Philip M. Weintraub

Synthesis of 21,21-difluoro-3β-hydroxy-20-methylpregna-5,20-diene and 5,16,20-triene as potential inhibitors of steroid C17(20) lyase

Novel 21,21-difluorovinyl steroids, designed as difluorinated C20(21) enol mimics of pregnenolone, were targeted as potential mechanism-based inhibitors of C17(20) lyase, a crucial enzyme in the biosynthesis of testosterone. Addition of (difluoromethyl)diphenylphosphine oxide reagent to 17-acetyl steroids was the approach chosen for the construction of these compounds. Of particular interest were the abnormal Wittig products which formed during attempted preparation of the triene 9. The target difluoroolefin 3 was found to be a moderately potent, time-dependent inhibitor of the enzyme.

Novel Steroidal Vinyl Fluorides as Inhibitors of Steroid C17(20) Lyase

20-fluoro-17(20)-pregnenolone derivatives were designed as enol mimics of pregnenolone. All of the targeted, novel fluoroolefins were potent inhibitors of C17(20) lyase.

PREPARATION OF N-ARYL-2-HYDROXYPROPIONAMIDES FROM HYDROXY AROMATIC COMPOUNDS USING A ONE-POT SMILES REARRANGEMENT PROCEDURE

Abstract Acylation of hydroxy aromatic compounds with 2-bromo-2-methylpropionamide followed by Smiles rearrangement of the resulting 2-aryloxypropionamide in a one-pot procedure produced the corresponding 2-hydroxy-2-methyl-N-arylpropionamides which can be converted to arylamines by hydrolysis. Particularly important applications of this new process were the conversions of estrone ( 6 ) and estradiol ( 14 ) to the corresponding 3-aminoestratriene derivatives 8 and 15 , respectively. In addition, an improved Semmler-Wolff procedure is described for the conversion of 19-nortestosterone ( 22 ) to 3-aminoestra-1,3,5(10)-trien-17β-ol hydrochloride ( 26 ).

Novel silylated steroids as aromatase inhibitors

Androst-4-en-3-one analogs incorporating a trimethylsilyl or a trimethylsilylmethyl group at C-1, C-2 or C-19 were prepared and evaluated as inhibitors of aromatase. Only 10-[1-hydroxy-2-(trimethylsilyl)ethyl]estr-4-ene-3,17-dione inhibited human placental aromatase. Enzyme kinetic analysis revealed competitive inhibition [apparent dissociation constant (Ki) of 562 +/- 12 nM] associated with marginal time-dependent inhibition.

The synthesis and biological activity of a highly selective adenosine A2a receptor agonist.

Three novel nucleosides 1, 2, and 3 were prepared that contained side chains at the 2-position of adenosine. Compound 1 was shown to be the most selective A2a receptor agonist reported to date having an A1/A2 ratio of 2400. In addition, compound 1 was shown to reduce blood pressure in rats and dogs with only minimal effects on heart rate.

Conformationally restricted leukotriene antagonists. Stereoselective synthesis of some leukotriene D4 analogs

Abstract The stereocontrolled synthesis of conformationally restricted LTD4 analogs 2a, b is described. Epoxidation of enone 4 affords a 2.4:1 mixture of trans-epoxide 5 and cis-epoxide 9. Stereocontrolled elaboration of each epoxide to final product involves stereoselective Wittig olefination to Z-olefins 6 and 10, regiospecifie epoxide ring opening with methyl mercaptoacetate to diesters 8 and 12, and saponification to 2a, b.

Inhibition of hamster adrenal 11β19-hydroxylase activity

Abstract Increased mineralocorticoid activity has been associated with elevated urinary levels of 19-nordeoxycorticosterone in several forms of experimental and human hypertension. Biosynthesis of 19-norsteroids involves hydroxylation of the C-19 methyl group. We synthesized the 4-hydroxy analogs of deoxycorticosterone, deoxycorticosterone acetate, progesterone, and androstenedione and evaluated them as inhibitors of deoxycorticosterone llβll9-hydroxylase using hamster adrenal mitochondrial preparations. These 4-hydroxy analogs were inhibitors of this P 450 hydroxylase, with approximately 10 times weaker affinity than their respective natural substrates. 4-Hydroxydeoxycorticosterone was the most potent inhibitor evaluated in this study. The half-maximal inhibitory concentration of deoxycorticosterone hydroxylation was 5 μm, 15 μm, more than 50 μm, and 14 μM, respectively, for the above compounds. (Steroids 55 :378–382, 1990)