Synthesis and Evaluation of Pregnane Derivatives as Inhibitors of Human Testicular 17α-Hydroxylase/C_17,20-Lyase^,

Abstract

The pregnene derivatives with modifications at the 17,20-side chain and D-ring were synthesized and evaluated as inhibitors of human testicular 17 alpha-hydroxylase/C17,20-lyase. The results demonstrate that compounds which have 20-substituents with moderate to strong dipole properties, such as 20-oxime (3, 20), 20 beta-ol (24, 30), and 20 beta-carboxaldehyde (27), are potent inhibitors of this enzyme complex. The 20-substituents with hydrophobic property were devoid of inhibitory activity, e.g., the dimethylhydrazones 8 and 9. The 16-ene together with 20-oxime (20) showed the most potent inhibition of this enzyme complex, whereas 17(20)-ene modification as in 17(20)-ene-20-carbonitrile (14) did not increase activity in comparison to the 20 beta-carbonitrile (16). The bioisotere of 27 with 20-aza (19) also reduced the inhibitory activity. The results showed that isomeric configurations at the 20-position of some steroidal compounds are important factors which influence the potency of the inhibition significantly (e.g., 20 beta-ols 24 and 30 were 3-5-fold more potent than 20 alpha-ols 23 and 29). As expected, some compounds based on the pregn-5-en-3 beta-ol skeleton, which is similar to the natural substrate of human testicular 17 alpha-hydroxylase/C17,20-lyase in A- and B-rings, showed more potent inhibition than similar compounds which are based on the pregn-4-en-3-one skeleton (e.g., 23-25 compared to 29-31). These results suggest that A- and B-rings make significant contributions to the binding of these steroidal compounds to the 17 alpha-hydroxylase and C17,20-lyase. In comparison to ketoconazole, a nonsteroidal inhibitor of 17 alpha-hydroxylase and C17,20-lyase which has been used in the treatment of prostatic cancer, the steroidal compounds 20, 24, and 27 demonstrate more potent inhibition for this enzyme complex. These inhibitors warrant further investigation in biological systems. The structural features of these compounds may serve as leads in the design of new inhibitors.

Synthesis, biochemical evaluation of a range of potent 4-substituted phenyl alkyl imidazole-based inhibitors of the enzyme complex 17α-Hydroxylase/17,20-Lyase (P45017α)

“…The synthesised azole compounds were initially screened (the data is not shown here) and IC 50 values determined (Table 1) against both 17␣-OHase and lyase using modified literature methods [13][14][15]. The modification involved the use of a different mobile phase to that used by previous workers within the field in the separation and identification of the radiolabelled substrate from the radiolabelled products.…”

Synthesis, biochemical evaluation and rationalisation of the inhibitory activity of a range of phenyl alkyl imidazole-based compounds as potent inhibitors of the enzyme complex 17α-hydroxylase/17,20-lyase (P45017α)

“…(10). Compound 10 was synthesised following the same procedure as for compound 5, except that compound 9 (1.00 g, 6.09 mmol) was added to PBr 3 (1.65 g, 6.09 mmol) and anhydrous pyridine (5 drops) in anhydrous diethyl ether (50 mL).…”

“…(max) (Film) cm −1 : 3032 (CH aromatic), 2920 (CH aliphatic), 1605 (Ar, C C); ı H (300 MHz, CDCl 3 ): 7.33 (1H, s, NCHN imidazole), 7.16 (5H, m, H Ar), 6.95 (1H, s, NCH imidazole), 6.77 (1H, s, NCH imidazole), 3.78 (2H, t, J = 7 Hz, Ar CH 2 ), 2.50 (2H, t, J = 7 Hz, NCH 2 ), 1.60 (4H, m, Ar CH 2 CH 2 , NCH 2 CH 2 ), 1.24 (2H, m, Ar(CH 2 ) 2 CH 2 ); ı C (75 MHz, CDCl 3 ): 142. 10 (12). Compound 12 was synthesised following the same procedure as for compound 7, except that malonic acid diethyl ester (0.75 g, 4.69 mmol), potassium tert-butoxide (0.53 g, 4.69 mmol) and com- 2.1.1.13.…”

Synthesis of Novel Oximes of 2-Aryl-6-methoxy-3,4-dihydronaphthalene and Their Evaluation as Inhibitors of 17α-Hydroxylase-C17,20-Lyase (P450 17)

“…While the heterocyclic N complexes the heme iron of P450 17, the rest of the molecule interacts with the apoprotein moiety. In the case of steroidal compounds, it has recently been shown [7,8] that an oxime group at the substituent in C-17 position also leads to potent inhibitors (e.g., II, Chart 1 [7] ). The first attempt to obtain the nonsteroidal oximes as inhibitors of P450 17 has recently been published (e.g., III, Chart 1 [9] ).…”