Anthraquinone-fused enediynes: discovery, biosynthesis and development

Area of Science:

• Natural Products Chemistry
• Medicinal Chemistry
• Molecular Biology

Background:

• Anthraquinone-fused enediynes (AFEs) are a class of enediyne natural products, with Dynemicin A (DYN A) being the first discovered member.
• Extensive research has focused on DYN A for its DNA interactions and mechanism of action.
• Progress in discovery, biosynthesis, and clinical applications of AFEs has been historically limited.

Purpose of the Study:

• To review recent advancements in the discovery, biosynthesis, total synthesis, and preclinical applications of AFEs.
• To highlight the development of AFE-based antibody-drug conjugates (ADCs).

Main Methods:

• Literature review of studies on AFEs published up to July 2021.
• Analysis of research on AFE discovery, biosynthesis pathways, and total synthesis strategies.
• Examination of preclinical data for AFE-based therapeutics, particularly ADCs.

Main Results:

• Four new AFEs have been discovered in the last five years.
• Significant progress has been made in understanding AFE biosynthesis, including the anthraquinone moiety formation and tailoring.
• Streamlined total synthesis of AFEs and analogues facilitates the creation of AFE-based linker-drugs for ADCs.

Conclusions:

• Recent discoveries and synthetic advancements have revitalized interest in AFEs.
• The development of AFE-based ADCs represents a promising avenue for targeted cancer therapy.
• Further preclinical studies are crucial to evaluate the therapeutic potential of these novel AFE derivatives.