Structure-activity relationships of 3-deoxy androgens as aromatase inhibitors. Synthesis and biochemical studies of 4-substituted 4-ene and 5-ene steroids.

Tohoku Pharmaceutical University, 4-1 Komatsushima-4-chome, Aobaku, 981-8558, Sendai, Japan.
Steroids (Impact Factor: 2.64). 09/2003; 68(6):533-42. DOI: 10.1016/S0039-128X(03)00085-0
Source: PubMed


As part of our investigation into the structure-activity relationship of a novel class of aromatase inhibitors, two series of 3-deoxy androgens, androst-5-en-17-ones with a non-polar alkoxy (5 and 6), alkyl (20-22), or phenylalkyl (23 and 24) group at C-4beta and 4-acyloxyandrost-4-en-17-ones (29-32, and 34) were synthesized and evaluated. The 4beta-alkyl and 4beta-phenylalkyl compounds were obtained through reaction of 4alpha,5alpha-epoxy steroid (8) with RMgBr (R: alkyl and phenylalkyl) followed by dehydration of the 4beta-substituted 5alpha-hydroxy products (15-19) with SOCl(2) as key reactions. Acylation of 4alpha,5alpha-diol (25) with (RCO)(2)O in pyridine and subsequent dehydration with SOCl(2) gave the 4-acyloxy steroids. All of the steroids studied, except for 4-acetoxy-19-ol (34) that was a non-competitive inhibitor of human placental aromatase, blocked aromatase activity in a competitive manner. 4-Benzoyloxy- and 4-acetoxy steroids (31) and (32) were the most powerful inhibitors of aromatase (K(i)=70 and 60nM, respectively). Elongation of an acetoxy group in a series of 4-acyloxy steroids or a methyl group in a series of 4beta-alkyl steroids decreased affinity for aromatase principally in relation to carbon number of the acyl or alkyl function. The present findings are potentially useful for understanding the spatial and electronic nature of the binding site of aromatase as well as for developing effective aromatase inhibitors.

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    • "One of them consisted in C-3 decarbonylation in order to obtain 7a- allyl-3-deoxo-4-androstenes. Actually, it is known from previous works [13] [22] [23], that the C-3 carbonyl group is not essential for aromatase inhibition, since the C-17 carbonyl group remains in the molecule [14]. In fact, aromatase establishes two hydrogen bonds with the carbonyl groups at C-3 and C-17 [31] of its substrate androstenedione and, at least one of them must be present in the steroid molecule in order to bind the enzyme. "
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    ABSTRACT: Two series of derivatives of 7α-allylandrostenedione, namely its 3-deoxo and 1-ene analogs, were designed and synthesised and their biochemical activity towards aromatase evaluated. In each of these series, the C-17 carbonyl group was further replaced by the hydroxyl and acetoxyl groups. The attained data pointed out that the absence of the C-3 carbonyl group led to a slightly decrease in the inhibitory activity and the introduction of an additional double bond in C-1 revealed to be a very beneficial structural change in the studied compounds (compound 12, IC50=0.47 μM, Ki=45.00 nM). Furthermore, the relevance of the C-17 carbonyl group in the D-ring as a structural feature required to achieve maximum aromatase inhibitory activity is also observed for this set of derivatives.
    Steroids 03/2013; 78(7). DOI:10.1016/j.steroids.2013.02.016 · 2.64 Impact Factor
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    • "Numazawa et al. [6] [7] [8] in their structure-activity relationship studies on steroid aromatase inhibitors indicated the existence of a binding pocket in the active site of the enzyme that can accommodate several chemical groups placed at the C- 4 position of the steroid. Relying on this information, Cepa and co-workers [9] succeeded to combine in the same structure the diosphenol A-ring of formestane and the ␦-lactone d-ring of testolactone, as observed in 4-hydroxy-d-homo- 17a-oxaandrost-4-ene-3,17-dione. "
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    ABSTRACT: Starting from the D-homo lactones of androst-4-en-3-one 3 and 4, prepared from 1 and 2, the new 17a homolactones 5-12, 14 and 15, were synthesized. The 4-hydroxy compounds 9 and 10 were obtained through the reaction of 4alpha,5alpha- (5 and 7) and 4beta,5beta- (6 and 8) epoxides with formic acid. The epoxides 5 and 6 were prepared from compound 3, and epoxides 7 and 8 from compound 4 by oxidation with H(2)O(2) under basic conditions. Compound 1 served as a starting substance for obtaining lactones 11-13. Oxidation of compound 1 with m-chloroperbenzoic acid yielded 11 and 12, but compound 13 gave 14. Compound 15 was obtained from 13 by oxidation with H(2)O(2) under basic conditions. The structures of epoxides 6 and 14 were confirmed by X-ray structural analysis. Cytotoxic activity against three tumor cell lines (human breast adenocarcinoma ER+, MCF-7, human breast adenocarcinoma ER-, MDA-MB-231, and prostate cancer PC3) was evaluated. Compounds 6 and 14 showed strong activity against PC3, the IC(50) being 10.6 and 2.2 microM, respectively, whereas compounds 3 and 8 showed strong activity against MDA-MB-231 (IC(50) is 9.3 and 3.6 microM, respectively). Aromatase inhibition assay showed that the tested compounds 9, 10, and 14 possess lower activity compared to formestane.
    Steroids 08/2008; 73(6):681-8. DOI:10.1016/j.steroids.2008.02.006 · 2.64 Impact Factor
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    ABSTRACT: The purpose of this study was to determine the effects of 6OXO™, an aromatase inhibitor, in a dose dependent manner on serum hormone levels and clinical safety markers in resistance trained males. Sixteen healthy trained subjects, who participated in a resistance training protocol, had blood samples taken at weeks 0, 1, 3, 8, and 11. These samples were analyzed for total testosterone, free testosterone, DHT, estradiol, estriol, estrone, SHBG, LH, FSH, GH, and cortisol. There were no significant differences between groups (p>0.01). However, total testosterone concentration, free testosterone concentration, and DHT concentration increased over the course of the study (p=0.009). Measures of body composition did not change with supplementation (p>0.05). Safety markers were seen to not be adversely affected with ingestion of 6OXO™ (p>0.01). 6OXO™ supplementation appears to be safe and increases total testosterone, free testosterone, and DHT concentrations independent of the two different doses.
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