PHY34 inhibits autophagy through V-ATPase V0A2 subunit inhibition and CAS/CSE1L nuclear cargo trafficking in high grade serous ovarian cancer.

PHY34 is a synthetic small molecule, inspired by a compound naturally occurring in tropical plants of the Phyllanthus genus. PHY34 was developed to have potent in vitro and in vivo anticancer activity against high grade serous ovarian cancer (HGSOC) cells. Mechanistically, PHY34 induced apoptosis in ovarian cancer cells by late-stage autophagy inhibition.

Systematic Diversity-Oriented Synthesis of Reduced Flavones from γ-Pyrones to Probe Biological Performance Diversity.

Diversity-oriented synthesis (DOS) has historically focused on the development of small-molecule collections with considerable chemical diversity with the hypothesis that chemical diversity will lead to diverse biological activities. We took a systematic approach to DOS to develop a focused library of reduced flavones from γ-pyrones with diversity of appendage, stereochemistry, and chemical properties to determine which features of small molecules are most predictive of biological performance diversity. The effects of these systematic modifications on biodiversity were determined using Cell Painting and cytotoxicity assays to compare the results of multiple methods of assessment.

Phyllanthusmin Derivatives Induce Apoptosis and Reduce Tumor Burden in High-Grade Serous Ovarian Cancer by Late-Stage Autophagy Inhibition.

High-grade serous ovarian cancer (HGSOC) is a lethal gynecological malignancy with a need for new therapeutics. Many of the most widely used chemotherapeutic drugs are derived from natural products or their semi-synthetic derivatives. We have developed potent synthetic analogues of a class of compounds known as phyllanthusmins, inspired by natural products isolated from Beille.

Microwave-Assisted, Asymmetric Synthesis of 3-Amino-2,3-Dihydrobenzofuran Flavonoid Derivatives from Chalcones.

A route to access 3-amino-2,3-dihydrobenzofurans that utilizes microwave-assisted organic synthesis to rapidly generate analogues has been developed. The route begins with an acid-catalyzed, microwave-assisted aldol condensation to generate chalcone intermediates, followed by a Corey-Bakshi-Shibata reduction and subsequent Sharpless asymmetric epoxidation to access stereoisomeric epoxyalcohols. The final step is a one-pot, microwave-assisted, regioselective, acid-catalyzed epoxide opening with various amines followed by an intramolecular nucleophilic aromatic substitution reaction to generate the 3-amino-2,3-dihydrobenzofurans.