Total synthesis of the actinoallolides and a designed photoaffinity probe for target identification

Abstract

The actinoallolides are a family of polyketide natural products isolated from the bacterium Actinoallomurus fulvus. They show potent biological activity against trypanosomes, the causative agents of the neglected tropical diseases...

Conquering peaks and illuminating depths: developing stereocontrolled organic reactions to unlock nature's macrolide treasure trove

“…The other four members of the actinoallolide family were readily prepared by late-stage diversification from 178. Leveraging this expedient endgame, a photoaffinity probe was also designed and synthesised, 82 with a view to identifying the actinoallolide protein-binding target and mechanism of action.…”

Currently Available Strategies for Target Identification of Bioactive Natural Products

“…Benzophenone, aryl azide, and diazirine are the most commonly used photoaffinity groups for PAL-ABPP. Matthew’s group used diazirine as the photoaffinity group and terminal alkyne as the functional handle to synthesize a bioactive photoaffinity probe for actinomycin A by conveniently binding to the reporter group via a CuAAC reaction ( Anketell et al, 2020 ). Luo et al also used this label to study fruit extracts of Ligustrum lucidum Ait and discovered that 3-O-cis- or 3-O-trans-p-coumaroyl maslinic acid (OCMA) specifically acted on the S1 subsite of γ-secretase ( Luo et al, 2020 ), while Lamos et al identified multiple targets of action of cyclosporine using photosensitive moieties ( Lamos et al, 2006 ).…”

A synthesis-enabled relative configurational assignment of the C31–C46 region of hemicalide

“…From here, a parallel cross-metathesis with 3a (containing the 42,45- anti configuration) mediated by Hoveyda–Grubbs II catalyst (13 mol%), followed by PMB ether cleavage, gave the separate C29–C46 fragments 32,36- anti 21 and 32,36- syn 22 . 23 Global desilylation under fluorous conditions then gave the truncated tetraols 2a and 2b for detailed NMR spectroscopic comparison. An analogous sequence with 3b (42,45- syn configuration) and ent - 4a provided the 32,36- syn , 42,45- syn diastereomer 2c .…”