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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)
Author(s) -
Zhuang Yan,
Hartmann Rolf W.
Publication year - 1998
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/(sici)1521-4184(199801)331:1<36::aid-ardp36>3.0.co;2-0
Subject(s) - aryl , chemistry , enzyme , stereochemistry , chemical synthesis , enzyme inhibitor , biochemistry , combinatorial chemistry , organic chemistry , in vitro , alkyl
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 1 H 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(PPh 3 ) 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 (H 2 ), followed by reduction (NaBH 4 ), 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.