A general strategy for the synthesis of taxane diterpenes.

The carbon skeleton of any organic molecule serves as the foundation for its three-dimensional structure, playing a pivotal role in determining its physical and biological properties. As such, taxane diterpenes are one of the most well-known natural product families, primarily owing to the success of their most prominent compound, paclitaxel, an effective anticancer therapeutic for more than 25 years. In contrast to classical taxanes, the bioactivity of cyclotaxanes (also referred to as complex taxanes) remains significantly underexplored.

Solving a Mystery with Classical and Dual Photoredox Catalysis: Application of Nickel in the Synthesis of Ergot Alkaloids.

A short synthesis of the ergot alkaloid lysergene and a formal total synthesis of lysergic acid diethylamide (LSD) under the avoidance of palladium and including two nickel-catalyzed steps instead have been developed. A key intermediate of this approach has already been reported by Hendrickson et al. in 2004 (Hendrickson, J.

Diamond-blackfan anemia in pregnancy.

Background: Diamond-Blackfan anemia is a rare form of congenital red-cell aplasia. Approximately 90% of the patients are diagnosed by 1 year of age. This report presents two pregnancies with good outcomes in a patient over a period of 1.

Synthesis and biological testing of 4'-(dimethylamino)-17 beta-hydroxy-17 alpha-(1-propynyl)benzo[12,12a]-11 alpha,18-cyclo-12a,12b-dihomo-13 alpha-estr-4-en-3-one: an interesting RU 38 486 analog.

A partial synthesis of the title compound, 4'-(dimethylamino)-17 beta-hydroxy-17 alpha-(1-propynyl)benzo[12,12a]-11 alpha,18-cyclo-12a,12b- dihomo-13 alpha-estr-4-en-3-one 1, is reported. The key step in this synthesis represents an intramolecular alkenylaryl radical cyclization. Treatment of 18-[bromo-5-(dimethylamino)phenyl]gona-5,9(11)-diene-3,17-dione-3, 17- bis[cyclic 1,2-ethanediyl acetal] 5 with tributyl tin hydride and a radical initiator introduces the desired 11 beta,18-bridge.

Synthesis and biological activity of 17-chloro-16(17) unsaturated D-homo antiprogestins.

An efficient approach to 17-chloro-16(17) unsaturated D-homo antiprogestins is described. The key steps of the synthesis are a ring-expansion via dichlorocarbene addition to a 17-silyl enol ether and a palladium catalyzed coupling of an 11 beta-(4-aryltriflate) with tributyl(1-ethoxyethenyl)stannane or diethyl(3-pyridinyl)-borane. The new progesterone antagonists were tested for their biological activities and compared to those of known antiprogestins.

Aldosterone antagonists. 4. Synthesis and activities of steroidal 6,6-ethylene-15,16-methylene 17-spirolactones.

Several steroidal 6,6-ethylene-15,16-methylene 17-spirolactones were synthesized to find new progestogens that exhibit both progestational and antimineralocorticoidal activities. The influence of substituents in the 10- and 13-position of the steroidal framework on both properties was investigated. It was found that only compound 12, carrying methyl groups at the 10- and 13-positions, possesses high progestational and antimineralocorticoidal activity.

Aldosterone antagonists. 3. Synthesis and activities of steroidal 7 alpha-(alkoxycarbonyl)-15,16-methylene spirolactones.

Several A- and D-ring substituted steroidal 7 alpha-alkoxycarbonyl spirolactones were synthesized with the purpose of increasing the aldosterone antagonistic potency and reducing the endocrinological side effects relative to the standard drug spironolactone. It was found that the 15 beta,16 beta-methylene derivative 17 exhibited a 2-fold higher aldosterone antagonistic activity compared to either spironolactone or the 15,16-unsubstituted derivative 29 while showing remarkably reduced antiandrogenicity.

Aldosterone antagonists. 2. New 7 alpha-(acetylthio)-15,16-methylene spirolactones.

Some 15,16-methylene derivatives of the aldosterone antagonist spironolactone were synthesized with the purpose of increasing the antialdosterone potency and reducing the endocrinological effects of this standard compound. By introduction of a 1,2-double bond and a 15 beta,16 beta-methylene ring in the spironolactone molecule both goals were achieved. In animal studies mespirenone exhibited a threefold-greater antialdosterone potency and less than 10% of the antiandrogenic activity of spironolactone.

(Z)-17 beta-hydroxy-17 alpha-(2-[125I]iodovinyl)-4-estren-3-one: a new specific gamma-emitting ligand for determination of progesterone receptor.

An iodine-125 labeled ligand for progesterone receptor determination was synthesized: (Z)-17 beta-hydroxy-17 alpha-(2-[125I]iodovinyl)-4-estren-3-one ([125I]SH-D 510). The ligand is stable chemically as well as under the conditions of a receptor assay. The relative binding affinity of the nonradioactive compound towards human uterine progesterone receptor was 7.

Synthesis of antiprogestational steroids.

The discovery of the first competitive progesterone antagonist RU 38,486 has initiated an intense search for more potent and more selective anti-progestins. Among several hundreds of compounds under preliminary investigation, biological characterization is most advanced for derivatives RU 38,486, ZK 98,734 and ZK 98,299. These compounds do not only differ in relative potency, but are clearly distinguished by their different behaviour in various animal models.

Mespirenone and other 15,16-methylene-17-spirolactones, a new type of steroidal aldosterone antagonists.

The ability of a series of 15,16-methylene-spirolactones in comparison to known antimineralocorticoids to inhibit the renal actions of aldosterone was tested in adrenalectomized, glucocorticoid-treated rats. The standard procedure involved continuous i.v.

[Synthesis of gestodene].

The synthesis of the new progestogen, 17 alpha-ethinyl-17 beta-hydroxy-18-methyl-4,15-estradien-3-one (gestodene, 6), starting from 18-methyl-4-estren-3,17-dione (1) can be accomplished by several methods. The oral progestational activity of gestodene is greater than that of levonorgestrel. Gestodene, in combination with ethinylestradiol, is contained in a recently developed oral contraceptive.

Aldosterone antagonists. 1. Synthesis and activities of 6 beta,7 beta:15 beta,16 beta-dimethylene steroidal spirolactones.

Several derivatives of the highly active aldosterone antagonists dihydrospirorenone (2) and spirorenone (3) were synthesized. The purpose of these efforts was to prepare compounds exhibiting reduced endocrinological properties with the same or better aldosterone antagonistic activity than that of spirorenone. The 1 alpha,2 alpha-methylene derivative 20 has a similar aldosterone antagonistic potency compared to that of spirorenone but does not show decreased endocrinological side effects.

Synthesis of ent-17-(prop-1-ynyl-17 beta-hydroxy-11 beta-(4-(N,N-dimethylamino)-phenyl)-4,9-estradien-3-one, the antipode of RU-38 486.

The title compound was synthesized and tested for its biological activities. It showed neither antiprogesterone nor antiglucocorticoid properties.

New steroids with antiprogestational and antiglucocorticoid activities.

A number of 11-substituted 19-norsteroids with inverse configuration at C-13 were synthesized. 11 beta-Aryl compounds in this series were found to possess antiprogestational and antiglucocorticoid activities.

Methyl 5'-(6-aminopurin-9-yl)-5'-deoxy-beta-D-ribofuranoside 2',3'-cyclic monophosphate: a novel, biologically active, structural analogue of cyclic AMP.

A novel structural analogue of cyclic AMP has been synthesized. This compound has been found to activate protein kinase from skeletal muscle (Ka 5.0 microM).

[Synthesis of Butyl 6alpha-Fluoro-11beta-hydroxy-16alpha-methyl-3,20-dioxo-1,4-pregnadien-21-oate (Fluocortin Butylester) (author's transl)].

Among the metabolites of fluocortolone (1) there was found the alpha-keto acid 4a. This acid, as well as the esters 4b--4k were synthesized and the butyl ester 4c was chosen for local anti-inflammatory therapy.

Comparative evaluation of the dissociation rate between the vaginotrophic and uterotrphic activities of 1-hydroxy-1, 3, 5 (10)-estratriene derivatives with natural and unnatural configuration at C8 using ovariectomized mice.

Influences on estrogenic.activities of 1-hydroxylation and C8-isomerization in the molecules of naturally occurring estrogens have been studied. All compounds tested behaved qualitatively in the same manner as estradiol, as far as the decrease in the vaginal and uterine sialic acid levels and the increase in the organ weights of the vagina and uterus of castrated mice are concerned.