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    • Steroidal CYP inhibitors can further be classified

    2024-03-28

    Steroidal CYP17 inhibitors can further be classified based on their mode of action, namely as mechanism-based inhibitors and type I and type II competitive inhibitors [129]. Recent studies investigated other biological targets than CYP17, and some new compounds have shown interesting dual activity as both enzyme inhibitors and AR antagonists. It is also important to highlight the variations in evaluation and assay procedures of different inhibitors that makes difficult to compare the inhibitory activity obtained from different studies. For this reason, authors usually include known potent CYP17 inhibitors in the assays for comparison (e.g. ketoconazole). A relevant steroidal CYP17 inhibitor group is the mechanism-based inhibitors which have the ability to act as substrates for the normal catalytic activity of the enzyme, leading to a species capable of forming a covalent bond with the active site of the enzyme. Due to this covalent binding, an irreversible inhibition occurs [75]. In this context, Angelastro et al. prepared a series of 17-substituted cyclopropylamine androstanes (e.g. compound 161) and their corresponding cyclopropyl ether derivatives 162–165 that have showed inhibitory activity of the cynomolgus monkey testicular CYP17 (Fig. 11, Table 8) [133], [134], [135], [136], [137]. The authors suggested that the mechanism associated with the 17-substituted cyclopropylamine derivatives involves the one electron oxidation of the heteroatom bound to C17, that contributes for the rapid ring opening of the cyclopropyl ring, to form a β-iminium radical [134]. This very reactive species reacts covalently with the enzyme active site, inhibiting irreversibly their activity (Scheme 3). Several fluorinated pregnene derivatives bearing at least one fluor Golgicide A at the C17-unsaturated side chain 166–171 have been synthesized and evaluated for their CYP17 inhibitory activity (Fig. 11, Table 8) [138], [139]. These compounds are believed to act as enol mimics and have been found to be potent time-dependent inhibitors of the 17,20-lyase activity of cynomolgous monkey testicular CYP17. The authors demonstrated that the presence of a Δ16-double bond in compound 170 enhance inhibition, although not in a time-dependent manner. Potent inhibition has also been found for the 16-keto-pregna-5,17(20)-diene derivative 171[140]. Again, due the presence of the enone moiety, that confers Michael acceptor properties to this compounds, a irreversible reaction with a nucleophile at the active site may account for the enzymatic inhibition [140]. A patent has been published claiming that the sulfoxide derivatives 172 and 173 are irreversible inhibitors of CYP17 (Fig. 11, Table 8) [141]. As previously mentioned, competitive inhibitors of cytochrome P450 enzymes can be classified into type I and type II, according to the binding mode of the inhibitor to the enzyme active site. Type I inhibitors displace water, as the sixth ligand of the Fe heme, occupying the steroid binding site and inhibiting the substrate for binding. Consequently, Fe exists in a pentacoordinate state and the Soret band maximum changes to near 390nm. On the other hand, type II inhibitors coordinate directly with the heme group as the sixt ligand, the Fe exists in a hexacoordinate state and the Soret maximum band is at 421–430nm. The most successful type II inhibitors have a heteroatom capable of donating a lone pair of electrons to the Fe, originating a coordinate bond. The inhibitor structure should resemble the original substrates [75], [129]. The first reports on CYP17 steroidal competitive inhibitors date back to 1971 when Arth et al. synthesized and evaluated T (9) derivatives against rat testicular CYP17 [144], following the observation that testosterone acetate (174) was a potent inhibitor of the enzyme. In this study was observed almost total inhibition of CYP17 activity after treatment with 1.5μM of compounds 175, 176, and 178 with the acetamide derivative 177 being less potent (Fig. 12) [144]. Nakajin et al. reported that the anabolic steroids mestanolone (179), stanozolol (180), and furazobol (181) are competitive inhibitors of pig CYP17 [145]. Weak inhibition (high μM range) was found with compounds 179 and 181 against the C17,20-lyase activity whereas stanozolol (180) inhibited both enzyme activities with IC50 values of 2.9μM and 0.74μM, for the 17α-hydroxylase and C17,20-lyase activities, respectively [145].