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Synthesis and antiproliferative activity of derivatives of the phyllanthusmin class of arylnaphthalene lignan lactones
Authors:John L. Woodard  Andrew C. Huntsman  Pratiq A. Patel  Hee-Byung Chai  Ragu Kanagasabai  Soumendrakrishna Karmahapatra  Alexandria N. Young  Yulin Ren  Malcolm S. Cole  Denisse Herrera  Jack C. Yalowich  A. Douglas Kinghorn  Joanna E. Burdette  James R. Fuchs
Affiliation:1. Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, United States;2. Division of Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, United States;3. Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois-Chicago, Chicago, IL 60612, United States
Abstract:A series of arylnaphthalene lignan lactones based on the structure of the phyllanthusmins, a class of potent natural products possessing diphyllin as the aglycone, has been synthesized and screened for activity against multiple cancer cell lines. SAR exploration was performed on both the carbohydrate and lactone moieties of this structural class. These studies have revealed the importance of functionalization of the carbohydrate hydroxy groups with both acetylated and methylated analogues showing increased potency relative to those with unsubstituted sugar moieties. In addition, the requirement for the presence and position of the C-ring lactone has been demonstrated through reduction and selective re-oxidation of the lactone ring. The most potent compound in this study displayed an IC50 value of 18?nM in an HT-29 assay with several others ranging from 50 to 200?nM. In an effort to elucidate their potential mechanism(s) of action, the DNA topoisomerase IIa inhibitory activity of the most potent compounds was examined based on previous reports of structurally similar compounds, but does not appear to contribute significantly to their antiproliferative effects.
Keywords:Corresponding author at: 500 W. 12th Avenue   College of Pharmacy   The Ohio State University   Columbus   OH 43210   United States.
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