Tetrahydronaphthalenes:  Influence of Heterocyclic Substituents on Inhibition of Steroidogenic Enzymes P450 arom and P450 17

Abstract

In search of new leads for selective inhibition of estrogen and androgen biosynthesis, respectively, heterocyclic substituted 2-(arylmethylene)-1-tetralones (1-4, 9-17), 2-(aryl-hydroxymethyl)-1-tetralones (5-8), exo-1a,2,3,7b-tetrahydro-1H-cyclopropa[alpha] naphthalenes (18-24), and 3-alkyl substituted 4,5-dihydronaphtho[1,2-c]pyrazoles (25-27) were synthesized and tested for inhibitory activity toward four steroidogenic enzymes (P450 arom, P450 17, P450 18, and P450 scc, as well as another P450 enzyme, thromboxane A(2) (TXA(2)) synthase. The test compounds inhibited human placental P450 arom, showing a wide range of inhibitory potencies. (Z)-4-Imidazolyl compound 17 was the most potent inhibitor, with a relative potency (rp) of 110 [rp of aminoglutethimide (AG) = 1), rp of fadrozole = 359]. A competitive type of inhibition was shown by the (E)-4-imidazolyl compound 16(rp = 71). On the other hand some of these compounds inhibited rat testicular P450 17. Maximum activity was shown by the 3-pyridyl compound 20 (rp = 10, ro of ketoconazole = 1). 20 was the only compound which exhibited a marked inhibition of TXA(2) synthase (IC(50) = 14.5 microM; IC(50) of dazoxiben = 1.1 microM). Regarding selectivity toward the steroidogenic enzymes, compound 16 was relatively selective toward P450 arom, whereas compound 20 was relatively selective toward P450 17. (P450 arom: K(m) testosterone = 42 nM, K(i)16 = 33 nM, K(i)20 = 3 microM. P450 17: K(m)progesterone = 7 microM, K(i)16 = 9 microM, K(i)20 = 80 nM). 17 and 24 were not selective since they showed strong inhibition of P450 arom (K(i)17 = 26 nM, K(i)24 = 0.12 microM) and P450 17 (K(i) 17 = 0.7 microM, K(i)24 = 0.11 microM).

Metal–Organic Frameworks for Catalysis

“…The selective oxidation of tetralin to 1-tetralone, a reactive intermediate for pharmaceuticals, dyes and agrochemicals, and also an additive to enhance the cetane number in diesel fuels [60][61][62], was carried out. A porous chromium terephthalate metal organic framework MIL-101 containing a redox active Cr(III) ions and Cu(II)-1,3,5-benzenetricarboxylate Cu 3 (BTC) 2 was applied to the liquid-phase oxidation of tetralin in (1) using tertbutylhydroperoxide (t-BuOOH) or O 2 in the presence of trimethylacetaldehyde as an oxidant [49,63].…”

5-Chloropyrazole-4-carboxaldehydes as synthon in heterocyclic synthesis

“…Pyrazoles are valuable moieties of bioactive compounds showing antimicrobial [1], anticancer [2], anti-inflammatory [3], and selective enzyme inhibitory activities [4]. Moreover, a series of pyrazole derivatives is used as insecticides [5], fungicides [6,7], and herbicides [8][9][10][11].…”

Electrochemical studies of certain nitro substituted pyrazolin-5-ones

“…Pyrazoles have an extensive history of application in agrochemical and pharmaceutical industry for varied purposes. Pyrazole derivatives have been reported to demonstrate a broad spectrum biological activity including antibacterial [1], antimicrobial [2], antifungal [3], antitumor [4], analgesic [5], antiinflammatory [6], anticonvulsant [7], antipyretic [8], enzyme inhibitory activities [9].…”