A. Wongmayura et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1756–1760
1757
Figure 1. Structures of VDR ligands.
between the interactions of the C–H surface of hydrocarbons and
the B–H surface of carborane with the receptor.
dienes 21 and 22, respectively. Hydrogenation, followed by
Grignard reaction, gave diethylcarbinol 25 and 26, and removal
of the benzylidene group under acidic conditions gave the target
compounds 6 and 7, respectively. The 1,2-diol derivative 8 was
synthesized by a similar method to that used for synthesis of 6
and 7. Ether formation of 13 using tosylate 27 corresponding to
the 1,2-diol moiety afforded 28, and oxidation of alcohol gave alde-
hyde 29. Then, the Horner–Wadsworth–Emmons type reaction
afforded diene 30, followed by hydrogenation, Grignard reaction
and removal of the acetonide group to give the target compound
8, although the yield was low due to the formation of by-product
caused by ether cleavage reaction (Scheme 1).
The synthesis of the carborane derivatives is summarized in
Scheme 2. Reaction of the C-lithiated form of carborane13 and para-
formaldehyde gave carboranylmethanol 34, and ether formation
using tosylates 14 or 15 afforded 35 and 36, respectively. The
side-chain moiety was introduced at the other carbon atom of car-
borane using bromide 37 to afford triol precursors 38 and 39,
respectively. Finally, removal of protective groups under acidic
conditions gave the target compounds 9 and 10. The 1,2-diol deriv-
ative 11 was similarly synthesized. Ether formation of 34 using tos-
ylate 27 afforded 40, and introduction of the side-chain part gave
41. Then, removal of protective groups under acidic conditions
gave the target compound 11 (Scheme 2).
Four structural elements are required for effective binding to
VDR; one is a hydrophobic core with appropriate bulkiness, and
the others are three appropriately positioned hydroxyl groups, as
in 1. As a spherical hydrocarbon core structure of novel VDR ligand
candidates, we chose the bicyclo[2.2.2]octane skeleton, based on
its spatial volume and its symmetric structure, resembling that of
p-carborane. As a side chain structure, we chose diethylcarbinol,
as in 5, in place of dimethylcarbinol, as in 1, based on reports that
the diethylcarbinol moiety enhances vitamin D potency.11 Our pre-
vious study indicated that the 1,3-diol moiety of 5 corresponds to
the two hydroxyl groups of the A-ring of 1, and the 1,2-diol struc-
ture can also serve this purpose. Therefore, we designed bicy-
clo[2.2.2]octane derivatives with a 1,2- or 1,3-dihydroxylalkoxyl
side chain 6–8, as well as the corresponding p-carborane deriva-
tives 9–11 (Fig. 2). The designed derivatives have the ether oxygen
atom at a different position from the spherical core structure, com-
pared to compound 5. X-ray analysis of the complex of the VDR–
LBD with 5 suggested that the ether oxygen atom of 5 does not
form a hydrogen bond to amino acid residues of the receptor,
and so the position of the oxygen atom may not affect the vitamin
D potency. We anticipated that examination of the structure–activ-
ity relationships of compounds 6–11 would clarify this point.
Scheme 1 summarizes the synthetic route to the designed
bicyclo[2.2.2]octane derivatives using 1,4-bisethoxycarbonylbicy-
clo[2.2.2]octane 1212 as the starting material. Reduction of 12 gave
diol 13, and ether formation using tosylates 14 or 15 corresponding
to the 1,3-diol moiety afforded 16 and 17, respectively. Oxidation
of alcohol gave aldehydes 18 and 19, and then Horner–Wads-
worth–Emmons type reaction using phosphonate 20 afforded
Vitamin D activity of the synthesized molecules was evaluated
in terms of cell differentiation-inducing activity toward human
acute promyelocytic leukemia cell line HL-60.14 The bicy-
clo[2.2.2]octane derivatives exhibited HL-60 cell differentiation-
inducing activity at the concentration of 10À5 M (Fig. 3A), and
the most potent compound 7, bearing 1,3-diol structure, exhibited
moderate activity at the concentration of 10À6 M. The activity of
compound
7 was weaker than that of 1 by approximately
two orders of magnitude. Compound 6 bearing a shorter 1,3-
dihydroxylalkoxyl structure than that of 7 and compound 8 with
1,2-diol structure exhibited lower potency than did 7. On the other
hand, the corresponding carborane derivatives exhibited more po-
tent activity in HL-60 cell assay (Fig. 3B). Compound 10 with 1,3-
diol structure exhibited the highest HL-60 cell differentiation-
inducing potency among the three compounds. The potency of
10 was approximately one-tenth of that of 1, and 10 is one of the
most potent non-secosteroidal VDR ligands so far discovered. Com-
pound 11 with 1,2-diol structure also exhibited potent activity,
while compound 9, bearing a shorter 1,3-dihydroxylalkoxyl struc-
ture than that of 10, showed lower potency.
Figure 2. Structures of novel VDR ligand candidates bearing a spherical hydropho-
bic core.