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    • Several dehidropregnenolone derivatives functionalized at C

    2022-11-16

    Several 16-dehidropregnenolone derivatives functionalized at C3, C4, C5 and C6 (Fig. 7) were prepared and evaluated as 5α-reductase inhibitors bearing in mind that after the formation of an enzyme-steroid complex a nucleophilic portion of the enzyme attacks the double bond of the steroid through Michael addition reaction. In fact, it was observed that steroids 108, 110, 112 and 114 efficiently inhibited the enzyme whereas compounds 109 and 111 have not shown inhibitory properties (Fig. 7, Table 6, entries 1–7). This lack of biological activity can possibly be attributed to the weak Michael acceptor reactivity of compound 109 and low solubility of compound 111. [73]. Later, 3-substituted pregna-4,16-diene-6,20-dione derivatives were also prepared and it was observed that 3β-(3-halopropanoyl)pregnanes (Fig. 7) produced a significant decrease of the prostate weight in castrated animals treated with T (9) and inhibited the activity of the 5α-reductase (Table 6, entries 8–11) [74]. Several pregnane-20-oximes, including 20-hydroximineprogesterone, have interesting 5α-reductase inhibitory properties [46], [47]. Interestingly, as can be seen in section 5, the introduction of this functionality to a number of pregnanes and other similar steroids is also associated with high CYP17 inhibitory activity. Furthermore, many 20-hydroxypregnanes and pregn-4-ene-3-one-20β-carboxaldehyde have the same dual CYP17 and 5α-redutase inhibitory activities, which could also be of potential interest in prostatic diseases [9], [18], [75]. In addition to previously described pregnanes, several androstane derivatives, including D-lactones and D-lactams, have also been developed, as potential 5α-redutase inhibitors and antiprostate cancer agents. In fact, several esters of 3β-hydroxy-17a-aza-D-homo-5-androsten-17-one, have antiproliferative activity on DU-145 PC cells and lowers serum T (9) levels in rat model [76]. Similar studies were effected with 17-oximino- [77] and 17-oxo-5-androsten-3β-yl esters as well as 3β-alkoxy-5-androsten-17-ones [78]. In these studies, it was generally observed that esterification of the 3-hydroxyl group with p-substituted aromatic Cilostazol gives compounds with interesting antiproliferative and antiandrogenic activity. Other ester derivatives of dehydroepiandrosterone were also developed by Arellano et al. as antiandrogens. These include 5α,6β-dibromo and Δ5-unsaturated steroidal structures with several linear esters attached to the 3β-OH group (compounds 120–125, Fig. 8). In vitro and in vivo experiments demonstrated that the dibromo derivatives significantly decreased the weight of the prostate and seminal vesicles as compared to T (9) treated animals and that Δ5-unsaturated steroidal esters have the highest 5α-redutase inhibitory activity (Table 7, entries 2–4) [79]. However, it was also observed that none of these compounds binds to AR [79]. The same group effected a similar study involving D-ring steroidal lactones, again having the 5α,6β-dibromo moiety or Δ5-unsaturated structures and linear esters attached to the 3β-OH group (compounds 126–135, Fig. 8). Biological experiments evidenced that all compounds not only decreased the weight of the prostate and seminal vesicles but also inhibited the enzyme 5α-reductase (Table 7, entries 8–17). On contrary to previous studies with 5-membered D-ring steroids, several of these lactones also bind to AR [80]. The introduction of heterocyclic moieties fused to the steroidal D-ring was another approach explored in the development of 5α-reductase inhibitors. In this context, Wölfling et al. reported that several steroidal tetrahydrooxazin-2-ones (e.g. compounds 136–139, Fig. 9), have some 5α-reductase inhibitory effect, however, lower than finasteride (13) [81]. More recently, the same group prepared novel (5'S)-17β-(4,5-dihydrooxazol-5-yl)androst-5-en-3-one compounds containing various derivatized phenyl substituents coupled to the exo-heterocyclic moiety (e.g. compounds 140–143, Fig. 9) that revealed to have moderate 5α-reductase inhibitory activities (5α-reductase isolated from rat liver; IC50 values ranging from 720 to 2750nM) [82]. Other steroids with heterocycles bound to C17, including aziridine, pyridine, isoxazole, pyrazole, imidazole, triazole, benzimidazole and benzotriazole rings, that are more known to be CYP17 inhibitors (please see Section 5) have also been reported to have concomitant 5α-reductase inhibitory properties [9], [18], [75]. Very recently, Al-Mohizea et al. prepared and performed the pharmacological screening, including the 5α-reductase inhibitory activities and anti-tumor properties (e.g. in LNCaP and PC-3 PC cell lines), of several steroids with cyanopyridone and cyanothiopyridone heterocycles fused with its D-ring. The authors reported that these compounds have potent 5α-redutase inhibitory properties (in vivo assay with Sprague-Dawley rats), that have been associated not only with the functionalized pyridone ring, but also with the steroidal A and B-ring substitution pattern. The best results were observed for the cyanopyridone structures with an oxygen bound to C3 (e.g. compounds 144, 145, 148–152, Fig. 9). Furthermore, it was observed a similar SAR in the anti-PC activity against LNCaP and PC-3 cell lines [83].