From plant hormones to human health: progress and challenges in strigolactone biosynthetic structural diversity and...

Strigolactones are plant growth regulatory compounds produced by plants through the breakdown of carotenoid pigments. The continued identification of key strigolactone biosynthetic enzymes and pathway branches, along with increasing evidence that synthetic strigolactone compounds have diverse biological activities, has led to the concept that strigolactones not only serve a dual role as plant hormones but also represent a class of potential medicinal scaffolds. Recent research summarizes the key components of strigolactone biosynthesis, highlights the conserved backbone and the key intermediate MeCLA generated through methylation and oxidation steps. Furthermore, the role of cytochrome P450 enzymes at the final stages of cyclization and oxidative modifications is highlighted to provide a molecular basis for the ability to generate canonical and noncanonical strigolactones simultaneously. This biosynthetic diversity is pharmacologically relevant since enzyme generated differences in scaffold architecture and oxidation pattern expand the strigolactone chemical space available for structure guided analog design and usage. In the field of biomedicine, strigolactone analogues have anticancer potential, which are able to inhibit the proliferation of tumor cells and modulate the process of angiogenesis, and most importantly, represent a new class of late-stage autophagy and mitophagy inhibitors that prevent the fusion of autophagosomes with lysosomes and enhance the efficacy of antitumor therapy. Strigolactones possess additional therapeutic activity, strigolactones have antioxidant and anti-inflammatory properties. Furthermore, there are several key barriers to strigolactone based drug development that have been identified, including chemical instability, inadequate in vivo testing for safety and metabolism profiles, and the absence of defined mammalian targets. Current evidence also indicates that the potential is more strongly supported for synthetic strigolactone inspired analogs than for canonical natural strigolactones. The future of strigolactones as potential drug candidates lies in their optimization through structure activity relationships and systems pharmacology validation for their target identification.