Novel oxazolinyl derivatives of pregna-5,17(20)-diene as 17α-hydroxylase/17,20-lyase (CYP17A1) inhibitors

Kuzikov, Alexey V.; Dugin, Nikita O.; Stulov, Sergey V.; Shcherbinin, Dmitrii S.; Zharkova, M. S.; Tkachev, Yaroslav V.; Timofeev, Vladimir P.; Veselovsky, A. V.; Shumyantseva, Victoria V.; Misharin, A. Yu.

doi:10.1016/j.steroids.2014.06.014

Cited by 36 publications

(19 citation statements)

References 38 publications

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“…Оксазолин-содержащее производное [17(20)E]-21-норпрегнена 296 ингибировало каталитическую активность СYP17A1 сильнее, чем абиратерон; замена оксазолинового фрагмента на 4,4-диметилоксазолиновый (297) снижало ингибиторную активность на порядок, а замена на бензоксазоловый (301) -на два порядка [64][65][66]. Производные [17(20)E]-21-норпрегнена, содержащие полярные (299 и 300) или объёмистые (298) заместители в положении 4 оксазолинового цикла, не связывались с ферментом и не проявляли ингибиторной активности [40,65] (формула 31).…”

Section: формула 24unclassified

Steroidal Inhibitors of CYP17A1 as a Template For Novel Anti-Cancer Agents Development

Latysheva

Misharin

2018

BMCRM

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This review deals with studies of researches of novel CYP17A1 steroidal inhibitors and relative compounds published over the last ten years. The review contains six chapters in which novel targets of well-known CYP17A1 inhibirors (abiraterone and galeterone), anti-cancer and anti-proliferative activities of them major metabolites and new synthetic analogs, and in addition another nitrogen-containing androstane and pregnane derivatives are considered. In the review 354 structures of novel steroid derivatives and them anti-cancer efficiency data are considered. Analysis of the literature data allows us to consider steroidal inhibitors of CYP17A1 as multi-target anti-cancer agents with high pharmacological potential.

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Section: формула 24unclassified

Steroidal Inhibitors of CYP17A1 as a Template For Novel Anti-Cancer Agents Development

Latysheva

Misharin

2018

BMCRM

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“…Электрохимические свойства иммобилизованного CYP17A1 были исследованы нами ранее в работах [17,23]. Значения IC 50 для соединений 1 -6 рассчитывали по снижению максимального каталитического тока CYP17A1 при хроноамперо-метрическом титровании раствором прегненолона, как в работе [17].…”

Section: электрохимическое определение ингибирования активности сYp17a1unclassified

“…Значения IC 50 для соединений 1 -6 рассчитывали по снижению максимального каталитического тока CYP17A1 при хроноамперо-метрическом титровании раствором прегненолона, как в работе [17].…”

Section: электрохимическое определение ингибирования активности сYp17a1unclassified

“…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]. В работе [18] [2][3][4][5][6][7][8][9][10][11][12][13].…”

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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“…Oxazolone and its derivatives make a prominent structure of number of well established marketed drugs such as rilmenidine, furazolidone, nifurantoin, oxaprozin, and especially linezolid, which is an active against methicillin-resistant Staphylococcus aureus. Indeed, oxazolone based derivatives have shown diverse biological and pharmacological applications such as anticancer 1,2 , antibacterial 3 , antimycobacterial against tuberculosis 4 , and antioxidant 5,6 activity.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Antioxidant Properties of New Oxazole-5(4<i>H</i>)-one Derivatives

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Özdamar

et al. 2017

tjps

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Amaç: Bu çalışma, 4-(sübstitüe benziliden)-2-(sübstitüefenil)oksazol-5(4H)-on (E1-E10) türevlerini sentezlemek, yapılarını aydınlatmak ve antioksidan etkilerini araştırmaktır. Gereç ve Yöntemler: Oksazol-5(4H)-on türevleri iki yolak ile sentezlenmiştir. Yeni hippürik asit türevlerini (7-13) elde etmek için, glisin ve açillenmiş uygun benzoik asitler kullanıldı ve bu bileşiklerin (7-13) uygun benzaldehitler ile kondensasyon reaksiyonu ile de sonuç ürünlere (E1-E10) ulaşılmıştır. Bu ürünler etil asetat/n-hekzan solvan sistemi kullanılarak kolon kromatografisi ile temizlenmiştir. Tüm bileşikler için 1 H and 13 C-nükleer manyetik rezonans, mass spektrometresi (ESI-MS), elemental analiz yöntemleri kullanılarak yapıları tanımlanmıştır. Lipid peroksidasyon inhibisyonu ve karaciğer sitokrom P450 bağımlı Etoksirezorfin-O-deetilaz (EROD) enzimi üzerindeki etkileri sıçanlarda in vitro olarak tespit edildi. Bulgular: Mikrozomal EROD aktivitesi üzerinde en aktif analog, EROD aktvitesini %89 ile inhibe eden E3'tür, benzer şekilde 10-3 M konsantrasyonda spesifik inhibitör kafeinden (%85) daha iyi idi. Sonuç: Bu çalışmanın bulguları, E3 gibi sentezlenen bileşiklerin, önemli antioksidan aktivite sergilediğini göstermektedir. Anahtar kelimeler: Oksazolidinonlar, sentez, antioksidan aktivite, lipid peroksidasyon, EROD aktivite Objectives: To synthesize and characterize 4-(substituted benzylidene)-2-(substituted phenyl)oxazol-5(4H)-one derivatives (E1-E10), and evaluate them for antioxidant activity. Materials and Methods: Required oxazole-5(4H)-one derivatives were synthesized in two steps to obtain novel hippuric acid derivatives (7-13); glycine and acylated appropriate benzoic acid derivatives were used and then, final compounds were obtained with condensation of 7-13 with appropriate benzaldehydes (E1-E10). These products were purified by column chromatography using ethyl acetate/n-hexane as eluent. All the compounds were unequivocally characterized using the combination of 1 H and 13 C-nuclear magnetic resonance, mass spectrometry (ESI-MS), and elemental analysis. The inhibition of lipid peroxidation and its effects on hepatic cytochrome P450-dependent ethoxyresorufin-O-deethylase (EROD) enzyme were determined in rats in vitro. Results: The most active analogue on the microsomal EROD activity was E3 which inhibited the microsomal EROD activity (89%) and was similarly better than that of the specific inhibitor caffeine (85%) at 10-3 M concentration. Conclusion:The findings of this study indicate that the synthesized compounds, such as E3, display significant antioxidant activity.

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Novel oxazolinyl derivatives of pregna-5,17(20)-diene as 17α-hydroxylase/17,20-lyase (CYP17A1) inhibitors

Cited by 36 publications

References 38 publications

Steroidal Inhibitors of CYP17A1 as a Template For Novel Anti-Cancer Agents Development

Steroidal Inhibitors of CYP17A1 as a Template For Novel Anti-Cancer Agents Development

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

Synthesis and Antioxidant Properties of New Oxazole-5(4<i>H</i>)-one Derivatives

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