Partial Synthesis of Compounds Related To Adrenal Cortical Hormones. XV. 17α, 21-Dihydroxy-▵<sup>4</sup>-pregnene-3,20-dione (Reichstein's “Substance S”)<sup>1</sup>

Koechlin, Bernard A.; Kritchevsky, Theodore H.; Gallagher, T. F.

doi:10.1021/ja01145a065

Cited by 17 publications

(5 citation statements)

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“…The isolation and identification of 11-oxygenated 17- 17 has not been reported (4). It seems probable that the increases noted with these alpha-ketols without a 17-hydroxyl group were primarily due to keto groups at other than the 17-position since the Zimmerman reaction is not specific for 17-ketosteroids.…”

Section: Group Reactionsmentioning

confidence: 99%

Urinary Alpha-Ketolic Steroid Metabolites of Cortical Hormones Administered to Subjects With Adrenal Cortical Insufficiency 1

Richardson¹,

Touchstone²,

Dohan³

et al. 1955

J. Clin. Invest.

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The analysis of urinary excretory products following the administration of known compounds is one of the classical methods for the study of their metabolism. The developments in paper chromatographic (1) and micro-analytic (2) technics and the use of glucuronidase hydrolysis (3) have considerably decreased the difficulties of investigating steroid metabolism by this method. Using these newer technics, we have studied the urinary excretion pattern of the major alpha-ketolic steroids after the administration of the six "active" adrenal cortical steroids to individuals with severe adrenal cortical insufficiency. We have found, as has been demonstrated for other steroids (4), that the major alpha-ketolic metabolites result from the reduction in ring A of the steroid nucleus to the 3-alpha-hydroxy pregnane derivatives (the socalled "tetrahydro" form) and that the hydroxyl and ketone groups on carbon atom 11 are interconvertible for corticosterone and 1 1-dehydrocorticosterone as well as for hydrocortisone and cortisone. METHODS I. TerminologySince steroid terminology is varied and the proper chemical names consume considerable space, the terms and abbreviations more commonly used in physiological research will be employed in this paper. Definitions and abbreviations are listed below.Alpha-ketolic steroids: Pregnane derivatives having 20-keto and 21-hydroxy substituents (i.e., alpha-ketol group). A4-pregnene-21-ol-3, 11, 20-trione.DOC; li-desoxycorticosterone; A'-pregnene-21-ol-3, 20-dione. These are listed in order of decreasing polarity. The acetate is indicated by the abbreviation ac.Alpha-ketolic steroid metabolites (AKSM): Steroids with the alpha-ketolic side chain found in the urine. These are detectable by reaction of the alpha-ketol side chain with alkaline blue tetrazolium to produce a blue color. The unmodified abbreviation H4 indicates reduction in ring A to form the 3a normal (i.e., pregnane) reduction product. In addition to the alpha-ketolic cortical hormones, the major metabolites are: H4F; tetrahydro-hydrocortisone; pregnane-3a, 11P, 17a, 21-tetrol-20-one. H4E; tetrahydro-cortisone; pregnane-3a, 17a, 21-triol-11, 20-dione. H4S; tetrahydro-11-desoxy-17-hydroxycorticosterone; pregnane-3a, 17a, 21-triol-20-one. H,B; tetrahydro-corticosterone; pregnane-3a, Ilfi, 21-triol-20-one. H4A; tetrahydro-dehydrocorticosterone; pregnane-3a, 21-diol-11, 20-dione. H4DOC; tetrahydro-l1-desoxycorticosterone; pregnane-3ca, 21-diol-20-one. Polarity: In the chromatograms, the most polar steroids (i.e., those with the most hydroxyl and keto substituents) appear in the slowest moving fraction, X, and the least polar in the fastest moving fraction, Z. (See III, B Paper chromatographic and micro-analytic technics.) 285

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Section: Group Reactionsmentioning

confidence: 99%

Urinary Alpha-Ketolic Steroid Metabolites of Cortical Hormones Administered to Subjects With Adrenal Cortical Insufficiency 1

Richardson¹,

Touchstone²,

Dohan³

et al. 1955

J. Clin. Invest.

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“…The 3-acetate of VIII18•19 exhibited a double melting point, 90-100°; 153-155°, previously reported, 154-157018 and 149-151°. 18 21-Acetoxy-33,17a-dihydroxy-6-pregnen-20-one (IX). Similarly, 15.26 g. of 3/3,17a-dihydroxy-5-pregnen-20-one16 gave 10 g. of IX,20 m.p.…”

Section: -192°mentioning

confidence: 99%

Steroidal Sapogenins. LXIV. C-21 Acetoxylation of 12-Keto Steroids²

Rothman¹,

Perlstein²,

Wall³

1960

J. Org. Chem.

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“…Such reactions often require multistep processes involving the introduction of protective groups and the use of toxic reagents such as halogens. In addition, by‐products increase the total expenditure and thus reduce production efficiency due to required purification by chromatographic methods (Koechlin, Kritchevsky, & Gallagher, ). The replacement of chemical by biotechnological processes has therefore aroused interest in recent decades, as the latter are highly suitable for the environmentally sustainable and economic production of pharmaceuticals.…”

Section: Introductionmentioning

confidence: 99%

Identification and circumvention of bottlenecks in CYP21A2‐mediated premedrol production using recombinant Escherichia coli

König

Brixius‐Anderko

Milhim

et al. 2019

Biotech & Bioengineering

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Synthetic glucocorticoids such as methylprednisolone are compounds of fundamental interest to the pharmaceutical industry as their modifications within the sterane scaffold lead to higher inflammatory potency and reduced side effects compared with their parent compound cortisol. In methylprednisolone production, the complex chemical hydroxylation of its precursor medrane in position C21 exhibits poor stereo‐ and regioselectivity making the process unprofitable and unsustainable. By contrast, the use of a recombinant E. coli system has recently shown high suitability and efficiency. In this study, we aim to overcome limitations in this biotechnological medrane conversion yielding the essential methylprednisolone‐precursor premedrol by optimizing the CYP21A2‐based whole‐cell system on a laboratory scale. We successfully improved the whole‐cell process in terms of premedrol production by (a) improving the electron supply to CYP21A2; here we use the N‐terminally truncated version of the bovine NADPH‐dependent cytochrome P450 reductase (bCPR−27) and coexpression of microsomal cytochrome b5; (b) enhancing substrate access to the heme by modification of the CYP21A2 substrate access channel; and (c) circumventing substrate inhibition which is presumed to be the main limiting factor of the presented system by developing an improved fed‐batch protocol. By overcoming the presented limitations in whole‐cell biotransformation, we were able to achieve a more than 100% improvement over the next best system under equal conditions resulting in 691 mg·L−1·d−1 premedrol.

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Partial Synthesis of Compounds Related To Adrenal Cortical Hormones. XV. 17α, 21-Dihydroxy-▵⁴-pregnene-3,20-dione (Reichstein's “Substance S”)¹

Cited by 17 publications

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Urinary Alpha-Ketolic Steroid Metabolites of Cortical Hormones Administered to Subjects With Adrenal Cortical Insufficiency 1

Urinary Alpha-Ketolic Steroid Metabolites of Cortical Hormones Administered to Subjects With Adrenal Cortical Insufficiency 1

Steroidal Sapogenins. LXIV. C-21 Acetoxylation of 12-Keto Steroids²

Identification and circumvention of bottlenecks in CYP21A2‐mediated premedrol production using recombinant Escherichia coli

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Partial Synthesis of Compounds Related To Adrenal Cortical Hormones. XV. 17α, 21-Dihydroxy-▵4-pregnene-3,20-dione (Reichstein's “Substance S”)1

Cited by 17 publications

References 0 publications

Urinary Alpha-Ketolic Steroid Metabolites of Cortical Hormones Administered to Subjects With Adrenal Cortical Insufficiency 1

Urinary Alpha-Ketolic Steroid Metabolites of Cortical Hormones Administered to Subjects With Adrenal Cortical Insufficiency 1

Steroidal Sapogenins. LXIV. C-21 Acetoxylation of 12-Keto Steroids2

Identification and circumvention of bottlenecks in CYP21A2‐mediated premedrol production using recombinant Escherichia coli

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Product

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Partial Synthesis of Compounds Related To Adrenal Cortical Hormones. XV. 17α, 21-Dihydroxy-▵⁴-pregnene-3,20-dione (Reichstein's “Substance S”)¹

Steroidal Sapogenins. LXIV. C-21 Acetoxylation of 12-Keto Steroids²