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)

Abstract

The synthesis and biological evaluation of oximes of 2‐aryl‐6‐methoxy‐3,4‐dihydronaphthalene (7a, 7b, 14a, 14b) as nonsteroidal inhibitors of 17α‐hydroxylase‐C17,20‐lyase (P450 17, CYP 17) is described. The target compounds were synthesized and identified by 1H NMR and MS. The preparation of the key intermediates 5a and 5b was accomplished by coupling 4a and 4b with 1 (2‐hydroxy‐6‐methoxy‐3,4‐dihydronaphthalene‐2‐trifluoromethanesulfonate) using the palladium complex Pd(PPh3)4 as catalyst. Hydrolysis of 5a and 5b in THF‐HCl solution at room temperature gave the corresponding keto compounds 6a and 6b. The other important intermediates – the substituted (E)‐2‐methylene‐1‐tetralones 10a and 10b – were obtained by condensation of 1‐tetralone with the corresponding aromatic aldehydes (9a and 9b). Hydrogenation (H2), followed by reduction (NaBH4), and subsequent hydrolysis and elimination led to the keto compounds 13a and 13b. The title compounds, the oximes 7a, 7b and 14a, 14b were formed by reaction of hydroxylamine hydrochloride with the corresponding keto compounds. Using a microsomal fraction of human testicular enzyme, 7a, 7b, 14a, and 14b inhibited the target enzyme only marginally.

Non-steroidal CYP17A1 Inhibitors: Discovery and Assessment

“…Attempts have been made to introduce an element of unsaturation into the tetralin ring as well as an oxime group into the side chain. These modifications yielded only marginal or no inhibitory properties when tested in human CYP17A1. − …”

CYP17 Inhibitors for Prostate Cancer Treatment – An Update

“…Only marginal inhibitory activity of human CYP17 was seen with compounds 98 and 99, the E-and Z-1-methyl-2-(1-hydroximinoethyl)-6-methoxy-3,4-dihydronaphthalene isomers, respectively [207], as well as with other nonsteroidal oximes such as 100-103 [208]. The azole substituted naphthalenes 104-107 were also found not to inhibit the human enzyme [179].…”