Synthesis and molecular modeling of (4′R)- and (4′S)- 4′-substituted 2′-{[(E)-androst-5-en-17-ylidene]-methyl}oxazolines

In order to find novel inhibitors of 17α hydroxylase 17,20 lyase (cytochrome P450 17A1, CYP17A1), a key enzyme of biosynthesis of androgens, molecular docking of six new oxazoline containing derivatives 17(20)E pregna 5,17(20) diene has been carried out to the active site of the crystal structure of CYP17A1 (pdb 3ruk). Results of this study indicate that: (1) complex formation of docked compounds with CYP17A1 causes their isomerization in energetically less favorable 17(20)Z isomer; (2) the localization of the steroid moiety of all compounds in the active site is basically the same; (3) the structure of the oxazoline moi ety significantly influences its position relative to heme as well as the energy of complex formation; (4) coor dination of the nitrogen atom of the oxazoline moiety and the heme iron is only possible in the 17(20)Z con formation with anti oriented double bonds 17(20), and C=N; (5) the presence of two substituents at C4' of the oxazoline moiety significantly impairs ligand binding; (6) oxazoline and benzoxazole containing deriv atives 17(20)E pregna 5,17(20) diene can effectively inhibit the catalytic activity CYP17A1 and may be of interest as a basis for the development of new drugs for the treatment of androgen dependent cancer.

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“…The oxazoline containing derivatives of [17(20) E] pregna 5,17(20) diene 1-6 were synthesized as described in [15,16] (Fig. 1).…”

Section: Methodsmentioning

confidence: 99%

“…Recently, we have developed a synthesis of oxazo line derivatives [17(20)E] pregna 5,17 (20) diene [15,16], satisfying the requirements of this pharma cophore. It has previously been shown that 2' {[(E) 3β hydroxyandrost 5 ene 17 ylidene] methyl} 4',5' dihydro 1',3' oxazol 1 (Fig.…”

Section: Introductionmentioning

confidence: 99%

Interaction of novel oxazoline derivatives of 17(20)E-pregna-5,17(20)-diene with cytochrome P450 17A1

Stulov

Dugin

Zharkova

et al. 2015

Biochem. Moscow Suppl. Ser. B

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“…В работе использованы оксазолин-содержащие производные [17(20)E)]-прегна-5,17(20)-диена 1 -6, синтезированные как описано в работах [15,16] (рис. 1); абиратерон, полученный от компании "ChemLeader Ltd" (Шанхай, КНР); препарат рекомбинантого СYP17A1, полученный из ИБОХ HAHБ (Минск, Республика Беларусь); прегненолон, дидодецилдиметиламмоний бромид (DDAB) и тритон Х-100, полученные от фирмы "Sigma" (США); трёхконтактные электроды, полученные методом трафаретной печати (ООО НПП "Автоком", Россия, http://www.membrans.ru/) с графитовым рабочим и вспомогательным электродами (графит фирмы "Achison", США) и хлорсеребряным электродом сравнения; диаметр рабочего электрода 2 мм.…”

Section: материалыunclassified

“…1); благодаря сопряжению двух двойных связей [17(20) и C=N] стероидный фрагмент и оксазолиновый (в соединениях 1, 3 -6) или бензоксазоловый (в соединении 2) цикл лежат в одной плоскости. Для каждого из соединений существуют два (примерно равных по энергии) стабильных конформера, различающихся значением двугранного угла C 20-C2' и соответствующих син-и анти-ориентации двойных связей 17 (20) и C=N [18] (значения двугранного угла C 20-C2' для син-и анти-конформеров составляют 0°и ~ 180°, соответственно [16]). Для соединений с ассимметрическим центром при С4' (3 и 4) 4'-гидроксиметильный заместитель выведен из плоскости молекулы и должен располагаться или над, или под этой плоскостью в зависимости от конфигурации хирального центра С4' и величины двугранного угла C 20-C2' .…”

Section: результаты и обсуждениеunclassified

“…Недавно нами разработан синтез оксазолиновых производных [17(20)E)]-прегна-5,17 (20)-диена [15,16], удовлетворяющего требованиям данного фармакофора. Ранее было показано, что 2'-{[(E)-3b-гидроксиандрост-5-ен-17-илиден]-метил}-4',5'-дигидро-1',3'-оксазол 1 связывается с рекомбинантным препаратом CYP17A1 и ингибирует каталитическую активность фермента подобно абиратерону [17].…”

Section: Introductionunclassified

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Interaction of novel oxazoline derivatives of 17(20)e-pregna-5,17(20)-diene with cytochrome P450 17A1

et al. 2016

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In order to find novel inhibitors of 17a-hydroxylase-17,20-lyase (cytochrome P450 17A1, CYP17A1), a key enzyme of biosynthesis of androgens, molecular docking of six new oxazoline-containing derivatives 17(20)E-pregna-5,17(20)-diene has been carried out to the active site of the crystal structure of CYP17A1 (pdb 3ruk). Results of this study indicate that: 1) complex formation of docked compounds with CYP17A1 causes their isomerization in energetically less favorable 17(20)Z-isomer; 2) the localization of the steroid moiety of all compounds in the active site is basically the same; 3) the structure of the oxazoline moiety significantly influences its position relative to heme as well as the energy of complex formation; 4) coordination of the nitrogen atom of the oxazoline moiety and the heme iron is only possible in the 17(20)Z-conformation with anti oriented double bonds 17(20), and C=N; 5) the presence of two substituents at C4' of the oxazoline moiety significantly impairs ligand binding; 6) oxazoline - and benzoxazole-containing derivatives 17(20)E-pregna-5,17(20)-diene can effectively inhibit the catalytic activity CYP17A1 and may be of interest as a basis for the development of new drugs for the treatment of androgen-dependent cancer.

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Design and Synthesis of New Agents for Prostate Cancer Treatment Inspired by Steroidal CYP17 A1 Inhibitors

et al. 2022

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Steroid derivatives modified with nitrogen containing heterocycles attract attention as anticancer agents for prostate cancer treatment. In this study we have developed a simple and convenient procedure for preparation of 17(20)-21-norpregnene and androst-16-ene 2'-oxazolinyl and 2'-benzoxazolyl derivatives, based on the reaction of an appropriately modified steroidal carboxylic acid with 1,2-amino alcohols or o-aminophenol. Using this method we conducted synthesis a series of new steroid hybrids differing either in the structure of steroidal part, or in the structure of nitrogen containing heterocycle (23 compounds in total). Some of compounds revealed high antiproliferative activity in prostate carcinoma LNCaP and PC-3 cells, exceeding that for well-known agents abiraterone and galeterone. Oxazoline containing derivative of [17(20)]-21norpregnene potently stimulated apoptosis in DU-145 cells and inhibited the growth of tumors in DU-145 and 22Rv1 derived xenograft models in direct comparison with abiraterone.

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Synthesis and molecular modeling of (4′R)- and (4′S)- 4′-substituted 2′-{[(E)-androst-5-en-17-ylidene]-methyl}oxazolines

Cited by 8 publications

References 42 publications

Interaction of novel oxazoline derivatives of 17(20)E-pregna-5,17(20)-diene with cytochrome P450 17A1

Interaction of novel oxazoline derivatives of 17(20)E-pregna-5,17(20)-diene with cytochrome P450 17A1

Interaction of novel oxazoline derivatives of 17(20)e-pregna-5,17(20)-diene with cytochrome P450 17A1

Design and Synthesis of New Agents for Prostate Cancer Treatment Inspired by Steroidal CYP17 A1 Inhibitors

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