Ortho-alkyl phenylalkenoyl natural products: structural diversity, bioactivities and biosynthesis.
Covering: up to 2026.Ortho-alkyl phenylalkenoyl-containing natural products, including cinnamoyl-containing nonribosomal peptides (CCNPs) and ortho-alkyl phenylalkenoic acids (APAs), are structurally and biologically diverse bacterial metabolites that have become a major focus of natural product research. These metabolites exhibit broad bioactivities, including antimicrobial, antiangiogenic, cytotoxic, anti-inflammatory, and nematicidal effects. Biosynthetically, CCNPs and APAs share a conserved, highly reduced (HR) type II polyketide synthase (PKS)-derived framework, featuring characteristic isoenzymes (ISOs) and specialised cyclases that assemble the ortho-alkyl phenylalkenoyl core. They diverge fundamentally in pathway architecture: CCNPs contain NRPS-synthesised peptide backbones, whereas APAs lack NRPS components and possess expanded KS/CLF pairs. Biosynthetic studies have revealed novel mechanisms (e.g., isomerization, 6π-electrocyclisation) and multifunctional enzymes, providing valuable biocatalysts for synthetic biology. Although their biological activities depend strongly on structural context, emerging evidence highlights these metabolites as a promising source of lead compounds. Continued interdisciplinary efforts integrating natural product chemistry, biosynthesis, and medicinal chemistry are expected to unlock their therapeutic potential.