Synthesis of C (6)-epimer derivatives of diacetoxy acetal derivative of santonin and their inducing effects on HL-60 leukemia cell differentiation.

Abstract

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 D(3) [1,25-(OH)(2)D(3)] or all-trans retinoic acid (ATRA). Using combination of either 1,25-(OH)(2)D(3) or ATRA and chemotherapy, adverse effects 1,25-(OH)(2)D(3) 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 C(6)-epimer derivatives of diacetoxy acetal derivative of santonin and tested their effects on HL-60 cell differentiation. Some of the C(6)-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)(2)D(3) or ATRA. The ability to enhance the differentiation potential of 1,25-(OH)(2)D(3) or ATRA by 7 may improve outcomes in the therapy of acute promyelocytic leukemia.

• Authors: Sin Ho Kweon, Keun Tae Kim, Joon Hee Hong, Tae Sung Kim, Bo Gil Choi
• Journal: Archives of pharmacal research (Arch Pharm Res) Vol. 34 Issue 2 Pg. 191-8 (Feb 2011) ISSN: 1976-3786 [Electronic] Korea (South)
• PMID: 21380800 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 3,3-(ethylenedioxy)-eudesmano-13,6-diacetate
• Acetals
• Antineoplastic Agents
• Vitamin D
• Santonin
• Tretinoin
• 1,25-dihydroxyvitamin D

Topics

• Acetals (analysis, chemical synthesis, pharmacology)
• Antineoplastic Agents (analysis, chemical synthesis, pharmacology)
• Cell Differentiation (drug effects)
• Dose-Response Relationship, Drug
• Drug Screening Assays, Antitumor
• Drug Synergism
• HL-60 Cells
• Humans
• Leukemia, Promyelocytic, Acute (drug therapy)
• Santonin (analogs & derivatives, chemical synthesis, chemistry, pharmacology)
• Tretinoin (pharmacology)
• Vitamin D (analogs & derivatives, pharmacology)