James W. Cessac

Synthesis and antimitotic activity of novel 2-methoxyestradiol analogs.

The syntheses and antimitotic activity of several novel 2-methoxyestradiol analogs are described. Structural modifications investigated include introduction of additional unsaturation in rings B and D; inversion at C-13; and substitution at the C-2, C-15, C-16, and C-7 alpha positions. Of 15 analogs synthesized, 2 have demonstrated superior biological activities compared to 2-methoxyestradiol.

New 11β-aryl-substituted steroids exhibit both progestational and antiprogestational activity

The syntheses of three 11 beta-aryl-19-norpregna-4,9-dien-3-one derivatives with 17-spirolactone and 17 beta-hydroxy-17 alpha-cyanoethyl substitutions are described. The progesterone agonist/antagonist activities of the new compounds are investigated using a recently developed tissue culture system that relies on the progesterone agonist up-regulation of the prostate-specific antigen (PSA) gene in female breast tumor cell lines. Two of the newly synthesized compounds exhibit mixed agonistic/antagonistic progestational activity.

Preparative chemical methods for aromatization of 19-nor-Δ4-3-oxosteroids ☆

Abstract Two preparative chemical methods for aromatization of 19-nor-Δ4-3-oxosteroids are described. The first method consist of an oxidative aromatization of 19-nor-Δ4-3-oxosteroids with iodine-ceric ammonium nitrate in methanol to give a mixture of 3-methoxy ring-A aromatized derivatives consisting of the desired product, the Δ9,11 derivative, the 6-oxo derivative as well as some ring-A iodinated material. Conversion of this material to a mixture of the 3-methoxy ring-A aromatized derivative and its 6-oxo derivative was achieved by catalytic hydrogenation. Finally, reduction of the 6-oxo function with triethylsilane in trifluoroactive acid gave the 3-methoxy-17-trifluoroacetate ring-A aromatized derivative as a single product. In the second method, reaction of 19-nor-Δ4-3-oxosteroids with copper (II) bromide in acetonitrile at room temperature resulted in aromatic steroids in a single in excellent yields. The second method was used in the first practical synthesis of a 6-dehydroestrogen from a 19-nor-Δ4,6-3-oxosteroid.

A practical large-scale synthesis of 17α-acetoxy-11β-(4-N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione (CDB-2914) ☆

A new practical synthesis of 17α-acetoxy-11β-(4-N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione (CDB-2914) is described. The synthesis gives easily isolable solids at all steps and is amenable to large-scale process.

A new, practical synthesis of 2-methoxyestradiols.

An efficient and practical approach to synthesize moderate to large amounts of 2-methoxyestradiol (2-ME2) is described. The key step in the synthesis is the regioselective introduction of an acetyl group at the C-2 position of estradiol using a zirconium tetrachloride mediated Fries rearrangement carried out on estradiol diacetate. The seven step synthetic procedure readily gave 2-ME2 in 49% overall yield. Application of this method to the synthesis of 2-methoxy-7 alpha-methylestradiol is also described.

Synthesis and biological evaluation of partially fluorinated antiprogestins and mesoprogestins.

A series of antiprogestins have been synthesized by partially fluorinating the steroid molecule in positions relevant for receptor binding. By introducing fluorine at the exo-methylene of the 17 spirofuran ring, we obtained partial agonists (mesoprogestins) with significant applications for antiproliferative and antiovulatory treatment strategies in gynecological therapy such as uterine fibroids, endometriosis and heavy menstrual bleeding. Compared to the standard drug RU486, our synthesized compounds exhibited considerable dissociation between antiprogestational and antiglucocorticoid PR receptors. Furthermore, our studies have shown that pure antiprogestins can be generated by partially fluorinating the 17 propenyl and propynl group or by substituting the 4 acetyl phenyl group in the 11 position using trifluromethyl group.

Oxidative demethylation of 4-substituted N,N-dimethylanilines with iodine and calcium oxide in the presence of methanol

Reaction of para-substituted N,N-dimethylarylamines with iodine–calcium oxide in tetrahydrofuran–methanol affords N-methylarylamines in good yield.

11β-Substituted 13β-ethyl gonane derivatives exhibit reversal of antiprogestational activity

Abstract The syntheses of three 17α-acetoxy-13β-ethyl-11β-aryl-18,19-dinorpregna-4,9-diene-3,20 diones from levonorgestrel are described. Despite their close structural similarity to the antiprogesterone CDB-2914, one of the compounds exhibits agonistic progestational activity, and the other two compounds are totally inactive.

A direct radioimmunoassay for 5α-androstane-3α,17β-diol 17-glucuronide ☆

Abstract Synthesis of the 11α-hemiglutaryl derivative of 5α-androstane-3α,17β-diol 17-glucuronide (androstanediol-17G) starting from androsta-4, 9(11)-diene-3,17-dione through a 10-step sequence and the preparation of its bovine serum albumin conjugate is described. By using this conjugate, antiserum was raised in rabbits which proved to be very specific for androstanediol-17G. A direct radioimmunoassay using a double antibody procedure is described for the measurement of androstanediol-17G from plasma without prior chromatography.

Synthesis of New Immunogens for Estrone and Estradiol-17β and Antisera Evaluation

Syntheses of the 6 alpha-O-carboxymethyl ether derivatives of estrone and estradiol-17 beta and the preparation of their bovine serum albumin conjugates are described. The generation and evaluation of antisera produced from these conjugates is discussed.