95464-25-8Relevant academic research and scientific papers
Stereoselective Synthesis of Four Calcitriol Lactone Diastereomers at C23 and C25
Nagata, Akiko,Akagi, Yusuke,Masoud, Shadi Sedghi,Yamanaka, Masahiro,Kittaka, Atsushi,Uesugi, Motonari,Odagi, Minami,Nagasawa, Kazuo
, p. 7630 - 7641 (2019)
(23S,25R)-Calcitriol lactone is a major metabolite of vitamin D3, but its synthesis has been far less well investigated than that of 1α,25(OH)2 vitamin D3, the active form of vitamin D3, even though the lactone
A new insight into the role of rat cytochrome P450 24A1 in metabolism of selective analogs of 1α,25-dihydroxyvitamin D3
Rhieu, Steve Y.,Annalora, Andrew J.,Gathungu, Rose M.,Vouros, Paul,Uskokovic, Milan R.,Schuster, Inge,Palmore, G. Tayhas R.,Reddy, G. Satyanarayana
experimental part, p. 33 - 43 (2012/03/07)
We examined the metabolism of two synthetic analogs of 1α,25- dihydroxyvitamin D3 (1), namely 1α,25-dihydroxy-16-ene-23-yne- vitamin D3 (2) and 1α,25-dihydroxy-16-ene-23-yne-26,27- dimethyl-vitamin D3 (4) using rat cytochrome P450 24A1 (CYP24A1) in a reconstituted system. We noted that 2 is metabolized into a single metabolite identified as C26-hydroxy-2 while 4 is metabolized into two metabolites, identified as C26-hydroxy-4 and C26a-hydroxy-4. The structural modification of adding methyl groups to the side chain of 1 as in 4 is also featured in another analog, 1α,25-dihydroxy-22,24-diene-24,26,27-trihomo-vitamin D3 (6). In a previous study, 6 was shown to be metabolized exactly like 4, however, the enzyme responsible for its metabolism was found to be not CYP24A1. To gain a better insight into the structural determinants for substrate recognition of different analogs, we performed an in silico docking analysis using the crystal structure of rat CYP24A1 that had been solved for the substrate-free open form. Whereas analogs 2 and 4 docked similar to 1, 6 showed altered interactions for both the A-ring and side chain, despite prototypical recognition of the CD-ring. These findings hint that CYP24A1 metabolizes selectively different analogs of 1, based on their ability to generate discrete recognition cues required to close the enzyme and trigger the catalytic mechanism.
Facile Stereoselective Synthesis of (23S,25R)-1α,25-Dihydroxyvitamin D3 26,23-Lactone, a Major Metabolite of 1α,25-Dihydroxyvitamin D3
Yamamoto, Keiko,Shimizu, Masato,Yamada, Sachiko,Iwata, Suguru,Hoshino, Osamu
, p. 33 - 39 (2007/10/02)
(23S,25R)-1α,25-Dihydroxyvitamin D3 26,23-lactone (1a), a major metabolite of 1α,25-dihydroxyvitamin D3 2, was synthesized efficiently and stereoselectively from 1α-hydroxydehydroepiandrosterone (3).The 17-oxosteroid 3 was first converted to C(22)-steroid aldehyde 9 with the natural stereochemistry at C(17) and C(20) using a stereoselective ene reaction as the key step.Then it was combined with the chiral C5 sulfone 4 having the correct stereochemistry for the lactone in 1a.Sulfone 4 was readily obtained from commercially available (R)-citramalic acid.The side-chain lactone with the natural stereochemistry at C(23) was constructed with high stereoselectivity (84percent) by iodo lactonization of the Δ22-26-carboxylic acid 16b under kinetically controlled conditions in the presence of γ-collidine.The stereoselectivity of the iodo lactonization of steroidal Δ22-25-hydroxy-26-carboxylic acids 16b, 24, and 25 was studied in detail, and a mechanism is proposed in which the configuration at C(25) and an added pyridine base play an important role.
