Biomedical Chemistry: Research and Methods, 2018, 1(2), e00020

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

A.S. Latysheva, A.Yu. Misharin*

Institute of Biomedical Chemistry, 8119121 Pogodinskaya Str., 10 bldg. 8, Moscow, Russia,*e-mail: alexander.misharin@ibmc.msk.ru

Keywords: CYP17A1 inhibitors; abiraterone; galeterone; nitrogen-containing steroidal derivatives; anti-proliferative activity; anti-cancer activity

DOI: 10.18097/BMCRM00020

The whole version of this paper is available in Russian.

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.

Figure 1. Metabolism of abiraterone and galeterone. 5αSR - 5α-reductase; 5β-reductase, 3βHSD - 3β-hydroxysteroid dehydrogenase

Oxazoline comprising [17(20)E]-21-norpregnene derivative 296 inhibited СYP17A1 catalytic activity more potently than abiraterone; changes of the oxazoline fragment for 4,4-dimethyl oxazoline (297) and benzoxazole (301) reduced inhibiting potency by one and two orders of magnitude, respectively [64-66]. [17(20)E]-21-Norpregnene derivatives comprising either polar (299 and 300), or bulky (298) substituents at C4’ in the oxazoline moiety did not bind to enzyme and did not demonstrate any inhibiting potency [40,65].

Among analogs of oxazoline comprising derivative 296 differing in structures of А and B rings, the most potent inhibiting activity exhibited 3-keto-4-еn- and seco-A-derivatives (302, 303). The removal of oxygen containing group at C3, its substitution for chloro- or methoxy- function, as well as introducing of ketogroup into C6 position, led to non active compounds 305-309 [66].

The inhibitory potency of oxazolines towards CYP17A1 activity as well as their ability to inhibit of prostate carcinoma LNCaP and РС-3 cells growth was decreased in the following row: 296 > 303 > 302. (Table 1).

CLOSE
Table 1. Biological activity of compounds 296-309

ACKNOWLEDGEMENTS

This work was performed within the framework of the State Academies of Sciences Fundamental Research Program for 2013–2020.

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