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Quantum mechanical calculations at the semiempirical level (AM1 method) were conducted for estragole (1), methyleugenol (2), safrole (3), alpha-asarone (4), beta-asarone (5), elemicin (6), allylbenzene (7), eugenol (8), trans-anethole (9), isosafrole (10), and myristicin (11), and the results compared with the known genotoxicity of 1-6 and the absence of genotoxicity of 7-11 (unscheduled DNA synthesis assay). The various compounds showed no significant differences in the relative stability of the radical species formed as intermediates in C-sp3 hydroxylation (delta HR(radical)) and in the corresponding enthalpy of activation (delta H++). In contrast, the carbonium ions of the genotoxic congeners 1-6 were shown to be comparatively more stable than those of the inactive compounds 7-11, with the exception of eugenol (8). The inactivity of this compound could be due to a very rapid stabilization of the carbonium ion by deprotonation to form a quinone methide, as suggested by quantum chemical calculations. The relative stability of the carbonium ion thus appears to be one of the key factors in the genotoxicity of allylbenzenes and propenylbenzenes.

A short and efficient synthesis of novel benzo [c]quinolizin-3-one derivatives is described. The synthesis is based on the tandem Mannich-Michael cyclization between 2-silyloxy-l,3-butadienes and a N-t-Boc iminium ion. The prepared derivatives are selective inhibitors of human steroid 5c~-reductase isoenzyme 1, thus having potential application as drugs for treatment of male pattern baldness and other DHT-dependent skin disorders. © 1998 Elsevier Science Ltd. All rights reserved.Steroid 5ct-reductase is a family of two isozymes, named type 1 (5ctR-l) and type 2 (5~R-2), that catalyzes the NADPH-dependent reduction of testosterone (T) to dihydrotestosterone (DHT), and other 3-oxo-4-ene steroids (e.g., progesterone, corticosterone, etc.) to the corresponding 5ct compounds. The 5cc-reductase and its product DHT play an important role in the pathogenesis of some important human diseases, i.e. benign prostatic hyperplasia (BHP) and prostatic cancer, and skin disorders such as acne, alopecia, pattern baldness in men and hirsutism in women. Thus, the discovery of potent and selective inhibitors for the two isozymes appears of great importance for the pharmacological treatment of these pathologies.~ Although the precise role of each 5ctR isoenzyme in DHT-dependent diseases is yet to be fully elucidated, however it is now clear that inhibitors of both enzymes are best applied to the BPH treatment, whilst selective inhibitors of 5czR-1 could potentially be used for skin disorders treatment.As part of our studies on 5tx-reductase 2 and its inhibitors 3 we discovered a series of 19-nor-10-azasteroids 1 (Figure 1) which were potent inhibitors of both human 5ctR isoenzymes. 4 *

The "water-dragging" effect of various solutes was investigated in biphasic systems made of water and poorly hydrated solvents, namely 6-undecanone, chloroform, and halothane. Like in the di-n-butyl ether/water system,' the "water-dragging" effect is primarily determined by the H-bond-donor acidity of solutes, while the chemical nature of the organic solvent (provided it is a poorly hydrated one) plays a limited role only. A molecular interpretation is offered whereby the predominant influence of the H-bond-donor acidity of amphiprotic solutes (A) is due to their propensity to form cyclic hydrates of the type A2W and AW2 (W = HzO).

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