TY - JOUR
T1 - A non-calcemic sulfone version of the vitamin D3 analogue seocalcitol (EB 1089)
T2 - chemical synthesis, biological evaluation and potency enhancement of the anticancer drug adriamycin
AU - Posner, Gary H.
AU - Crawford, Kenneth R.
AU - Peleg, Sara
AU - Welsh, Jo Ellen
AU - Romu, Saara
AU - Gewirtz, David A.
AU - Gupta, Mona S.
AU - Dolan, Patrick
AU - Kensler, Thomas W.
N1 - Funding Information:
The authors thank the NIH (CA 44530 to G.H.P. and T.W.K., CA 69700 to J.W., and DK 50583 to S.P.) and the American Institute for Cancer Research (99A091 to D.A.G.) for support of this research and H. Brem and S. Zand for the malignant melanoma assay.
PY - 2001
Y1 - 2001
N2 - Novel side-chain diene sulfones 5, analogues of the natural hormone 1α 25-dihydroxyvitamin D3 (calcitriol, 1), were designed to incorporate some of the therapeutically most favorable structural features of the Leo Pharmaceutical Companys drug candidate diene EB 1089 (seocalcitol, 4) and of the Hopkins' non-calcemic side-chain sulfone analogues 2 and 3. Synthesis of diene sulfones 5 features selective Swern oxidation of a primary silyl ether in the presence of a secondary silyl ether (9→10) and Horner Wadsworth Emmons aldehyde addition by a 1-phosphonyl-3-sulfonyl stabilized carbanion regiospecifically at the 1-position to form E,E-diene sulfone 11. Sulfone diene analogue 5a with natural 1α,3b-diol functionality, but not its diastereomer 5b with unnatural A-ring stereochemistry, is antiproliferative in vitro toward murine keratinocytes and malignant melanoma cells, as well as toward MCF-7 human breast cancer cells. Combining diene sulfone 5a with the currently used anticancer drug adriamycin (ADR) caused a noteworthy 3-fold enhancement of ADR antiproliferative potency in MCF-7 cells. Sulfone diene analogue 5a is weakly active transcriptionally in MCF-7 and ROS 17/2.8 cells, binds poorly but measurably to the vitamin D receptor (VDR), and desirably is non-calcemic in vivo at a daily dose (7 days) of 10 mg/kg of rat body weight.
AB - Novel side-chain diene sulfones 5, analogues of the natural hormone 1α 25-dihydroxyvitamin D3 (calcitriol, 1), were designed to incorporate some of the therapeutically most favorable structural features of the Leo Pharmaceutical Companys drug candidate diene EB 1089 (seocalcitol, 4) and of the Hopkins' non-calcemic side-chain sulfone analogues 2 and 3. Synthesis of diene sulfones 5 features selective Swern oxidation of a primary silyl ether in the presence of a secondary silyl ether (9→10) and Horner Wadsworth Emmons aldehyde addition by a 1-phosphonyl-3-sulfonyl stabilized carbanion regiospecifically at the 1-position to form E,E-diene sulfone 11. Sulfone diene analogue 5a with natural 1α,3b-diol functionality, but not its diastereomer 5b with unnatural A-ring stereochemistry, is antiproliferative in vitro toward murine keratinocytes and malignant melanoma cells, as well as toward MCF-7 human breast cancer cells. Combining diene sulfone 5a with the currently used anticancer drug adriamycin (ADR) caused a noteworthy 3-fold enhancement of ADR antiproliferative potency in MCF-7 cells. Sulfone diene analogue 5a is weakly active transcriptionally in MCF-7 and ROS 17/2.8 cells, binds poorly but measurably to the vitamin D receptor (VDR), and desirably is non-calcemic in vivo at a daily dose (7 days) of 10 mg/kg of rat body weight.
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U2 - 10.1016/S0968-0896(01)00159-6
DO - 10.1016/S0968-0896(01)00159-6
M3 - Article
C2 - 11553477
AN - SCOPUS:0034846931
SN - 0968-0896
VL - 9
SP - 2365
EP - 2371
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 9
ER -