Dmitri V. Kazakov

Synthesis, structure, and pharmacological activity of (7r,8s)-epoxy-(13r,17r)-trioxolane abietic acid

The synthesis of (7R,8S)-epoxy-(13R,17R)-trioxolane abietic acid was carried out and its structure was established by X-ray diffraction. The antineoplastic activity and the ability to induce apoptosis that were predicted by a PASS computer system, correlate well with the experimentally found cytotoxic activity towards the MeWo malignant cell line. The results of tests on animals showed that abietic acid and its (7R,8S)-epoxy-(13R,17R)-trioxolane derivative have anti-inflammatory and antiulcer activities in the absence of side effects.

Chemiluminescence from the biomimetic reaction of 1,2,4-trioxolanes and 1,2,4,5-tetroxanes with ferrous ions

The 1,2,4-trioxolane and 1,2,4,5-tetroxane pharmacophores are currently considered as the next generation of synthetic antimalarial drugs. This fact has stimulated the exploration of the chemiluminescence displayed by these cyclic peroxides in biomimetic reactions with Fe(II). The CL has been induced by FeSO4 and/or the FeCl3/L-cysteine/Rhodamine G system in aqueous (50%) acetonitrile. The light emission in the visible spectral region has been recorded for triterpenoid-based 1,2,4-trioxolanes, purely synthetic ozonide OZ03, bicyclic 1,2,4,5-tetroxanes, a tetroxane derived from deoxycholic acid, the diperoxide of trifluoroacetone, as well as the natural artemisinin. The herein discovered CL provides a promising perspective for the study of pharmacologically active peroxides in biomedical applications.

Anomalous ozonolysis product of 3β,28-di-O-acetyl-29-norlupan-20-one-O-methyloxime

Ozonolysis of 3β,28-di-O-acetyl-29-norlupan-20-one-O-methylketoxime in the presence of ketones was used as an example to show that secondary ozonides at the C20 position of betulin are unstable and decompose to form the “anomalous product” methyl-3β,28-di-O-acetyl-29,30-bisnorlupan-20-oate, the structure of which was proved by an x-ray crystal structure analysis.

Singlet-oxygen generation in the catalytic reaction of dioxiranes with nucleophilic anions

Nucleophilic anions such as Cl(-), I(-), Br(-), t-BuO(-), O(2)(-) and OH(-) efficiently catalyze the decomposition of dimethyldioxirane (DMD) and methyl(trifluoromethyl)dioxirane (TFD). Singlet oxygen ((1)O(2)) is formed in these catalytic reactions, as demonstrated by the characteristic infrared chemiluminescence (IR-CL) at 1268 nm. The yield of (1)O(2) generation, measured by the IR-CL method, lies in the range between 2 and 98%, which depends on the particular anion employed. For the bromide ion, the catalytic decomposition of the dioxirane is in competition with the oxidation of Br(-) to elemental bromine.

Ozonolytic transformations of (S)-(−)-limonene

Partial ozonolysis of (S)-(−)-limonene in cyclohexane-methanol yields 1-methyl-4-(prop1-en-2-yl)-7,8,9-trioxabicyclo[4.2.1]nonane as a mixture of diastereoisomers at a ratio of 2: 3. Nitrogen-containing organic compounds (semicarbazide and hydroxylamine hydrochlorides) favor cyclization of intermediate ozonolysisreduction products, whereas the reduction with dimethyl sulfide, NaBH4, and NaBH(OAc)3 follows conventional pattern.

A novel chemiluminescence from the reaction of dioxiranes with alkanes. Proposed mechanism of oxygen-transfer chemiluminescence

Oxidation of adamantane and 2,3-dimethylbutane by methyl(trifluoromethyl)dioxirane is accompanied by chemiluminescence (CL); formation of the emitter of CL, triplet excited trifluoropropanone, is proposed to occur via a concerted oxenoid mechanism of oxygen insertion into C–H bond of the hydrocarbons.

Synthesis of a Triterpenoid with a 1,2,4,5-Tetraoxane Fragment

Acid-catalyzed formation of the peroxyacetal of cyclohexanone bis-hydroperoxide and a triterpene ketone synthesized for the first time 19β,28-epoxy-28-oxo-18α-olean-3-spiro-6′-(1′,2′,4′,5′-tetraoxacyclohexane)-3′-spirocyclohexane, the structure of which was confirmed by NMR spectroscopy and an x-ray crystal structure analysis. 19β,28-Epoxy-28-oxo-18α-olean-1-en-3-one was formed as a side product during oxidative dehydration of 28-oxoallobetulone.

First synthesis of steroidal 1,2,4-trioxolanes

Griesbaum ozonolysis of mixtures of methyl 3-(methoxyimino)-5β-cholan-24-oate with ketones (cyclohexanone, methyl trifluoromethyl ketone, and phenyl trifluoromethyl ketone) afforded for the first time steroidal 1,2,4-trioxolanes which were isolated as mixtures of stereoisomers.

Synthesis and antimalarial activity of 3′-trifluoromethylated 1,2,4-trioxolanes and 1,2,4,5-tetraoxane based on deoxycholic acid

HIGHLIGHTSDeoxycholic acid ozonides were synthesized via the Griesbaum coozonolysis for the first time.Two novel steroidal tetraoxanes were obtained by acid‐catalyzed peroxycondensation.Antimalarial activity was evaluated and potency for related compounds was compared. ABSTRACT A series of new steroidal peroxides – 3′‐trifluoromethylated 1,2,4‐trioxolanes and 1,2,4,5‐tetraoxanes based on deoxycholic acid were prepared via the reactions of the Griesbaum coozonolysis and peroxycondensation, respectively. 1,2,4‐Trioxolanes were synthesized by the interaction of methyl O‐methyl‐3‐oximino‐12&agr;‐acetoxy‐deoxycholate with CF3C(O)CH3 or CF3C(O)Ph and O3 as the mixtures of four possible stereoisomers at ratios of 1:2:2:1 and in yields of 50% and 38%, respectively. The major diastereomer of methyl 12&agr;‐acetoxy‐5&bgr;‐cholan‐24‐oate‐3‐spiro‐5′‐(3′‐methyl‐3′‐trifluoromethyl‐1′,2′,4′‐trioxolane) was isolated via crystallization of a mixture of stereoisomers from hexane and its (3S,3′R)‐configuration was determined using X‐ray crystallographic analysis. Peroxycondensation of methyl 3‐bishydroperoxy‐12&agr;‐acetoxy‐deoxycholate with CF3C(O)CH3 or acetone led to 1,2,4,5‐tetraoxanes in yields of 44% and 37%, respectively. Antimalarial activity of these new steroidal peroxides was evaluated in vitro against the chloroquine‐sensitive (CQS) T96 and chloroquine‐resistant (CQR) K1 strains of Plasmodium falciparum. Deoxycholic acid 3′‐trifluoromethylated 1,2,4,5‐tetraoxane demonstrated a good IC50 value against CQR‐strain (IC50 (K1)=7.6nM) of P. falciparum. Tetraoxane with the acetone subunit demonstrated the best results among all tested peroxides with an IC50 value of 3nM against the CQ‐resistant K1 strain. In general, 1,2,4‐trioxolanes of deoxycholic acid are less active than 1,2,4,5‐tetraoxanes.