Historically, natural products have been an important starting point for developing new cancer chemotherapeutics. In 2014, bioactivity-guided fractionation furnished several novel arylnaphthalene lignan glycosides from extracts of Phyllanthus poilanei possessing potent in vitro activity against the HT-29 cancer cell line. Additional in vivo activity, shown for phyllanthusmin D, prompted our lab to elucidate structure activity relationships for this class of compound. Initial studies with this series focused on substitutions of the glycoside, lactone, and aryl substituents. With the synthesis of over 60 analogues, a new lead compound, PHY-34, has emerged. The potent antiproliferative activity (both in vitro and in vivo) of PHY-34 warrants further studies to both improve pharmacokinetic properties and elucidate its mechanism of action. Utilizing the available hydroxy groups as functionalizable handles, mechanistic probes and prodrugs have been designed and synthesized to fuel these studies. In addition, efforts to both recognize and minimalize metabolic liabilities will be reported.

Development of the phyllanthusmin class of natural products: SAR, mechanistic probes, and drug property optimization

255th National Meeting (2018)

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