Novel Nitrogen Containing Steroid Derivatives for Prostate Cancer Treatment

Latysheva, Alexandra S.; Zolottsev, Vladimir A.; Pokrovsky, Vadim S.; Khan, Irina I.; Misharin, A. Yu.

doi:10.2174/0929867328666210208113919

Cited by 4 publications

(3 citation statements)

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“…The last drug discussed here is seviteronel, which is a novel nonsteroidal CYP17A1 inhibitor and androgen receptor antagonist. It preferentially inhibits 17,20-lyase over 17α-hydroxylase, but the clinical trials were terminated due to unsatisfactory tolerance and clinical responses [ 4 , 11 , 12 ]. It is important to note that both orteronel and seviteronel share the same scaffold, viz., scaffold 5 shown in Figure 4 b.…”

Section: Discussionmentioning

confidence: 99%

Exploring the Chemical Space of CYP17A1 Inhibitors Using Cheminformatics and Machine Learning

Huang

et al. 2023

Molecules

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Cytochrome P450 17A1 (CYP17A1) is one of the key enzymes in steroidogenesis that produces dehydroepiandrosterone (DHEA) from cholesterol. Abnormal DHEA production may lead to the progression of severe diseases, such as prostatic and breast cancers. Thus, CYP17A1 is a druggable target for anti-cancer molecule development. In this study, cheminformatic analyses and quantitative structure–activity relationship (QSAR) modeling were applied on a set of 962 CYP17A1 inhibitors (i.e., consisting of 279 steroidal and 683 nonsteroidal inhibitors) compiled from the ChEMBL database. For steroidal inhibitors, a QSAR classification model built using the PubChem fingerprint along with the extra trees algorithm achieved the best performance, reflected by the accuracy values of 0.933, 0.818, and 0.833 for the training, cross-validation, and test sets, respectively. For nonsteroidal inhibitors, a systematic cheminformatic analysis was applied for exploring the chemical space, Murcko scaffolds, and structure–activity relationships (SARs) for visualizing distributions, patterns, and representative scaffolds for drug discoveries. Furthermore, seven total QSAR classification models were established based on the nonsteroidal scaffolds, and two activity cliff (AC) generators were identified. The best performing model out of these seven was model VIII, which is built upon the PubChem fingerprint along with the random forest algorithm. It achieved a robust accuracy across the training set, the cross-validation set, and the test set, i.e., 0.96, 0.92, and 0.913, respectively. It is anticipated that the results presented herein would be instrumental for further CYP17A1 inhibitor drug discovery efforts.

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Section: Discussionmentioning

confidence: 99%

Exploring the Chemical Space of CYP17A1 Inhibitors Using Cheminformatics and Machine Learning

Huang

et al. 2023

Molecules

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“…Specific CYP17 inhibitors (both steroidal and non-steroidal) are emerging representatives of important class of agents for prostate cancer treatment. [1][2][3][4][5][6][7][8][9] Considerable efforts have been made to develop synthetic strategies for preparation of steroidal CYP17 inhibitors -androstane and pregnane deriva-tives modified with nitrogen containing heterocycles. [10][11][12][13] Abiraterone 1 (molecule approved for treatment of advanced stage of PC) [14] and galeterone 2 (first in-class multi-target molecule with three reported mechanisms of activity: CYP17 A1 inhibition, AR antagonism, and induction of AR degradation) [15,16] are the most studied representatives of CYP17 A1 inhibitors.…”

Section: Introductionmentioning

confidence: 99%

“…Specific CYP17 inhibitors (both steroidal and non‐steroidal) are emerging representatives of important class of agents for prostate cancer treatment [1–9] . Considerable efforts have been made to develop synthetic strategies for preparation of steroidal CYP17 inhibitors – androstane and pregnane derivatives modified with nitrogen containing heterocycles [10–13] .…”

Section: Introductionmentioning

confidence: 99%

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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Exploration and biological evaluation of 20‐vinyl pregnenes: A step forward toward selective modulators of the estrogen receptor α signaling for breast cancer treatment

Malakhova,

Scherbakov,

Sorokin

et al. 2024

Archiv der Pharmazie

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A series of D‐ring modified steroids bearing a vinyl ketone pendant were synthesized and evaluated for antiproliferative activity against breast cancer cell line and cytochromes P450. The lead compound, 21‐vinyl 20‐keto‐pregnene (2f) (IC50 = 2.4 µM), was shown to be a promising candidate for future anticancer drug design, particularly against estrogen receptor α (ERα)‐positive breast cancer. The lead compound was found to have a significant effect on the signaling pathways in parental and 4‐hydroxytamoxifen‐resistant cells. Compound 2f modulated the ERK, cyclin D1, and CDK4 pathways and blocked the expression of ERα, the main driver of breast cancer growth. Compound 2f significantly reduced 17β‐estradiol‐induced progesterone receptor expression. Accumulation of cleaved poly(ADP‐ribose) polymerase in cells treated with compound 2f indicated induction of apoptosis. The selectivity analysis showed that lead compound 2f produces no significant effects on cytochromes P450, CYP19A1, CYP21A2, and CYP7B1.

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Novel Nitrogen Containing Steroid Derivatives for Prostate Cancer Treatment

Cited by 4 publications

References 0 publications

Exploring the Chemical Space of CYP17A1 Inhibitors Using Cheminformatics and Machine Learning

Exploring the Chemical Space of CYP17A1 Inhibitors Using Cheminformatics and Machine Learning

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

Exploration and biological evaluation of 20‐vinyl pregnenes: A step forward toward selective modulators of the estrogen receptor α signaling for breast cancer treatment

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