Molecules, Vol. 25, Pages 362: New Zampanolide Mimics: Design, Synthesis, and Antiproliferative Evaluation

Molecules, Vol. 25, Pages 362: New Zampanolide Mimics: Design, Synthesis, and Antiproliferative Evaluation Molecules doi: 10.3390/molecules25020362 Authors: Guanglin Chen Ziran Jiang Qiang Zhang Guangdi Wang Qiao-Hong Chen Zampanolide is a promising microtubule-stabilizing agent (MSA) with a unique chemical structure. It is superior to the current clinically used MSAs due to the covalent nature of its binding to β-tubulin and high cytotoxic potency toward multidrug-resistant cancer cells. However, its further development as a viable drug candidate is hindered by its limited availability. More importantly, conversion of its chemically fragile side chain into a stabilized bioisostere is envisioned to enable zampanolide to possess more drug-like properties. As part of our ongoing project aiming to develop its mimics with a stable side chain using straightforward synthetic approaches, 2-fluorobenzyl alcohol was designed as a bioisosteric surrogate for the side chain based on its binding conformation as confirmed by the X-ray structure of tubulin complexed with zampanolide. Two new zampanolide mimics with the newly designed side chain have been successfully synthesized through a 25-step chemical transformation for each. Yamaguchi esterification and intramolecular Horner–Wadsworth–Emmons condensation were used as key reactions to construct the lactone core. The chiral centers at C17 and C18 were introduced by the Sharpless as...
Source: Molecules - Category: Chemistry Authors: Tags: Article Source Type: research