Effect of the position of the cyano-group of cyanopregnenolones on their drug metabolic inducing activity

Abstract

The effect of the position of the cyano-group of several cyanopregnenolones on the body's resistance to drugs and on drug metabolism was investigated. Female rats were pretreated with 2 alpha-, 6-, 16 alpha-, 17 alpha-cyano- or 16 alpha-cyanomethyl-pregnenolone or with pregnenolone, and the (in vivo) resistance to zoxazolamine, digitoxin and indomethacin, as well as the in vitro drug metabolism (post mitochondrial fraction) of zoxazolamine and ethylmorphine were determined. It was found that the 16-derivative was the most active in this respect, the 2- and 17-cyanopregnenolones were less active but significantly potent compared to controls, while the 6-cyano, the 16-cyanomethyl derivatives and pregnenolone were essentially inactive. These differences were explained in terms of an effective or poor fit of the steroids to their receptor. The poor performance of pregnenolone-16 alpha-acetonitrile was attributed to electronic effects. A hypothesis of some structural features of the receptor site for its interaction with the cyanopregnenolone inducers was presented.

Biologic Stress, Oxidative Stress, and Resistance to Drugs: What Is Hidden Behind

“…This order, as expected, was the same for the resistance to drugs [ 62 ]. In our investigation on the effect of the position of the CN-group on the steroidal skeleton on drug metabolism and resistance to drugs [ 63 ], we used pregnenolone-2α-CN, 6-CN, 16α-CN, 17α-CN, and 16α-CH 2 CN, studying zoxazolamine paralysis time, digitoxin, and indomethacin mortality, as well as zoxazolamine and ethylmorphine in vitro metabolism. We found that the 16α-CN derivative was the most active in this respect, the 2α-CN and the 17α-CN-pregnenolones were less active, but significantly potent, compared with the controls, while the 6-CN and 16α-CH 2 CN derivatives, as well as pregnenolone itself, were essentially inactive.…”

“…If this compound is turned around 180°, it seems to fit the three points fairly well. The fit of 6-CN, 17α-CN-pregnenolones to the described receptor is poorer [ 63 ]. Finally, concerning the effect of various groups at 16α-position of pregnenolone with different electronic and steric effects on drug metabolism and response, we studied the following 16α-substituted pregnenolones: CN-, H-, CH 3 -, CN-CH 2 -, -CONH 2 , and -COOH.…”

Design, Synthesis, Antifungal Activity, and Molecular Docking of Streptochlorin Derivatives Containing the Nitrile Group

“…In classical medicinal chemistry, the nitrile group was commonly considered as bioisosteres of carbonyl, hydroxyl, and carboxyl groups, as well as halogen atoms [ 17 ]. As nitrile-containing drugs account for 2.4% of the 2327 approved small-molecule drugs according to the DrugBank database by 2018 [ 18 ], the presence of the nitrile group in the structure of compounds is a very common feature of drug molecules [ 19 , 20 ], such as Enzalutamide, a hormone treatment that blocks testosterone from reaching prostate cancer cells [ 21 ], Escitalopram, a medication used in the management and treatment of major depressive disorder and generalized anxiety disorder [ 22 ]; Tofacitinib, as an oral JAK3 inhibitor to treat adults with moderately to severely active rheumatoid arthritis [ 23 ]; Verapamil, a medication for treating hypertension, angina, and certain heart rhythm disorders [ 24 ]; Rilpivirine, a non-nucleoside reverse transcriptase inhibitor that inhibits the replication of HIV-1 [ 25 ]; and Vildagliptin, an orally administered dipeptidyl peptidase-4 (DPP-4) inhibitor for treating diabetes [ 26 ]. Meanwhile, Cyazofamid is a novel fungicide exhibiting specific activity against diseases caused by Oomycetes [ 27 ]; Azoxystrobin is a broad-spectrum β-methoxyacrylate fungicide that was first introduced in 1998, which inhibits mitochondrial respiration by binding to the Qo site of the cytochrome bc 1 complex [ 28 , 29 ]; and Phenamacril is a Fusarium-specific fungicide used for Fusarium head blight management [ 30 , 31 ].…”