Multidrug resistance (MDR) mediated by P-glycoprotein (P-gp) is a principal obstacle in anti-cancer treatment. As a result, discovering novel P-gp inhibitors with high potency and less adverse effects to fight MDR is a high priority.

Natural molecules which contain macrocyclic skeleton have proven to be an effective and valuable source of drug discovery. Compare to their linear precursors, the three-dimensional structure and the self-assembly of cyclic products contribute to the high affinity and selectivity for protein targets and flexible modulation of ADMET properties (bioavailability, metabolic stability, etc.). Although natural macrocyclic molecules have many advantages, the increasing challenges of limited expression in biological genes and the difficulty of resupply could hamper the sustainability and diversity of macrocyclic molecules.

In order to solve the problem, Prof. YANG Weibo and Prof. LOU Liguang from the Shanghai Institute of Materia Medica (SIMM) of the Chinese Academy of Sciences developed a biomimetic modularization strategy to create macrocyclic molecules which efficiently surmount P-gp-mediated MDR in cancer chemotherapy. This study was published in Nature communication on May 1.

In the study, the researchers realized the Rh (III)-catalyzed C-H allylation of carboxylic acids, and utilized the readily available building blocks (natural amino acids) to assemble allylic-supported macrolides that would be difficult or impossible to obtain by other methods.

In vitro experiments showed that the activity of macrolides with 180 fold-reversals is much more potent than that of the first-generation P-gp inhibitor verapamil.

This study would be helpful in developing inhibitors of P-gp to reverse the MDR in cancer chemotherapy.

Link to the article: https://www.nature.com/articles/s41467-020-16084-0

Modular Biomimetic Strategy and C-H Activation Method to Create Macrolides P-glycoprotein Inhibitors (Image by SIMM)

Contact:
Prof. YANG Weibo
Email: yweibo@simm.ac.cn

(Credit: YANG Weibo)