The disorazole family of potent anticancer agents: structures, bioactivity, total synthesis, and heterologous biosynthesis.
TL;DR
This review articulates a paradigm shift in disorazole research: from confronting the extreme challenge of total chemical synthesis towards harnessing programmable biosynthetic engineering (F & Z), and highlights how key technologies have revolutionized the production and diversification of these molecules.
Abstract
Background
Disorazoles are a family of exceptionally potent, macrodiolide natural products originally isolated from the myxobacterium Sorangium cellulosum. They exert picomolar cytotoxicity by disrupting microtubule dynamics, placing them among the most potent Microtubule-targeting agents (MTAs) known. Their intricate chemical structures, featuring distinct 30-membered (A/C series) and 26-membered (Z-F family) macrocycles, present formidable challenges for chemical synthesis while offering rich opportunities for exploring structure-activity relationships (SAR) and developing novel anticancer therapeutics.
Aim
OF REVIEW This review aims to provide a comprehensive and systematic analysis of the disorazole family, bridging the gap between complex chemical synthesis and modern biosynthetic engineering. It contrasts classical and emerging structural subfamilies, critically evaluates landmark total syntheses, and highlights the transformative role of synthetic biology in overcoming historical production bottlenecks to enable structural diversification and scalable manufacturing. KEY SCIENTIFIC CONCEPTS OF REVIEW This review articulates a paradigm shift in disorazole research: from confronting the extreme challenge of total chemical synthesis (e.g., of A1, C1, Z1 via macrolactonization or cyclodimerization) towards harnessing programmable biosynthetic engineering (F & Z). It highlights how key technologies--particularly heterologous expression, Red/ET recombineering - based pathway refactoring, and modular polyketide synthase (PKS) engineering - have revolutionized the production and diversification of these molecules, enabling analogs like disorazole F with improved properties. Ultimately, the review frames these advances within a forward-looking perspective, outlining a convergent future strategy that integrates biosynthetic scalability with the precision of synthetic chemistry for clinical translation.