- AN IMPROVED PROCESS FOR THE PREPARATION OF 4-OXOISOTRETINOIN
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The present invention relates to an improved process for the preparation of 4-Oxoisotretinoin and purification process of 4-Oxoisotretinoin (I) and crystalline 5 form of 4-Oxoisotretinoin (I).
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Page/Page column 12-13
(2022/02/28)
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- CYP26C1 is a hydroxylase of multiple active retinoids and interacts with cellular retinoic acid binding proteins
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The clearance of retinoic acid (RA) and its metabolites is believed to be regulated by the CYP26 enzymes, but the specific roles of CYP26A1, CYP26B1, and CYP26C1 in clearing active vitamin A metabolites have not been defined. The goal of this study was to
- Zhong, Guo,Ortiz, David,Zelter, Alex,Nath, Abhinav,Isoherranen, Nina
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p. 489 - 503
(2018/04/12)
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- Stereoselective formation and metabolism of 4-hydroxy-retinoic acid enantiomers by cytochrome p450 enzymes
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All-trans-retinoic acid (atRA), the major active metabolite of vitamin A, plays a role in many biological processes, including maintenance of epithelia, immunity, and fertility and regulation of apoptosis and cell differentiation. atRA is metabolized mainly by CYP26A1, but other P450 enzymes such as CYP2C8 and CYP3As also contribute to atRA 4-hydroxylation. Although the primary metabolite of atRA, 4-OH-RA, possesses a chiral center, the stereochemical course of atRA 4-hydroxylation has not been studied previously. (4S)- and (4R)-OH-RA enantiomers were synthesized and separated by chiral column HPLC. CYP26A1 was found to form predominantly (4S)-OH-RA. This stereoselectivity was rationalized via docking of atRA in the active site of a CYP26A1 homology model. The docked structure showed a well defined niche for atRA within the active site and a specific orientation of the β-ionone ring above the plane of the heme consistent with stereoselective abstraction of the hydrogen atom from the pro-(S)-position. In contrast to CYP26A1, CYP3A4 formed the 4-OH-RA enantiomers in a 1:1 ratio and CYP3A5 preferentially formed (4R)-OH-RA. Interestingly, CYP3A7 and CYP2C8 preferentially formed (4S)-OH-RA from atRA. Both (4S)- and (4R)-OH-RA were substrates of CYP26A1 but (4S)-OH-RA was cleared 3-fold faster than (4R)-OH-RA. In addition, 4-oxo-RA was formed from (4R)-OH-RA but not from (4S)-OH-RA by CYP26A1. Overall, these findings show that (4S)-OH-RA is preferred(4R)-OH-RA by the enzymes regulating atRA homeostasis. The stereoselectivity observed in CYP26A1 function will aid in better understanding of the active site features of the enzyme and the disposition of biologically active retinoids.
- Shimshoni, Jakob A.,Roberts, Arthur G.,Scian, Michele,Topletz, Ariel R.,Blankert, Sean A.,Halpert, James R.,Nelson, Wendel L.,Isoherranen, Nina
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p. 42223 - 42232
(2013/02/22)
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- A sensitive and specific method for measurement of multiple retinoids in human serum with UHPLC-MS/MS
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Retinol (vitamin A) circulates at 1-4 μM concentration and is easily measured in serum. However, retinol is biologically inactive. Its metabolite, retinoic acid (RA), is believed to be responsible for biological effects of vitamin A, and hence the measurement of retinol concentrations is of limited value. A UHPLC-MS/MS method using isotope-labeled internal standards was developed and validated for quantitative analysis of endogenous RA isomers and metabolites. The method was used to measure retinoids in serum samples from 20 healthy men. In the fed state, the measured concentrations were 3.1 ± 0.2 nM for at RA, 0.1 ± 0.02 nM for 9-cisRA, 5.3 ± 1.3 nM for 13-cisRA, 0.4 ± 0.4 nM for 9,13-dicisRA, and 17.2 ± 6.8 nM for 4oxo-13-cisRA. The concentrations of the retinoids were not significantly different when measured after an overnight fast (3.0 ± 0.1 nM for atRA, 0.09 ± 0.01nM for 9-cisRA, 3.9 ± 0.2 nM for 13-cisRA, 0.3 ± 0.1 nM for 9,13-dicisRA, and 11.9 ± 1.6 nM for 4oxo-13-cisRA). 11-cisRA and 4OH-RA were not detected in human serum. The high sensitivity of the MS/MS method combined with the UHPLC separation power allowed detection of endogenous 9-cis RA and 4oxo-atRA for the first time in human serum. Copyright
- Arnold, Samuel L. M.,Amory, John K.,Walsh, Thomas J.,Isoherranen, Nina
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experimental part
p. 587 - 598
(2012/05/31)
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- All-Trans-Retinol: All-Trans-13,14-Dihydroretinol Saturase and Methods of Its Use
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Compositions of all-trans-retinol: all-trans-13,14-dihydroretinal saturase and methods of use thereof are provided.
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- 4-OXO-FENRETINIDE, ADMINISTERED ALONE AND IN COMBINATION WITH FENRETINIDE, AS PREVENTIVE AND THERAPEUTIC AGENT FOR CANCER
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A drug based on a metabolite of fenretinide, or N-(4-hydroxyphenyl)retinamide (4-HPR), specifically 4-oxo-N-(4-hydroxyphenyl)retinamide (4-oxo-4-HPR), is used in the treatment of different kinds of tumors, in particular in the treatment of ovarian carcino
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Page/Page column 9-10
(2008/06/13)
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- A convenient synthesis of retinal derivatives with modified trimethylcyclohexene ring
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A method of simultaneous one-stage synthesis of three retinal derivatives (5,6-dioxo-5,6-seco-, 5,6-dihydro-5,6-epoxy-, and 4-oxoretinal) was proposed, with the yield of the first derivative being ～50%. These compounds are useful tools for studying the an
- Mironova,Leont'eva,Shevyakov,Alexeeva,Shvets,Demina,Krasnokutskaya,Finkel'shtein,Khodonov
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p. 487 - 493
(2007/10/03)
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- SYNTHESYS OF THE MAJOR METABOLITES OF (2E,4E,6E,8E)- AND (2Z,4E,6E,8E)-3,7-DIMETHYL-9-(2,6,6,-TRIMETHYL-1-CYCLOHEXEN-1-YL)-2,4,6,8-MONOTETRAENOIC ACIDS (RETINOIC ACID AND 13-cis-RETINOIC ACID)
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Wittig condensation of (2E,4E)-triphenylphosphonium bromide with ethyl formylcrotonate or 4-hydroxy-3-methylbutenolide gives, respectively, the (all-E) and (2Z,4Z)-3,7-dimethyl-9-(2,6,6-trimethyl-3-oxo-1-cyclohexen-1-yl)-2,4,6,8-nonatetraenoic acids.These are converted to oxo and hydroxy metabolites of retinoic acid and 13-cis-retinoic acid.
- Aig, Edward,Focella, Antonino,Parrish, David R.,Rosenberger, Michael,Scott, John W.,Zenchoff, Gladys B.
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p. 419 - 430
(2007/10/02)
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