FT-IR), structure of new synthetic cannabinoids, representatives of indol- and indazole-3-carboxylates groups, used in smoke mixtures, was determined. Obtained analytical data make reliable identification of these compounds in a course of analysis of criminal seizures possible.

Human steroid and oxysterol 7α‐hydroxylase CYP7B1: substrate specificity, azole binding and misfolding of clinically relevant mutants

Oxysterols and neurosteroids are important signaling molecules produced by monooxygenases of the cytochrome P450 family that realize their effect through nuclear receptors. CYP7B1 catalyzes the 6‐ or 7‐hydroxylation of both steroids and oxysterols and thus is involved in the metabolism of neurosteroids and bile acid synthesis, respectively. The dual physiological role of CYP7B1 is evidenced from different diseases, liver failure and progressive neuropathy, caused by enzyme malfunction. Here we present biochemical characterization of CYP7B1 at the molecular level to understand substrate specificity and susceptibility to azole drugs. Based on our experiments with purified enzyme, the requirements for CYP7B1 hydroxylation of steroid molecules are as follows: C5 hydrogen in the α‐configuration (or double bond at C5), a polar group at C17, a hydroxyl group at C3, and the absence of the hydroxyl group at C20–C24 in the C27‐sterol side chain. 21‐hydroxy‐pregnenolone was identified as a new substrate, and overall low activity toward pregnanes could be related to the increased potency of 7‐hydroxy derivatives produced by CYP7B1. Metabolic conversion (deactivation) of oxysterols by CYP7B1 in a reconstituted system proceeds via two sequential hydroxylations. Two mutations that are found in patients with diseases, Gly57Arg and Phe216Ser, result in apo‐P450 (devoid of heme) protein formation. Our CYP7B1 homology model provides a rationale for understanding clinical mutations and relatively broad substrate specificity for steroid hydroxylase.

Synthesis of new biosynthetically important diarylheptanoids and their oxa- and fluoro-analogues by three different strategies

Abstract Wittig, aldol and Wittig-Horner reactions have been used to synthesize new diarylheptanoids, which are putative intermediates in phenylphenalenone biosynthesis in plants. The Wittig-Horner approach was most suitable and gave significantly higher yields in comparison with other methods.

A new ELISA for quantification of brassinosteroids in plants

Starting from (22R,23R)-2α,3α,22,23,26-pentahydroxy-5α-cholestan-6-one 26-hemisuccinate, conjugates of 28-norcastasterone with horse radish peroxidase and bovine serum albumin were prepared. The latter conjugate was injected into rabbits; produced polyclonal antibodies were used to quantitate 6-keto-brassinosteroids. The newly developed analytical system was used in combination with two other immunoenzymatic assays for brassinosteroids to determine individual compounds of this series. In addition, a direct method of brassinosteroid analysis was proposed. It has the advantage of requiring no sample pretreatment steps such as extraction with organic solvents and chromatography.

Enantioselective synthesis of cadinanes starting from R-(−)- or S-(+)-carvone

A new enantioselective synthesis of cadinanes, using the Mukaiyama-Michael reaction, was developed starting from R-(−)- or S-(+)-carvone. This approach gives an easy and direct access to the cadinane skeleton and the scope proved to be complementary to a formylation-annelation sequence. The applicability of the method was demonstrated by the enantioselective synthesis of 1,9-cadinadien-3-one and 4-methoxy-1,9-cadinadien-3-one.

Diels–Alder reaction of androsta-14,16-dien-17-yl acetates with nitroethylene: Product distribution and selected adduct transformations

The Diels-Alder cycloaddition of nitroethylene to some androsta-14,16-dien-17-yl acetates has been studied. The addition occurs stereoselectively, giving predominantly head-to-head-adduct. 14β-Cyanomethyl steroids were obtained via the reductive cleavage reaction of bridged nitro compounds. The structures of the new compounds have been fully characterized by 2D NMR and tandem mass-spectrometry methods.

Synthesis and in vitro cytostatic activity of 1,2- and 1,3-diacylglycerophosphates of clofarabine.

The conjugates of anticancer nucleoside clofarabine [2-chloro-9-(2-deoxy-2-fluoro-β-d-arabinofuranosyl)adenine] with 1,2- and 1,3-diacylglycerophosphates have been prepared by the phosphoramidite method using a combination of 1,1,3,3-tetraisopropyldisiloxane-1,3-diyl protecting group for the sugar moiety of the nucleoside and 2-cyanoethyl protection for the phosphate fragment. Some of the synthesized conjugates exhibited cytostatic activity against HL-60, A-549, MCF-7, and HeLa tumor cell lines.

The synthesis of 2α,3α-isopropylidenedioxy-6,6-ethylenedioxy-5α-androst-15-en-17-one and its 2β,3β-isomer

Androstane and Δ15-androstane analogues of brassinosteroids were synthesized from dehydroepiandrosterone. The key stage, hydroxylation of 17β-acetoxyandrost-2-en-6-one double bond with OsO4, yielded the corresponding 2α,3α-and 2β,3β-diols. The target 2α,3α-isopropylidenedioxy-6,6-ethylenedioxy-5α-androst-15-en-17-one and its 2β,3β-isomer were obtained by dehydrosilylation of the corresponding silylenol ethers with palladium acetate.

Synthesis of novel lupane triterpenoid-indazolone hybrids with oxime ester linkage.

Graphical abstract Figure. No Caption available. HighlightsNovel lupane triterpenoid‐indazolone hybrids with oxime linkage are obtained.This is the first report on oxime esters derived from betulonic and betulinic acid at their C(28).X‐ray structure of the hybrid molecule is reported.Purification procedure for betulonic acid via its cyclohexylammonium salt is developed. Abstract An efficient protocol for the synthesis of novel lupane triterpenoid‐indazolone hybrids with oxime ester linkage has been developed from naturally accessible precursor betulin. For the first time a series of betulonic acid‐indazolone hybrids have been synthesized via an acylation of corresponding 6,7‐dihydro‐1H‐indazol‐4(5H)‐one oximes with betulonic acid chloride. Diastereoselective reduction of the obtained betulonic acid conjugates with NaBH4 resulted in a formation of betulinic acid‐indazolone hybrids in excellent yields. The configuration of the key compounds has been fully established by X‐ray and 2D NMR analysis.

Synthesis of fluorine-containing 6,7-dihydrobenzisoxazolones from 2-(fluorobenzoyl)cyclohexane-1,3-diones and their methyl enol ethers

Regioisomeric fluorine-containing 6,7-dihydro-1,2-benzisoxazol-4(5Н)-ones and 6,7-dihydro-2,1-benzisoxazol-4(5Н)-ones were prepared by reactions of 2-(fluorobenzoyl)cyclohexane-1,3-diones or their methyl enol ethers with hydroxylamine.