jm0c00580_si_001.pdf (10.06 MB)
Synthesis and Biological Activity of 2,22-Dimethylene Analogues of 19-Norcalcitriol and Related Compounds
journal contribution
posted on 2020-06-24, 14:36 authored by Izabela
K. Sibilska-Kaminski, Rafal R. Sicinski, Lori A. Plum, Hector F. DeLucaContinuing our search
for vitamin D analogues, we explored the
modification of the steroidal side chain and inserted a methylene
moiety in position C-22 together with either lengthening the side
chain or introducing a ring at the terminal end. Our conformational
studies confirmed that the presence of a methylene group attached
to C-22 restricts the conformational flexibility of the side chain,
which can result in changes in biological characteristics of a molecule.
All synthesized 1α,25-dihydroxy-2,22-dimethylene-19-norvitamin
D3 analogues proved equal to calcitriol in their ability
to bind to the vitamin D receptor, and most of them exert significantly
higher differentiation and transcriptional activity than calcitriol.
The most active compounds were characterized by the presence of an
elongated side chain or 26,27-dimethylene bridge. The synthetic strategy
was based on the Wittig–Horner coupling of the known A-ring
phosphine oxide with the corresponding Grundmann ketones prepared
from a 20-epi-Inhoffen-Lythgoe diol derived from
vitamin D2.