Hershel L. Herzog

A history of significant steroid discoveries and developments originating at the Schering Corporation (USA) since 1948.

A firsthand historical account of some of the significant contributions of the steroid research group at the Schering Corporation (Bloomfield, NJ, USA) to the discovery and/or development of important therapeutic agents is presented. These include the discovery of the antiinflammatory corticosteroid drugs prednisone, prednisolone, and betamethasone, all of which, more than 30 years after their introduction, continue to enjoy wide use in human and animal medical practice throughout the world.

Microbiological transformation of steroids—X: 1-dehydro analogs of cortical steroids

Abstract The transformation of the principal adrenocortical ormones into the corresponding 1-dehydro analogs by the action of Corynebacterium simplex (A.T.C.C. 6946) is described.

17-Esters and 17, 21-diesters of 9α, 11β-dichlorocorticoids. Synthesis and anti-inflammatory activity

Abstract The syntheses of some 17,21-diesters of dichlorisone (9α, 11β-dichloro-17α, 21-dihydroxy-1,4-pregnadiene-3, 20-dione), 16α-methyldichlorisone and 16β-methyldichlorisone and some 17-monoesters of 16α-methyldichlorisone are reported. Anti-inflammatory activity, as measured by a granuloma pouch technique, reached a maximum for the 17-butyrate and 17-valerate of 16α-methyldichlorisone and for the 17, 21-dipropionate and 17, 21-dibutyrate of 16α-methyldichlorisone.

Microbiological transformation of steroids—XI : The action of corynebacterium simplex on non-corticoid steroid substrates

Abstract Corynebacterium simplex (A.T.C.C. 6946) causes the following reactions to occur with appropriate steroid substrates: (1) oxidation of Δ5-3β-hydroxyl to Δ4-3-ketone, (2) oxidation of Δ5-3β-hydroxyl to Δ1,4-diene-3-ketone, (3) oxidation of secondary 17β-hydroxyl to 17-ketone, (4) oxidation of 20β-hydroxyl to 20-ketone, (5) oxidation of 19-nor-Δ4-3-ketone to Δ1,3,5 (10)-triene-3-hydroxyl and (6) hydrolysis of 3- and 21-acetate groups.

THE CONSTRUCTION AND USE OF

Publisher Summary This chapter presents the table I in which the entries are all products of microbial transformation. With few exceptions, compounds are recorded in this table only when a detailed procedure has been given in the cited reference. Products of known empirical formula, but unknown structure, are shown at the end of each group of entries having common empirical formulas. Systematic organic chemical nomenclature has been used, except for sapogenins and steroidal alkaloids. Common names of the principal hormones are given parenthetically. Configuration of any substituent attached to a ring carbon of the steroid nucleus is defined as β when that substituent projects above the plane of the steroid nucleus and as α when the substituent projects below the plane. Substituents that have the β-configuration are shown attached to the nucleus by solid lines, and those which have α configuration, by dotted lines. Configuration of hydrogen at the 5-position is always defined by 5 α- or 5 β-preceding the stem.

Recent advances in the structure-activity relationships of substituted corticosteroids

Abstract The influence of the 6-azido-6-ene grouping on corticosteroid activity has been studied. The 6-azido-6-ene-corticosteroids were synthesized by reaction of the methanesulfonate esters of 6β,7β-dihydroxycorti-costeroids with azide ion. These diols were the unexpected products of the reaction between OsO 4 and 6-ene-corticosteroids. Their β-stereochemistry was assigned unambiguously from their n.m.r. spectra and is contrary to that of some published assignments. Anti-inflammatory activity was measured by the suppression of exudate in the rat granuloma pouch assay. Potency of 9α-unsubstituted corticosteroids was found to be increased by 5–8 times on introduction of the 6-azido-6-ene group. Introduction of this modification into 9α-fluorocorticosteroids enhanced potency in the absence of a 1,2-double bond and left the potency substantially unchanged in the presence of a 1,2-double bond.

THE CONSTRUCTION AND USE OF – TRANSFORMATIONS BY GENUS

Publisher Summary This chapter presents the table III in which the entries include all the genera, species, sources, substrates, and reactions reported in the cited references. These include both inactive genera and assignments for reactions based solely on chromatographic evidence. Transformations that are documented with specific experimental details are cross-indexed with the product table. Occasional changes in spelling were made to conform to standard reference texts or culture collection catalogs. Systematic organic chemical nomenclature has been used, in most entries, except for sapogenins and steroidal alkaloids. There is no more than one class of suffix designation for substituents that is affixed to any stem.

RECENT ADVANCES IN THE STRUCTURE–ACTIVITY RELATIONSHIPS OF SUBSTITUTED CORTICOSTEROIDS

The influence of the 6-azido-6-ene grouping on corticosteroid activity has been studied. The 6-azido-6-ene-corticosteroids were synthesized by reaction of the methanesulfonate esters of 6β,7β-dihydroxycorti-costeroids with azide ion. These diols were the unexpected products of the reaction between OsO4 and 6-ene-corticosteroids. Their β-stereochemistry was assigned unambiguously from their n.m.r. spectra and is contrary to that of some published assignments. Anti-inflammatory activity was measured by the suppression of exudate in the rat granuloma pouch assay. Potency of 9α-unsubstituted corticosteroids was found to be increased by 5–8 times on introduction of the 6-azido-6-ene group. Introduction of this modification into 9α-fluorocorticosteroids enhanced potency in the absence of a 1,2-double bond and left the potency substantially unchanged in the presence of a 1,2-double bond.

CHEMICAL CLASSIFICATION OF MICROBIAL TRANSFORMATIONS OF STEROIDS

Publisher Summary Microbial transformations of steroids are part of the larger class of organic chemical reactions that are catalyzed by enzymes. The microorganisms function as a convenient source of the required enzymes and, in some cases, provide identifiable reagent species that act on the steroid in the presence of the enzyme or contribute to the regeneration of the active site on the enzyme. The fact that the reactions are indeed enzymatic has been proved in several cases by the isolation of the crystalline enzyme from the microbial species and by the subsequent transformation of the steroid in vitro, using the crystalline enzyme and an added reagent. The resulting transformation was identical with that obtained employing the intact microbial system with the same substrate. This chapter discusses the chemical classification of microbial transformations of steroids, classes of chemical reactions, esterification of steroid alcohols, and hydrolysis of oxides to alcohols. It also discusses some of the reaction classes, such as Wagner–Meerwein rearrangement, decarboxylation, aldol and reverse aldol reactions, and Michael addition.