Optimization of the Natural Product Calothrixin A to Discover Novel Dual Topoisomerase I and II Inhibitors with Improved Anticancer Activity.

Calothrixin A () is a dual Topo I and II inhibitor but exhibits poor antiproliferative activities and water solubility. Herein, a library of novel analogues was synthesized. Among them, compound exhibited superior water solubility (>5 mg/mL) as compared to (<5 μg/mL).

Development of dual inhibitors targeting pyruvate dehydrogenase kinases and human lactate dehydrogenase A: High-throughput virtual screening, synthesis and biological validation.

Most cancer cells feature an altered glucose metabolism from oxidative phosphorylation to cytoplasmic glycolysis. Pyruvate dehydrogenase kinases (PDKs) and lactate dehydrogenase A (LDHA) play crucial roles in promotion of glycolysis, thus the inhibition of both enzymes is considered a promising strategy for developing of anticancer therapeutics. Herein, we describe the first discovery of series novel dual inhibitors targeting PDKs and LDHA.

Catalytic Asymmetric [3 + 2] Cycloaddition Reaction between Aurones and Isocyanoacetates: Access to Spiropyrrolines via Silver Catalysis.

The first enantioselective formal [3 + 2] cycloaddition of aurone analogues with isocyanoacetates was developed via chiral Ag-complex catalysis. A variety of optically enriched spiro-1-pyrrolines were obtained in excellent yields, diastero- and enantioselectivities (up to 99% yield, >20:1 dr, >99% ee). This synthetic approach represents an extremely simple, efficient, and atom-economical method for spiro-1-pyrrolines synthesis.

Rational design of mitochondria-targeted pyruvate dehydrogenase kinase 1 inhibitors with improved selectivity and antiproliferative activity.

Herein, triphenylphosphonium cation moieties were incorporated into a dichloroacetophenone derivative, leading to the discovery of novel mitochondria-targeted and tumor-specific pyruvate dehydrogenase kinase 1 (PDK1) inhibitors. Biological studies suggested that all these synthesized compounds had significant in vitro activities, in particular compound 1f, which inhibited PDK1 with an EC value of 0.12 μM, and reduced the proliferation of NCI-H1650 cell with an IC value of 0.