Structure-activity relationships of 3-deoxy androgens as aromatase inhibitors. Synthesis and biochemical studies of 4-substituted 4-ene and 5-ene steroids.
ABSTRACT 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.
- Chemical & Pharmaceutical Bulletin - CHEM PHARM BULL TOKYO. 01/2004; 52(6):722-726.
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ABSTRACT: 3,7-Dimethyl-7-hydroxy-2-octen-1,6-olide (1) and 3,7-dimethyl-2,6-octadien-1,6-olide (2), the natural bioactive compounds isolated from the fruit of Litsea cubeba and the liverwort Plagiochila rutilans, were totally synthesized using easily available cis-geraniol as raw material in short, convenient, and low-cost, five-step reactions including three steps of oxidation, cyclization, and dehydration, with an overall yield of 47.5% and 37.3%.Journal of Asian natural products research 06/2013; · 0.61 Impact Factor
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ABSTRACT: Glasses with composition xFe2O3–5MgO–(95−x)SiO2, where x is equal to 1.25, 2.5, 5 and 10mol%, were prepared by the sol–gel method. The gel samples were heat-treated at temperature between 500 and 1000°C. The samples were studied using X-ray diffraction (XRD), scanning electron microscopy combined with X-ray microanalysis by energy dispersive spectrometer (SEM-EDS), visible–near infrared spectrometry and dc magnetic measurements.In most samples the presence of magnesium ferrite was detected by XRD. However, in the brown and transparent 1.25Fe2O3–5MgO–93.75SiO2 sample heat-treated at 500°C, there was no evidence, by XRD, of the presence of magnesium ferrite. In 10Fe2O3–5MgO–85SiO2 composition, heat-treated at 500 and 1000°C, hematite was also present. By the Scherrer method it was determined that the average size of magnesium ferrite crystals, in all the samples heat treated at 1000°C, varied from 8 to 10nm.All the samples heat treated at 1000°C exhibited ferro or ferrimagnetic interactions combined with superparamagnetism with a blocking temperature. The sample with composition 1.25Fe2O3–5MgO–93.75SiO2 treated at 500°C showed a paramagnetic behaviour down to 5K.Materials Chemistry and Physics - MATER CHEM PHYS. 02/2012;