2,2-Functionalized analogues of 1alpha,25-dihydroxyvitamin D3, the potent inducers of cell differentiation.
All four possible A-ring stereoisomers of 2,2-dimethyl-1,25-dihydroxyvitamin D(3) (4) were designed and convergently synthesized. Nine-step conversion of methyl hydroxypivalate 6 provided the desired A-ring enyne synthon (13a,b) in good overall yield. Cross-coupling reaction of the A-ring synthon 13a,b with the CD-ring portion in the presence of palladium catalyst, followed by deprotection, gave the vitamin analogues (4a-d). We also synthesized four stereoisomers of 2,2-ethano-1,25-dihydroxyvitamin D(3) (5), as novel spiro-ring analogues having cyclopropane fused at the C2 position. Biological potencies of the synthesized compounds were assessed in terms of the vitamin D receptor (VDR) binding affinity, as well as the HL-60 cell differentiation-inducing activity. The 2,2-ethano analogue 5a showed a comparable activity to the natural hormone 1, while the 2,2-dimethyl analogue 4a exhibited one-third of the activity of 1 in cell differentiation, with the reduced VDR binding affinity.
Fujishima
Toshie
T
Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Teikyo University, Kanagawa 199-0195, Japan. tofu@pharm.teikyo-u.ac.jp
Kittaka
Atsushi
A
Kurihara
Masaaki
M
Saito
Nozomi
N
Honzawa
Shinobu
S
Kishimoto
Seishi
S
Sugiura
Takayuki
T
Waku
Keizo
K
Takayama
Hiroaki
H
D002117:Calcitriol / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects*; D018922:HL-60 Cells; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation
C481038:2,2-dimethyl-1,25-dihydroxyvitamin D3; D002117:Calcitriol