Laboratory of Steroid Compounds (N22)

Head: Igor V. Zavarzin, DSc (Chem.) (e-mail: zavilioc.ac.ru, tel.+7(495)792-2656)
 

The laboratory was started on September 28 1962 by Afanasy A. Akhrem, Full Member of Belorussian Acad. Sci. It was headed by Alexei V. Kamernitsky in 1973-2009.

Main research areas

Search for ways to prepare new steroid compounds — bioregulators for use in medicine

For the first time, various synthetic progestins — pentacyclic steroids ("pentarans") were obtained and it was shown that they had high cytotoxic activity against breast cancer cells. In vivo metabolism of two main representatives of pentarans (mecigestone and its 6-desmethyl analogue) was studied by chromatomass spectrometry, and a number of their metabolites were synthesized for the first time. The similarity of metabolic pathways of synthetic pentarans and endogenous progesterone was established. Prototypes of mecigestone dosage forms with increased bioavailability have been developed. Derivatives of progesterone were synthesized, among which two promising ligands of the progesterone membrane receptor were found. A new type of steroidal antiestrogens was prepared, methods for their synthesis from natural raw materials were developed, their biological properties were studied, computer analysis of models of ligand binding to estrogen receptor was performed, structural details, which are responsible for their specific inhibition of the growth of malignant cells of hormone-dependent tumors, were shown, and the most promising compounds were proposed for practical use in medicine.

Selected publications:

1. I. S. Levina, A. K. Nazarov, G. V. Nazarov, L. E. Kulikova,Y. V. Kuznetsov, A. S. Dmitrenok, D. V. Minin, A. V. Aksenov, I. V. Zavarzin. In vivo study on biotransformation of pentacyclic analogs of progesterone:Identification of their metabolites by HPLC-MS method. J. Steroid Biochem. Mol. Biol. 2019, 194, 105436.
2. Yu. V. Kuznetsov, I. S. Levina, A. M. Scherbakov, O. E. Andreeva, I. V. Fedyushkina, A. S. Dmitrenok, A. S. Shashkov, I. V. Zavarzin. New estrogen receptor antagonists. 3,20-Dihydroxy-19-norpregna-1,3,5(10)-trienes: synthesis, molecular modeling, and biological evaluation. Eur. J. Med. Chem. 2018, 143, 670.
3. Yu. V. Kuznetsov, I. S. Levina, A. M. Scherbakov, O. E. Andreeva, A. S. Dmitrenok, O. R. Malyshev, I. V. Zavarzin. 3,20-Dihydroxy-13α-19-norpregna-1,3,5(10)-trienes. Synthesis, structures and cytotoxic, estrogenic, and antiestrogenic effects. Steroids 2018, 137, 1.
4. A. V. Polikarpova, A. A. Maslakova, I. S. Levina, L. E. Kulikova, Y. V. Kuznetsov, A. A. Guseva, T. A. Shchelkunova, I. V. Zavarzin, O. V. Smirnova. Selection of progesterone derivatives specific to membrane progesterone receptors. Biochemistry 2017, 82, 140.
5. A. K. Nazarov, I. V. Zavarzin, G. V. Nazarov, A. V. Aksenov, I. S. Levina. Preparation and bioavailability evaluation of micronized steroidal mecigestone drug substance. Pharm. Chem. J. 2016, 49, 706.

Development of new heterosteroids-based anti-cancer agents

Flexible strategies for the synthesis of heterosteroids have been proposed. Wide libraries of compounds with high antiproliferative activity were synthesized applying them. For the first time, pyridazine, thiadiazole, thiadiazine, spirothiadiazine, triazine, propargylamine, imidate, N-sulfonyltriazole and pyrimidine derivatives of steroids of estran and androstane series were obtained. New classes of estrogen receptor modulators have been discovered. In addition, for the first time, heterosteroids were shown to induce apoptosis of cancer cells by affecting the AR, NF-κB, ERK ½, and PARP signaling pathways.

Selected publications:

1. T. A. Tikhonova, I. V. Rassokhina, E. A. Kondrakhin, M. A. Fedosov, J. V. Bukanova, A. V. Rossokhin, I. N. Sharonova, G. I. Kovalev, I. V. Zavarzina, Y. A.Volkova. Development of 1,3-thiazole analogues of imidazopyridines as potent positive allosteric modulators of GABA_A receptors. Bioorg. Chem. 2020, 94, 103334.
2. T. A. Tikhonova, I. V. Zavarzin, Y. A. Volkova. Synthesis of Dibenzo[d,f][1,3]Diazepines via Elemental Sulfur-Mediated Cyclocondensation of 2,2′-Biphenyldiamines with 2-Chloroacetic Acid Derivatives.J. Org. Chem. 2019, 84, 24, 15817.
3. Y. A. Volkova, A. S. Kozlov, M. K. Kolokolova, D. Y. Uvarova, S. A. Gorbatov, O. E. Andreeva, A. M. Scherbakov, I. V. Zavarzin. Steroidal N-Sulfonylimidates: Synthesis and biological evaluation in breast cancer cells. Eur. J. Med. Chem. 2019, 179, 694.
4. M. Kozlov, A. Kozlov, A. Komkov, K. Lyssenko, I. Zavarzin, Y. Volkova. Synthesis of Phosphoryl Thioamides via Three-Component Reaction of Phosphinic Chlorides with Amines and Sulfur. Adv. Synth. Catal. 2019, 361, 12, 2904.
5. M. Kozlov, A. Komkov, T. Losev, A. Tyurin, A. Dmitrenok, I. Zavarzin, Y. Volkova*. Flexible Synthesis of Phosphoryl-Substituted Imidazolines, Tetrahydropyrimidines and Thioamides by Sulfur-Mediated Processes. J. Org. Chem. 2019, 84, 18, 11533.
6. A. S. Komendantova, A. M. Scherbakov, A. V. Komkov, V. V. Chertkova, A. O. Gudovanniy, E. I. Chernoburova, D. V. Sorokin, Y. U. Dzichenka, V. Z. Shirinian, Y. A. Volkova, I. V.Zavarzin. Novel steroidal 1,3,4-thiadiazines: Synthesis and biological evaluation in androgen receptor-positive prostate cancer 22Rv1 cells. Bioorg. Chem.2019, 91, 103142.
7. A. M. Scherbakov, A. V. Komkov, A. S. Komendantova, M. A. Yastrebova, O. E. Andreeva, V. Z. Shirinian, A. Hajra, I. V. Zavarzin, Y. A. Volkova. Steroidal Pyrimidines and Dihydrotriazines as Novel Classes of Anticancer Agents against Hormone-Dependent Breast Cancer Cells. Frontiers in Pharmacology 2018, 8, 979.
8. M. Scherbakov, I. V. Zavarzin, S. K. Vorontsovа, A. Hajra, O. E. Andreeva, A. V. Yadykov, I. S. Levina, Y. A. Volkova, V. Z. Shirinian. Synthesis and evaluation of the antiproliferative activity of benzylidenes of 16-dehydroprogesterone series. Steroids 2018, 138, 91.
9. V. Rassokhina, T. A. Tikhonova, S. G. Kobylskoy, I. Yu. Babkin, V. Z. Shirinian, V. Gevorgyan, I. V. Zavarzin, Y. A. Volkova. Synthesis of Imidazo[2,1-b]thiazoles via Copper-Catalyzed A³-Coupling in Batch and Continuous Flow. J. Org. Chem. 2017, 9682.
10. A. S. Komendantova, A. V. Komkov, Y. A. Volkova, Igor V. Zavarzin. Efficient Synthesis of 4- and 5-Substituted 2-Aminopyrimidines by Coupling of β-Chlorovinyl Aldehydes and Guanidines. Eur. J. Org. Chem.2017, 29, 4260.
11. I. V. Rassokhina, Y. A. Volkova, A. S. Kozlov, A. M. Scherbakov, O. E. Andreeva, V. Z. Shirinian, I. V. Zavarzin. Synthesis and antiproliferative activity evaluation of steroidal imidazo[1,2-a]pyridines, Steroids 2016, 113, 29.
12. Y. A. Volkova, Y. S. Antonov, A. V. Komkov, A. M. Scherbakov, A. S. Shashkov, L. G. Menchikov, E. I. Chernoburova, I. V. Zavarzin. Access to steroidal pyridazines via modified thiohydrazides. RSC Adv. 2016, 6, 42863.
13. I.V. Rassokhina, V.Z. Shirinian, I.V. Zavarzin, V. Gevorgyan, Y.A. Volkova. Copper(II)-Mediated Aerobic Synthesis of Imidazo[1,2-a]pyridines via Cascade Aminomethylation/Cycloisomerization of Alkynes. J. Org. Chem. 2015, 80 (21), 11212.
14. A.V. Komkov, A.S. Komendantova, L.G. Menchikov, E.I. Chernoburova, Y.A. Volkova, I.V. Zavarzin. A Straightforward Approach toward Multifunctionalized Pyridazines via Imination/Electrocyclization. Org. Lett. 2015, 17, 3734.

Synthesis of new highly effective antiparasitic avermectin B₁-based agents for veterinary science and medicine

Methods for the synthesis of avermectin B₁ derivatives have been developed and a number of compounds possessing potential antiparasitic activity have been obtained. It was shown that the effectiveness of new agents at minimum concentrations was 10–25% higher than that of known analogues. The resulting compounds are low toxic and non-resistant.

Patents

1. RU № 2554074. Zavarzin I.V., Dzhafarov M. Kh., Chernoburova E.I. “Antiparasitic agent”.
2. RU № 2554350. Zavarzin I.V., Dzhafarov M. Kh., Chernoburova E.I. “Insecticidal agent”.
3. RU № 2670107. Dzhafarov M. Kh., Mirzaev M.N., Vasilevich F.I., Zavarzin I.V., Shchetinina M.A., Chernoburova E.I. “Amides of avermectin B₁ 5-O-hemisuccinate, method for their preparation and antiparasitic agents based on them”
4. RU № 2670092. Dzhafarov M. Kh., Mirzaev M.N., Vasilevich F.I., Zavarzin I.V., Shchetinina M.A., Chernoburova E.I. “Ethyl ester of avermectin B₁ 5-O-succinate, method for its preparation and antiparasitic agents based on it”
5. RU №2670202. Dzhafarov M. Kh., Mirzaev M.N., Vasilevich F.I., Zavarzin I.V., Schetinina M.A., Chernoburova E.I. “5,4''-Bis[(aryl/alkyl)amino](thioxo) ivermectin acetates, method for their preparation and antiparasitic agents based on them”
6. RU№2627277. Blinnikov A.N., Dzhafarov M. Kh., Mirzaev M.N., Zavarzin I.V., Chernoburova E.I. “4'' -O,5-O-di (methyl carbamate) of ivermectin, method for its preparation and antiparasitic agent based on it"
7. RU№2629600. Dzhafarov M. Kh., Mirzaev M.N., Vasilevich F.I., Zavarzin I.V., Schetinina M.A., Chernoburova E.I. “5,4''-Bis[(aryl/alkyl)amino](thioxo) ivermectin acetates, method for their preparation and antiparasitic agents based on them”

Selected publications

1. M. A. Shchetinina, E. I. Chernoburova, А. V. Lyubeshkin, M. Kh. Dzhafarov, F. I. Vasilevich, I. V. Zavarzin. Avermectin B₁ 5-О-mono and 4´´,5-О,O-bis-derivatization with ethyl succinoyl moiety. Russ. Chem. Bull. 2019, 68, 3, 644.
2. M. A. Shchetinina, E. I. Chernoburova, N. G. Kolotyrkina, M. Kh. Dzhafarov, F. I. Vasilevich, I. V. Zavarzin. Synthesis of succinic monoamide avermectin esters, Russ. Chem. Bull. 2019,68, 1116.
3. M. A. Shchetinina, E. I. Chernoburova, N. G. Kolotyrkina, M. Kh. Dzhafarov, F. I. Vasilevich, I. V. Zavarzin. Synthesis of sodium 5-sulfate-ivermectin and disodium 4´´,5-disulfate-ivermectin. Russ. Chem. Bull. 2018, 67, 836.

Synthesis of hetaryl steroids using the boron chelate methodology

A new method for the construction of hetaryl steroids using the chelate synthesis methodology has been developed. Boron complexes serve to protect some functional groups and activate others. Applying this strategy, the possibilities of new 16-azahetaryl estrones synthesis, as well as annelating of the pyran ring to estrone at 17th and 16th positions, were discovered.

Selected publications

1. A. A. Sukhanova, M. I. Zuev, M. A. Prezent, A. N. Proshin, S. V. Baranin, Y. N. Bubnov. Synthesis of new 4-(pyrimidin-4-yl)pyrazol-3-one derivatives. Mendeleev Commun. 2019, 29, 196.
2. M. I. Zuev, A. A. Sukhanova, A. G. Smola, M. A. Prezent, A. N. Proshin, S. V. Baranin, Y. N. Bubnov. Boron- chelate assisted synthesis of new bipyrazole derivatives. Mendeleev Commun. 2018, 28, 612.