6-Methyl Steroids in the Androstane Series<sup>1</sup>

Campbell, J. Allan; Babcock, John C.; Hogg, John A.

doi:10.1021/ja01550a073

Cited by 37 publications

(16 citation statements)

References 13 publications

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“…1. 5␤,, and 5␣, (Campbell et al, 1958;Liston and Toft, 1969). To a stirring solution of 0.85 g of testosterone-3-ethyleneacetal (1) in 14 ml of chloroform was added 0.1 g of sodium acetate and 1 ml of peracetic acid (36%) with cooling in an ice-salt bath.…”

Section: Methodsmentioning

confidence: 99%

Development and Validation of a High-Throughput Radiometric Cyp3a4/5 Inhibition Assay Using Tritiated Testosterone

Marco¹,

Marcucci²,

Verdirame³

et al. 2004

Drug Metab Dispos

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ABSTRACT:A rapid and sensitive radiometric assay for assessing the potential of drugs to inhibit cytochrome P450 (P450) 3A4/5 in human liver microsomes is described. In contrast to the conventional testosterone 6␤-hydroxylation assay, the new method does not require high-performance liquid chromatography (HPLC) separation and mass spectrometry. The assay is based on the release of tritium as tritiated water that occurs upon CYP3A4/5-mediated 6␤-hydroxylation of testosterone labeled with tritium in the 6␤ position. The radiolabeled product is separated from the substrate using 96-well solid-phase extraction plates. The pharmacokinetic and toxicokinetic properties of pharmaceuticals depend in great part on their biotransformation by drug-metabolizing enzymes. The main drug-metabolizing system in mammals is cytochrome P450 (P450), a family of microsomal enzymes present predominantly in the liver. Multiple P450 enzymes catalyze the oxidation of chemicals of endogenous and exogenous origin, including drugs, steroids, prostanoids, eicosanoids, fatty acids, and environmental toxins (Ioannides, 1996). When a drug that is metabolized by a particular P450 enzyme is coadministered with an inhibitor of that same enzyme, changes in its pharmacokinetics can occur, which can give rise to adverse effects (Bertz and Granneman, 1997;Lin and Lu, 1998;Thummel and Wilkinson, 1998). It is therefore important to predict and prevent the occurrence of clearance changes due to metabolic inhibition. During the drug discovery process, it is routine practice in the pharmaceutical industry to assess the P450 inhibition potential of drug candidates to exclude potent inhibitors from further development (Lin and Lu, 1998;Crespi and Stresser, 2000;Riley, 2001). CYP3A4/5 is the most abundant P450 in human liver and is involved in the metabolism of about 50% of drugs used in human therapy (Guengerich, 1999). Inhibition of CYP3A4/5 activity can give rise to clinically significant and potentially life-threatening drug interactions (Thummel and Wilkinson, 1998). Several assay methods are currently used for determining the potential of drug candidates to inhibit CYP3A4/5 activity, and each of these methods presents distinct advantages and disadvantages. The most widely used method is the testosterone 6␤-hydroxylation assay, which is specific for enzymes of the CYP3A family (CYP3A4/5) (Waxman et al., 1988;Maenpaa et al., 1993;Wang et al., 1997;Yamazaki and Shimada, 1997). According to recent surveys conducted by reviewers in the Center for Drug Evaluation and Research of the United States Food and Drug Administration, the testosterone 6␤-hydroxylation assay represents the most commonly used probe reaction in support of new drug applications (Yuan et al., 1999(Yuan et al., , 2002. The practical challenge posed by this assay is that it requires HPLC separation of the reaction product from the substrate, followed by UV or mass spectrometric detection. This renders the assay relatively laborious, time-consumThis work was supported in part by a grant from t...

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Section: Methodsmentioning

confidence: 99%

Development and Validation of a High-Throughput Radiometric Cyp3a4/5 Inhibition Assay Using Tritiated Testosterone

Marco¹,

Marcucci²,

Verdirame³

et al. 2004

Drug Metab Dispos

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“…The possibilities of achieving a satisfactory general method for introducing substituents into the steroid nucleus by exploiting the properties of epoxides was drawn to our attention by the previous application of the reactions of As-epoxides with Grignard reagents (2)(3)(4)(5). Disappointingly, this approach to the stereospecific introduction of alkyl groups did not 'For part XI1 see ref.…”

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confidence: 99%

Steroids and Steroidases. XIII. Illustrations of the Potential of Lithiodithiane–Epoxide Reactions for the Stereospecific Introduction of Substituents into the Steroid Nucleus

Jones¹,

Grayshan²

1972

Can. J. Chem.

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The reactions of 2-lithio-1,3-dithiane with both 2c(,3c(-and 2/l,3/l-oxiranyl-5cc-cholestane have been used to prepare both epimers of 2-methyl-3-0x0-and 3-methyl-2-0x0-5a-cholestane. The results obtained illustrate the potential of the dithiane-epoxide route as an attractive and versatile general procedure for the stereospecific introduction of substituents into alicyclic compounds. Furthermore, since for six-membered ring compounds the epoxide ring is opened in a trans-diaxial manner, the substituent is introduced into the thermodynamically less stable orientation. Subsequent isomerization to the preferred equatorial isomer is thus possible and accordingly, both epimers are obtainable from the same synthetic sequence.On a utilisi' les reactions du 2-lithio-l,3-dithiane avec le 2a,3a-et le 2/l,3~-oxyranyl-5a-cholestane pour preparer les epimeres du 2-methyl-3-0x0-et du 3-methyl-2-0x0-5a-cholestane. Les resultats obtenus illustrent le potentiel du dithiane-epoxyde comme ttant une procedure generale attractive et versatile pour I'introduction sttreosptcifique de substituants dans les composes alicycliques. De plus, puisque le noyau epoxyde, de f a~o n trans-diaxiale pour les composts possedant un cycle a six, le substituant est introduit dans I'orientation la moins stable au point de vue thermodynamique. L'isomtrisation subsequente en isomere equatorial plus stable est alors possible e t a partir de cela, les deux epimeres peuvent itre obtenus a partir de la m&me sequence de synthtse.Canadian Journal of Chemistry, 50, 810 (1972) As a result of our interest in the mechanism of action of the A5+A4-3-ketoisomerase of P. testosteroni (la. b) we became interested in , , , developing convenient and versatile routes to stereospecifically substituted steroids suitable for "mapping" the active site of the enzyme. Of the general routes surveyed those based on a lithiodithiane-epoxide reaction appeared the most attractive and examples of the feasibility and advantages of this approach have been reported in communication form (lc). This note records the experimental and other details omitted from the preliminary communication since it is now apparent that the human resources required to continue the project as originally planned are unlikely to become available in the foreseeable future.The possibilities of achieving a satisfactory general method for introducing substituents into the steroid nucleus by exploiting the properties of epoxides was drawn to our attention by the previous application of the reactions of As-epoxides with Grignard reagents (2-5). Disappointingly, this approach to the stereospecific introduction of alkyl groups did not 'For part XI1 see ref. la. prove to be universally applicable since when the epoxide was not located at a ring junction, ring contraction predominated with both steroidal (6) and cyclohexene oxide (7) reactiom2 However, the fact that the latter compound underwent the expected ring opening with 2-lithio-1,3-dithiane (9a, b) indicated that similar reactions could be expected in the ...

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“…Cleavage of the epoxide ring of VIII with anhyclrous hydrogen fluoride (14,16) For personal use only.…”

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confidence: 99%

“…The fluorohydrin I X ( R = Ac) was also obtained, in good yield, by bromination of 3~-acetoxy-5a-hydroxy-6P-fluoropregnan-2O-one (XII) (16,17) with N-bromosuccinimide (21).…”

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confidence: 99%

“…In a second synthesis of XVIII, 3P-acetoxy-5a,Ga-epoxypregnan-20-one (XIX) (16,17) was allo\ved to react with hydrogen chloride in chloroform, and the resulting 5a-hydroxy-GP-chloro derivative X X was brominated a t C-17 with N-bromosuccinimide to give X X I ( R = Ac). Acid-catalyzed hydrolysis to the diol X X I ( R = H), oxidation to the diltetoile X X I I , and dehydration-inversion with hydrogen chloride then led to XVIII.…”

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confidence: 99%

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17α-Halogenated PROGESTERONES: ORALLY-ACTIVE PROGESTINS

Marshall¹,

Gaudry²

1960

Can. J. Chem.

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170-Chloroprogesterone, 60-fluoro -170-brornoprogesterone, l-dehydro-6a-fluoro-170-brornoprogestero~le, and 60-chloro-170-bromoprogesterone have been synthesized. These compounds have been found to be orally-active progestins without androgenic properties.In recent years, considerable effort has been devoted to the search for orally-active progestational agents to substitute for the natural hormone, progesterone. The newer synthetic progestogeils ~vhich have acquired prominence because of their oral activity fall into two classes: 19-ilorsteroids such as 19-norprogesterone (1) and 17a-ethynyl-19-ilortestosterone (2) and its A5('0)-isomer (3), and derivatives of progesterone containing a 17a-acetoxy substituent (4-7).I t has been shown recently that l'ia-bromoprogesteroile (8) is an orally-active progestogen (9), indicating that substituents other than acetoxyl a t C-17 can enhance the very wealc oral activity of progesterone. It was clearly of interest to prepare other 17a-halogenated progesterones, and to determine whether modifications in structure which enhance the activity of 17a-acetoxyprogesterone, such as the introduction of a Ga-halo substituent and a A'-double bond (4, 5), would have a similar effect on the comparatively wealc oral activity of 17a-broil~oprogesterone.In this paper, we record the synthesis and preliminary biological evaluation of 17a-chloroprogesteroi~e and of the Ga-fluoro-, I-dehydro-Ga-fluoro-, and Ga-chloroderivatives of 17a-bro~l~oprogesterone. I r a -ChloroprogesteronePregnenolone acetate (I) \\.as brominated a t a low temperature, and the 5,G-dibromide I1 jvas allowed to react with chlorine in acetic acid. The resulting mixture of 17-and 21-chloro derivatives (111) was treated with sodium iodide in acetone which regenerated the 5,G-double bond and replaced chlorine a t C-21 with iodine. Finallj., the iodine a t C-21 was ren~oved by reduction with aqueous sodium bisulphite solution (10) and 17a-chloropregnenolone acetate (IV, R = Ac) was isolated after chromatographic purification. The a-configuration of the chlorine was inferred from the general preference for "back-side" attack and from the fact that bromiilation of 20-lcetones has been clearly shown to result in the fornlation of 17a-broino derivatives (11).Acid-catalyzed hydrolysis of IV ( R = Ac) yielded 17a-chloropregnei~olone (IV, R = H), which, without purification, was oxidized with chromic acid in acetone (12).T h e shift of the double bond into conjugation with the carbonyl group to yield 17a-chloroprogesterone (V) was completed by treatment of the crude oxidation product with oxalic acid (13).Ga-Halo-1 7a-bromoprogesterones2 17a-Bromopregileilolone acetate (VI) (8, 10) was coilverted to a 6-fluoro derivative by conveiltional means (14). Epoxidation of VI with nlonoperphthalic acid gave a mixture of 50,GP-and 5a,Ga-epoxides, VII and VIII. T h e epoxides were separated by chromatog- 'Manzcscript received M a y 9 , 1960.

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6-Methyl Steroids in the Androstane Series¹

Cited by 37 publications

References 13 publications

Development and Validation of a High-Throughput Radiometric Cyp3a4/5 Inhibition Assay Using Tritiated Testosterone

Development and Validation of a High-Throughput Radiometric Cyp3a4/5 Inhibition Assay Using Tritiated Testosterone

Steroids and Steroidases. XIII. Illustrations of the Potential of Lithiodithiane–Epoxide Reactions for the Stereospecific Introduction of Substituents into the Steroid Nucleus

17α-Halogenated PROGESTERONES: ORALLY-ACTIVE PROGESTINS

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6-Methyl Steroids in the Androstane Series1

Cited by 37 publications

References 13 publications

Development and Validation of a High-Throughput Radiometric Cyp3a4/5 Inhibition Assay Using Tritiated Testosterone

Development and Validation of a High-Throughput Radiometric Cyp3a4/5 Inhibition Assay Using Tritiated Testosterone

Steroids and Steroidases. XIII. Illustrations of the Potential of Lithiodithiane–Epoxide Reactions for the Stereospecific Introduction of Substituents into the Steroid Nucleus

17α-Halogenated PROGESTERONES: ORALLY-ACTIVE PROGESTINS

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6-Methyl Steroids in the Androstane Series¹