Total Synthesis of the Actinoallolides and a Designed Photoaffinity Probe for Target Identification

The actinoallolides are a family of polyketide natural products isolated from the bacterium Actinoallomurus fulvus. They show potent biological activity against protozoa of the genus Trypanosoma, the causative agents of human African trypanosomiasis (sleeping sickness) and Chagas disease, while exhibiting no observable cytotoxicity against the MRC-5 human cell line. The side effects associated with most current antitrypanosomal drugs mean that there is an urgent need for new and effective treatments for these neglected tropical diseases, and the high selectivity index of actinoallolide A makes it a promising drug candidate. Enabled by the highly stereocontrolled aldol reactions of three chiral ketone building blocks, an efficient fi rst total synthesis of the potent antitrypanosomal macrolide (+)-actinoallolide A is described, which has been achieved in 17 steps and 8% overall yield. This convergent route features an adventurous ring-closing metathesis as the pivotal key step to form the requisite trisubstituted (8E)-alkene in the 12-membered macrolactone, followed by the controlled installation of the labile transannular hemiacetal motif. Late-stage diversi cation then provides ready access to the congeneric (+)-actinoallolides B-E. The unknown mechanism of action of the actinoallolides poses a barrier to their potential utilisation as lead compounds for drug development. With this in mind, a bifunctional analogue of actinoallolide A bearing a photoaffinity probe was designed and synthesised. This will allow labelling studies to identify the in vivo protein binding target(s) of the actinoallolides, shedding light on their mechanism of action and enabling further biological investigation of these highly potent and selective natural products.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2020

Author dc:creator

• Anketell, Matthew

Advisor dc:contributor.advisor

• Paterson, Ian

• Total synthesis
• Natural products
• RCM
• Photoaffinity

Licence

• https://www.repository.cam.ac.uk/bitstreams/69b97827-5ced-432d-8c4e-057113887050/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

Author Identifier

0000-0002-5347-5320

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/318554