Vladimir Petrow

Modified steroid hormones-XXXIII : Steroidal 6-formyl-3-alkoxy-3, 5-dienes and some of their transformations

Abstract Reaction between steroidal 3-alkoxy-3,5-dienes and the Vilsmeier reagent leads to high yields of the corresponding 6-formyl derivatives. These intermediates are reduced to 3-alkoxy-6-hydroxymethyl-3,5-dienes which undergo dehydration with acids to 6-methylene-4-en-3-ones.

Modified steroid hormones. XL. Some heterocyclic types.

Abstract The preparation of 17β-hydroxy-17α-methylandrostano [2,3-b]-(5′-hydroxyindole) along with other novel indolosteroids is described.

Antiprogestational agents. The synthesis of 7-alkyl steroidal ketones with anti-implantational and antidecidual activity.

A series of 7alpha- and 7beta- alkyl derivatives of steroidal 4-en- and 5-en-3-ones were prepared by 1,6-conjugate addition of organocopper reagents to various steroidal 4,6-dien-3-ones of the androstane, estrane and gonane series. Biological study of these and related compounds revealed that 17beta-hydroxy-7alpha-methyl-5-androsten-3-one (2), 17beta-hydroxy-7alpha-methyl-5-estren-3-one acetate and 17beta-hydroxy-7alpha-methyl-4-estren-3-one acetate had significant anti-implantational and antidecidual activities. The contragestative effects were associated with the latter anti-hormonal properties, and not with the androgenicity of these compounds.

Endocrine dependence of prostatic cancer upon dihydrotestosterone and not upon testosterone.

Growth of the Dunning R3327−H prostatic adenocarcinoma, implanted in the rat, is inhibited by 6−methylene progesterone. This compound is a potent inhibitor of rat prostatic 5‐α‐reductase and in‐vivo produces marked involution of the prostate. Thus the tumor requires dihydrotestosterone and not testosterone for growth.

Prostatic cancer. I. 6-Methylene-4-pregnen-3-ones as irreversible inhibitors of rat prostatic Δ4-3 ketosteroid 5α-reductase☆

Abstract Some derivatives of 6-methylene-4-pregnen-3-one were studied as inhibitors of Δ4-3-ketosteroid 5α-reductase. Maximum inhibitory activity was shown by 17-acetoxy-6-methylene-4-pregnene-3,20-dione (AMPD). Irreversible inactivation was observed following preincubation of the enzyme with NADPH and AMPD. This inactivation was found to occur only in the presence of NADPH. As such enzyme inactivation was not due to the formation of a more inhibitory metabolic product, or to the formation of Superoxide via a cytochrome P-450/NADPH pathway, it seemed likely that the observed inactivation was derived from an irreversible combination of the enzyme with AMPD. That this was probably the case was established by kinetic studies which revealed a pattern compatible with a kcat type of mechanism.

HYPOGLYCAEMIC AGENTS. PART II

Some structural analogues of the active compounds (I), (II) and (III) are described. Their biological study failed to reveal significant hypoglycaemic activity

Prostatic cancer—II. Inhibitors of rat prostatic 4-ene-3-ketosteroid 5α-reductase derived from 6-methylene-4-androsten-3-ones

The studied 6-methylene-4-androsten-3-ones proved to be significantly inferior to 6-methylene-4-pregnene-3,20-dione and its 17-acetoxy derivative described in Part 1 as inhibitors of 4-ene-3-ketosteroid 5 alpha-reductase [1] in vitro. Surprisingly, the 6-methylene derivative of testosterone was only weakly active until acetylated, when an effective inhibitor was obtained. Etherification of the hydroxyl-group, its replacement by a hydrocarbon chain, or introduction of a substituent at C17 or on the methylene group led to virtual loss of activity. 17 alpha-Chloro-6-methylene-4-androstene-3-one had ca 60-70% of the potency of progesterone, but was inactive as enzyme inhibitor in explants of rat prostate in tissue culture and in in vivo studies. 6-Methylenetestosterone acetate was weakly active as enzyme inhibitor in explants of human prostate in tissue culture and produced a histological picture closely resembling testosterone and differing from that of cyproterone acetate. In vivo in the rat it had 80% of the androgenic activity of testosterone propionate. The foregoing data have been used to define some structural characteristics necessary for enzyme inhibition and to draw some conclusions regarding the architecture of the androgen and progesterone receptors and of the enzyme active site.

Modified steroid hormones—XXXVIII : Some transformations of steroidal 3-alkoxy-6-formyl-3,5-dienes and related compounds☆

Abstract An improved route to 6-methylated steroidal 4-en-and 4,6-dien-3-ones is described.

Inhibitory effects of some steroidal 6-methylene derivatives on 5α-reductase activity in human and rat prostate

Using a short-term organ culture assay, some 6-methylene derivatives of progesterone and testosterone have been evaluated for their effects on testosterone metabolism in rat and human prostatic tissues, and on DNA synthesis in explants from 7-day castrated rats. Comparative studies showed that the ability to inhibit 5 alpha-reductase activity was fairly specific with respect to structural requirements. Methylene substitution at the C6 position of the progesterone molecule was associated with high inhibitory activity. In explants prepared from human prostates, 6-methylene progesterone (II) had 70-85% (mean of 79% for 4 BPH tissues) of the potency of unmodified progesterone (I). Its 17 alpha-acetoxy-6-methylene analog (III), however, had only 32-73% (mean of 53% for 5 BPH specimens) of the activity of (I). The degrees of inhibition in rat and human prostatic tissues were similar. Inhibition of 5 alpha-reductase activity in cultured explants by 6-methylene progesterone (II) could not be reversed by change in media. The 6-methylene derivatives had little or no effect on DNA synthesis. Histological examination confirmed a lack of effect on basal cell proliferation. However, morphological alterations affecting epithelial cell height and secretory activity were clearly evident. These results indicate that, under our experimental conditions, the main effect of inhibition of 5 alpha-reductase activity in prostatic tissues by 6-methylene derivatives of progesterone is related to suppression of differentiated function.

Modified steroid hormones—XLVIII : A new route to 17α-bromoethynyl- and 17α-iodoethynyl-17β-hydroxy steroids☆

Abstract Treatment of the lithium derivatives of 17α-ethynyl steroids with bromotrifluoromethane or heptafluoro-1-iodopropane in liquid ammonia afforded, respectively, the corresponding 17α-bromoethnynyl or 17α-iodoethynyl steroids in satisfactory yields.