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KMID : 0043320110340020191
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Archives of Pharmacal Research
2011 Volume.34 No. 2 p.191 ~ p.198
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Synthesis of C6-epimer derivatives of diacetoxy acetal derivative of santonin and their inducing effects on HL-60 leukemia cell differentiation
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Kweon Sin-Ho
Kim Keun-Tae
Hong Joon-Hee
Kim Tae-Sung
Choi Bo-Gil
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Abstract
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Induction of differentiation is a new and promising approach to leukemia therapy, well illustrated by the treatment of acute promyelocytic leukemia with 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] or all-trans retinoic acid (ATRA). Using combination of either 1,25-(OH)2D3 or ATRA and chemotherapy, adverse effects 1,25-(OH)2D3 or ATRA such as hypercalcemic effects have decreased, and long-term survival has improved. In a previous study, we demonstrated that santonin could be chemically modified into a diacetoxy acetal derivative of santonin with strong differentiation-inducing activity. In this study, we further synthesized C6-epimer derivatives of diacetoxy acetal derivative of santonin and tested their effects on HL-60 cell differentiation. Some of the C6-epimer derivatives themselves induced increases in cell differentiation. Especially, (11S)-3,3-(ethylenedioxy) eudesmano-13-ol-6β-acetate (7) was demonstrated to induce differentiation with larger than 80% of the cells attaining a differentiated phenotype. Importantly, 7 strongly enhanced differentiation of HL-60 cells in a dose-dependent manner when combined with either low doses of 1,25-(OH)2D3 or ATRA. The ability to enhance the differentiation potential of 1,25-(OH)2D3 or ATRA by 7 may improve outcomes in the therapy of acute promyelocytic leukemia.
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KEYWORD
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DAAS, 6-Epimer, Differentiation, Leukemia, 1, 25-dihydroxyvitamin D3, All-trans retinoic acid
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