Pyridyl-Substituted Tetrahydrocyclopropa[a]naphthalenes: Highly Active and Selective Inhibitors of P450 arom

Abstract

The synthesis and biological evaluation of substituted exo-1-(4-pyridyl)-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalene s as inhibitors of estrogen biosynthesis is described [H (1); 4-OCH3 (2); 5-OCH3 (3); 6-OCH3 (4); 1-CH3, 6-OCH3 (5); 4-OCH3, 7-Br (6); 6-OCH3, 5-Br (7); 4-OH (8); 5-OH (9); 6-OH (10)]. The synthetic key step--the formation of the cyclopropyl ring--was accomplished using the conditions of a modified Wolff-Kishner reduction (N2H5OH/KOH; delta T) and yielded exclusively the exo-configurated diastereomers. The racemic compounds 1-10 showed an inhibition of human placental aromatase (P450 arom) exhibiting relative potencies (rp) from 3.7 to 303 (compounds 8 and 4, respectively; rp of aminoglutethimide (AG) identical to 1, fadrozole = 359). The enantiomers of 4 and 7 were separated by LPLC on tribenzoyl cellulose and by crystallization of the diastereomeric tartrates (4). (1aS,2S,7bS)-(+)-4 (absolute configuration determined by X-ray crystallographic analysis) is the active P450 arom inhibiting enantiomer of 4 and shows a rp value of 617. Compound 4 is a reversible inhibitor showing a competitive type of inhibition and a type II difference spectrum. In vitro 4 influenced other steroidogenic P450 enzymes either not at all (bovine adrenal P450 scc) or only marginally (rat testicular P450 17, bovine adrenal P450 18). In ACTH-stimulated rat adrenal tissue, 4 was less active, inhibiting corticosterone and aldosterone formation compared to AG and fadrozole, respectively. In vivo 4 was not superior to AG as far as the inhibition of the uterotrophic activity of androstenedione (juvenile SD rats) and the reduction of the plasma estradiol concentration (pregnant mares' serum gonadotropin-primed SD rats) are concerned. Compound 4 shows marked antitumor activity in the dimethylbenzanthracene-induced mammary carcinoma of the SD rat: in the postmenopausal model it is at least as active as AG; in the premenopausal experiment it is clearly superior to AG. No induction of hepatic P450 enzymes was observed in the latter experiment. The rp value of 4 toward rat ovarian P450 arom, i.e., 23 (rp of AG identical to 1), is markedly decreased compared to the human enzyme (rp value of 303). From this fact it must be concluded that 4 should be more active in the human than in the rat.

Nonsteroidal aromatase inhibitors: Recent advances

“…50 The saturated methylene bridge of the latter compounds was constrained by fusing a cyclopropane ring to positions C1 and C2 of the tetraline nucleus. 53 This modification introduced asymmetry in the molecules, and in some cases, the stereoisomers were isolated and tested. Stereospecificity was shown, particularly in the case of the 6-methoxy derivative 5, whose (þ)-enantiomer (absolute configuration 1aS,1S,7bS) had IC 50 ¼ 0.030 mM, vs. IC 50 ¼ 10 mM for the (À)-enantiomer.…”

“…Unfortunately, 4 and (þ)-5 shared a disappointing in vivo activity as determined from rat experimental breast tumor models. 52,53 The tetralinic skeleton was further varied by changing it into a quinolinic one, in order to pursue the goal of simultaneously blocking both aromatase and another enzyme active in tumor tissues, i.e., thromboxane A 2 synthase (TxA 2 ). The involvement of TxA 2 in the proliferation of tumor cells, 54 as well as the possibility to control the metastasis production by means of TxA 2 inhibitors 55 had been earlier demonstrated.…”

Synthesis and biological evaluation of structurally diverse α-conformationally restricted chalcones and related analogues

“…3). [55][56][57][58] Ty and coworkers reported the synthesis of enantiomerically pure cyclopropyl analogues of CA4 to evaluate the effects of stereochemistry on biological activity. 59 We report synthetic strategies directed toward the preparation of conformationally restricted chalcones and corresponding derivatives, along with evaluation of inhibition of tubulin polymerization (cell-free assay) and cytotoxicity against NCI-H460 (non-small cell lung carcinoma), DU-145 (prostate carcinoma), and SK-OV-3 (ovarian adenocarcinoma) human cancer cell lines.…”

Inhibition of P450 17 as a New Strategy for the Treatment of Prostate Cancer

“…Based on the results of the steroidal inhibitor 1 shown in Fig. (2), Hartmann et al designed different classes of nonsteroidal compounds acting as mimics of 1 [31][32][33][34][40][41][42][43]. In Fluorine, the only element capable of mimicking hydrogen by virtue of comparable size ("isosterism"), may not only induce very specific properties to molecules due to its electron-withdrawing power, but may confer metabolic Fig.…”