Steroids and Combinatorial Chemistry

Maltais, René; Tremblay, Martin; Ciobanu, Liviu C.; Poirier, Donald

doi:10.1021/cc030118m

Cited by 38 publications

(13 citation statements)

References 98 publications

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“…The average purity of the library members was 91%, and the liquid chromatography chromatograms suggested that Ϸ50% of the library members contained Ͼ90% of a single product isomer. Although combinatorial methods have been extensively applied to steroidal derivatives and cardenolides in particular (25,26), the results reported herein represent the largest and most diverse glycorandomized library generated to date.…”

Section: Resultsmentioning

confidence: 99%

Enhancing the anticancer properties of cardiac glycosides by neoglycorandomization

Langenhan¹,

Peters²,

Guzei³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

216

174

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Glycosylated natural products are reliable platforms for the development of many front-line drugs, yet our understanding of the relationship between attached sugars and biological activity is limited by the availability of convenient glycosylation methods. When a universal chemical glycosylation method that employs reducing sugars and requires no protection or activation is used, the glycorandomization of digitoxin leads to analogs that display significantly enhanced potency and tumor specificity and suggests a divergent mechanistic relationship between cardiac glycosideinduced cytotoxicity and Na ؉ ͞K ؉ -ATPase inhibition. This report highlights the remarkable advantages of glycorandomization as a powerful tool in glycobiology and drug discovery.carbohydrate ͉ natural product ͉ sugar

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Section: Resultsmentioning

confidence: 99%

Enhancing the anticancer properties of cardiac glycosides by neoglycorandomization

Langenhan¹,

Peters²,

Guzei³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

216

174

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“…[42][43][44] Library synthesis using the steroid nucleus as a scaffold for SPOS has been relatively unexplored, although a number of novel solidphase strategies for the synthesis of steroid-derivative libraries have now been designed to expand this relatively unexplored area of combinatorial chemistry. [45][46][47] The identification of small druglike molecules using steroid templates is undoubtedly a rapidly growing area of research. Estradiol or estrone has been used as a scaffold in a number of drug-discovery programmes.…”

Section: Introductionmentioning

confidence: 99%

Focused Libraries of 16‐Substituted Estrone Derivatives and Modified E‐Ring Steroids: Inhibitors of 17ß‐Hydroxysteroid Dehydrogenase Type 1

Vicker¹,

Lawrence²,

Allan³

et al. 2006

ChemMedChem

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17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1), an oxidoreductase which has a preferential reductive activity using NADPH as cofactor, converts estrone to estradiol and is expressed in many steroidogenic tissues including breast and in malignant breast cells. As estradiol stimulates the growth and development of hormone-dependent breast cancer, inhibition of the final step of its synthesis is an attractive target for the treatment of this disease. The parallel synthesis of novel focused libraries of 16-substituted estrone derivatives and modified E-ring pyrazole steroids as new potent 17beta-HSD1 inhibitors is described. Substituted 3-O-sulfamoylated estrone derivatives were used as templates and were immobilised on 2-chlorotrityl chloride resin to give resin-bound scaffolds with a multi-detachable linker. Novel focused libraries of 16-substituted estrone derivatives and new modified E-ring steroids were assembled from these immobilised templates using solid-phase organic synthesis and solution-phase methodologies. Among the derivatives synthesised, the most potent 17beta-HSD1 inhibitors were 25 and 26 with IC50 values in T-47D human breast cancer cells of 27 and 165 nm, respectively. Parallel synthesis resulting in a library of C5'-linked amides from the pyrazole E-ring led to the identification of 62 with an IC50 value of 700 nM. These potent inhibitors of 17beta-HSD1 have a 2-ethyl substituent which will decrease their estrogenic potential. Several novel 17beta-HSD1 inhibitors emerged from these libraries and these provide direction for further template exploration in this area. A new efficient diastereoselective synthesis of 25 has also been developed to facilitate supply for in vivo evaluation, and an X-ray crystal structure of this inhibitor is presented.

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“…В работе [67] стероиды, дают уникальную возможность создания новых библиотек потенциальных лекарств [78][79][80][81], а накопленный специалистами огромный массив знаний о структуре и активности стероидов помогает быстро и эффективно проводить скрининг этих библиотек и поиск новых соединений-лидеров. …”

Section: прочие стероидные производныеunclassified

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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Steroids and Combinatorial Chemistry

Cited by 38 publications

References 98 publications

Enhancing the anticancer properties of cardiac glycosides by neoglycorandomization

Enhancing the anticancer properties of cardiac glycosides by neoglycorandomization

Focused Libraries of 16‐Substituted Estrone Derivatives and Modified E‐Ring Steroids: Inhibitors of 17ß‐Hydroxysteroid Dehydrogenase Type 1

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

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