“…For example Hartmann et al prepared various nitrogen bearing derivatives like the aziridine 1, depicted in Fig. (7) [8,[38][39][40]. Despite its high in vivo activity, 1 became not an appropriate Fig.…”
Cytochrome P450's are enzymes which catalyze a large number of biological reactions, for example hydroxylation, N-, O-, S- dealkylation, epoxidation or desamination. Their substrates include fatty acids, steroids or prostaglandins. In addition, a high number of various xenobiotics are metabolized by these enzymes. The enzyme 17alpha-hydroxylase-C17,20-lyase (P450(17), CYP 17, androgen synthase), a cytochrome P450 monooxygenase, is the key enzyme for androgen biosynthesis. It catalyzes the last step of the androgen biosynthesis in the testes and adrenal glands and produces androstenedione and dehydroepiandrosterone from progesterone and pregnenolone. The microsomal enzyme aromatase (CYP19) transforms these androgens to estrone and estradiol. Estrogens stimulate tumor growth in hormone dependent breast cancer. In addition, about 80 percent of prostate cancers are androgen dependent. Selective inhibitors of these enzymes are thus important alternatives to treatment options like antiandrogens or antiestrogens. The present article deals with recent patents (focus on publications from 2000 - 2006) concerning P450 inhibitor design where steroidal substrates are involved. In this context a special focus is provided for CYP17 and CYP19. Mechanisms of action will also be discussed. Inhibitors of CYP11B2 (aldosterone synthase) will also be dealt with.
“…For example Hartmann et al prepared various nitrogen bearing derivatives like the aziridine 1, depicted in Fig. (7) [8,[38][39][40]. Despite its high in vivo activity, 1 became not an appropriate Fig.…”
Cytochrome P450's are enzymes which catalyze a large number of biological reactions, for example hydroxylation, N-, O-, S- dealkylation, epoxidation or desamination. Their substrates include fatty acids, steroids or prostaglandins. In addition, a high number of various xenobiotics are metabolized by these enzymes. The enzyme 17alpha-hydroxylase-C17,20-lyase (P450(17), CYP 17, androgen synthase), a cytochrome P450 monooxygenase, is the key enzyme for androgen biosynthesis. It catalyzes the last step of the androgen biosynthesis in the testes and adrenal glands and produces androstenedione and dehydroepiandrosterone from progesterone and pregnenolone. The microsomal enzyme aromatase (CYP19) transforms these androgens to estrone and estradiol. Estrogens stimulate tumor growth in hormone dependent breast cancer. In addition, about 80 percent of prostate cancers are androgen dependent. Selective inhibitors of these enzymes are thus important alternatives to treatment options like antiandrogens or antiestrogens. The present article deals with recent patents (focus on publications from 2000 - 2006) concerning P450 inhibitor design where steroidal substrates are involved. In this context a special focus is provided for CYP17 and CYP19. Mechanisms of action will also be discussed. Inhibitors of CYP11B2 (aldosterone synthase) will also be dealt with.
“…In another series of steroids, pregnenolone 20-oxime derivatives showed relevant activity as CYP450 17α and 5α-R enzyme inhibitors [ 19 , 20 , 21 , 22 ]. The introduction of an oxime group at C6 in androstane series was explored in the development of aromatase inhibitors [ 23 ].…”
The interest in the introduction of the oxime group in molecules aiming to improve their biological effects is increasing. This work aimed to develop new steroidal oximes of the estrane series with potential antitumor interest. For this, several oximes were synthesized by reaction of hydroxylamine with the 17-ketone of estrone derivatives. Then, their cytotoxicity was evaluated in six cell lines. An estrogenicity assay, a cell cycle distribution analysis and a fluorescence microscopy study with Hoechst 3358 staining were performed with the most promising compound. In addition, molecular docking studies against estrogen receptor α, steroid sulfatase, 17β-hydroxysteroid dehydrogenase type 1 and β-tubulin were also accomplished. The 2-nitroestrone oxime showed higher cytotoxicity than the parent compound on MCF-7 cancer cells. Furthermore, the oximes bearing halogen groups in A-ring evidenced selectivity for HepaRG cells. Remarkably, the Δ9,11-estrone oxime was the most cytotoxic and arrested LNCaP cells in the G2/M phase. Fluorescence microscopy studies showed the presence of condensed DNA typical of prophase and condensed and fragmented nuclei characteristic of apoptosis. However, this oxime promoted the proliferation of T47-D cells. Interestingly, molecular docking studies estimated a strong interaction between Δ9,11-estrone oxime and estrogen receptor α and β-tubulin, which may account for the described effects.
“…Our rationale for designing 16-ene 25-oxime analogues ( 3 ) and oxime O-methyl ether analogues ( 4 ) was based on three major considerations: (i) the 16-ene modification usually amplifies an analogue's biological potency; (ii) the hydroxyl group of oximes 3 occupies the same region of space as the important 25-OH group of the natural hormone, and therefore oxime analogues 3 should bind well to the transporter D binding protein (DBP) and to the vitamin D receptor (VDR); and (iii) some oximes and oxime O-ethers have desirable biological activities including antibiotic nocardicin, an antibacterial pyrrolidine oxime O-methyl ether, a muscarinic agonist oxime O-alkynyl ether, a dehydroquinase inhibitor oxime, anticonvulsant oxime ethers, dioxygenase inhibitor sethoxydim, mitochondrial complex I inhibitor oximes, juvenile hormone biosynthesis inhibitor brevioxime, an agricultural fungicide oxime O-methyl ether, antihyperglycemic oximes ethers, an antitumor oxime O- tert -butyl ether, and a drug candidate oxime O-ethyl ether . Some steroidal (but not vitamin D) oximes are natural products, inhibitors of squalene-hopene cyclase, superestrogens, digitalis-like, and cytochrome P450 inhibitors. , …”
Section: Introductionmentioning
confidence: 99%
“…23 Some steroidal (but not vitamin D) oximes are natural products, 24 inhibitors of squalene-hopene cyclase, 25 superestrogens, 26 digitalis-like, 27 and cytochrome P450 inhibitors. 28,29…”
New chemical entities 16-ene-25-ketone 2b and the corresponding oxime 3b and oxime ether 4b, analogues of natural calcitriol (1), were rationally designed and synthesized on a milligram scale. Chemical introduction of the oxime ether functionality in analogue 4b was successful via direct oximation of an intact vitamin D conjugated triene system. Even though all three analogues are at least as antiproliferative in vitro as calcitriol (1) even at physiologically relevant low nanomolar concentrations, only side chain ketone 2b is more transcriptionally potent than calcitriol (1). Although oxime O-methyl ether 4b lacks the traditional side chain hydrogen bond-donating OH group of the natural hormone and lacks also the oxime-NOH group of analogue 3b, surprisingly, oxime ether 4b retains 20% of the transcriptional potency of natural calcitriol (1). In terms of in vivo toxicity (hypercalcemia), ketone 2b is strongly calcemic in rats, whereas oxime 3b and oxime ether 4b are considerably less calcemic (i.e., safer) than calcitriol (1).
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