The disorazole family of potent anticancer agents: structures, bioactivity, total synthesis, and heterologous biosynthesis

Guoan Fu; He Li; Ruijuan Li; Qiang Tu; Piwu Li; Youming Zhang

doi:10.1016/j.jare.2026.07.028

The disorazole family of potent anticancer agents: structures, bioactivity, total synthesis, and heterologous biosynthesis

J Adv Res. 2026 Jul 10:S2090-1232(26)00546-1. doi: 10.1016/j.jare.2026.07.028. Online ahead of print.

Authors

Guoan Fu¹, He Li², Ruijuan Li³, Qiang Tu⁴, Piwu Li⁵, Youming Zhang⁶

Affiliations

¹ School of Bioengineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China; State Key Laboratory of Biobased Material and Green Papermaking, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China; Shenzhen Key Laboratory of Genome Manipulation and Biosynthesis, CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong 518055, China.
² School of Pharmacy, Faculty of Medicine & Faculty of Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicines, Laboratory of Drug Discovery from Natural Resources and Industrialization, Macau University of Science and Technology, Macau 999078, China; Weifang Vocational College, Weifang, Shandong 262737, China.
³ Helmholtz International Lab for Anti-Infectives, State Key Laboratory of Microbial Technology, Shandong University, Qingdao, Shandong 266237, China.
⁴ Shenzhen Key Laboratory of Genome Manipulation and Biosynthesis, CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong 518055, China; Helmholtz International Lab for Anti-Infectives, State Key Laboratory of Microbial Technology, Shandong University, Qingdao, Shandong 266237, China.
⁵ School of Bioengineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China; State Key Laboratory of Biobased Material and Green Papermaking, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China. Electronic address: piwuli@qlu.edu.cn.
⁶ School of Pharmacy, Faculty of Medicine & Faculty of Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicines, Laboratory of Drug Discovery from Natural Resources and Industrialization, Macau University of Science and Technology, Macau 999078, China; Shenzhen Key Laboratory of Genome Manipulation and Biosynthesis, CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong 518055, China; Helmholtz International Lab for Anti-Infectives, State Key Laboratory of Microbial Technology, Shandong University, Qingdao, Shandong 266237, China. Electronic address: zhangyouming@sdu.edu.cn.

PMID: 42431458
DOI: 10.1016/j.jare.2026.07.028

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.

Keywords: Anticancer natural products; Biosynthesis; Biosynthetic gene cluster; Disorazole; Heterologous expression; Total syntheses.

Publication types

Review