Further synthetic and biological studies on vitamin D hormone antagonists based on C24-alkylation and C2alpha-functionalization of 25-dehydro-1alpha-hydroxyvitamin D(3)-26,23-lactones.
An efficient synthesis and the biological evaluation of 80 novel analogs of 25-dehydro-1alpha-hydroxyvitamin D3-26,23S-lactone 2 (TEI-9647) and its 23R epimer (3) in which the lactone ring was systematically functionalized by introduction of a C1 to C4 primary alkyl group at the C24 position (5 sets of 4 diastereomers), together with their C2alpha-methyl, 3-hydroxypropyl, and 3-hydroxypropoxy-substituted derivatives were described. The triene structure of the vitamin D3 was constructed using palladium-catalyzed alkenylative cyclization of the A-ring precursor enyne with the CD-ring counterpart bromoolefin having the C24-alkylated lactone moiety on the side chain. The CD-ring precursors having 23,24-cis lactones were prepared by using a chromium-mediated syn-selective allylation-lactonization process, and the 23,24-trans lactone derivatives were derived from these via inversion of the C23 stereochemistry. The biological evaluation revealed that both binding affinity for chick vitamin D hormone receptor and antagonistic activity (inhibition of vitamin D hormone induced HL-60 cell differentiation) were affected by the orientation and chain-length of the primary alkyl group on the lactone ring. Furthermore, the C2alpha-functionalization of the C24-alkylated vitamin D3 lactones dramatically enhanced their biological activities. The most potent compound to emerge, (23S,24S)-2alpha-(3-hydroxypropoxy)-24-propyl exhibited almost 1000-fold stronger antagonistic activity (IC50=7.4 pM) than 2 (IC50=6.3 nM).
Saito
Nozomi
N
Faculty of Pharmaceutical Sciences, Teikyo University, Sagamihara, Kanagawa 199-0195, Japan.
Matsunaga
Toshihiro
T
Saito
Hiroshi
H
Anzai
Miyuki
M
Takenouchi
Kazuya
K
Miura
Daishiro
D
Namekawa
Jun-ichi
J
Ishizuka
Seiichi
S
Kittaka
Atsushi
A
D000478:Alkylation; D000818:Animals; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002384:Catalysis; D002454:Cell Differentiation / Q000187:drug effects; D002645:Chickens; D002762:Cholecalciferol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002857:Chromium; D003500:Cyclization; D018922:HL-60 Cells; D006801:Humans; D066298:In Vitro Techniques; D007783:Lactones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010165:Palladium; D018167:Receptors, Calcitriol / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C517057:2-(3-hydroxypropoxy)-24-propylvitamin D3-26,23-lactone; D007783:Lactones; D018167:Receptors, Calcitriol; C400545:TEI 9647; D002857:Chromium; D002762:Cholecalciferol; D010165:Palladium; D002117:Calcitriol