Under water control: A cascade approach to the pseudolaric acid anti-tumour agents
Lead Research Organisation:
University of Manchester
Department Name: Chemistry
Abstract
In the constant battle against disease, we look to nature for inspiration in the design of new therapeutics. Biologically-active, naturally-occuring molecules often have unique, complex molecular architectures that have evolved over millennia to interact selectively with biological systems. We call these naturally-occuring molecules 'natural products'. With these wonderfully intricate structures comes a major scientific challenge: if we can't isolate what we need from nature, as is often the case, can we synthesise these substances efficiently from scratch in the laboratory?In this project, we will develop new reactions that will allow us to build natural products called the pseudolaric acids very quickly and efficiently. The pseudolaric acids have challenging structures and the potential to inspire ground-breaking, anti-tumour drugs. One member of this family, pseudolaric acid B, has been shown to circumvent the problems of resistance from which many anti-tumour drugs suffer, thus the natural product is active against multi-drug resistant cancers. For example, pseudolaric acid B has been shown to be active against a liver cancer that is resistant to treatment by the famous anti-cancer agent Taxol.Our approach to the pseudolaric acids will involve new 'cascade' reactions that allow simple starting materials to cascade through to complex molecules in just one reaction flask, using just one reagent. Cascade reactions make great economic sense as they extract high value from a chemical reaction, saving steps and therefore time, chemical resources, and minimising waste generation. The cascades that we will develop will also allow us to control the shape, or stereochemistry, of the molecule under construction. The cascade reactions will be triggered by supplying electrons to the starting materials. The electron-transfer processes will be facilitated by the water present in the reaction flask thus we say the reactions are 'under water control'.Improvements in the way we build molecules are urgently needed and are eagerly sought. The new, selective chemical reactions that result from our studies will allow chemists to streamline routes when building molecules in the future, thus saving precious resources. The preliminary results from our laboratory on the discovery of new organic reactions mediated by electron-transfer means that we are uniquely placed to meet this challenge. Obtaining analogues of the biologically-important natural product pseudolaric acid B is a significant and timely problem. While pseudolaric acid B has been shown to bind to a new site on tubulin and to be active against multi-drug resistant cancers, the link between the structure of the molecule and its anti-tumour activity is not understood. Our concise approach to the molecular skeleton of the pseudolaric acids will allow us to make changes to the structure and thus to prepare 'unnatural products' related to the pseudolaric acids. The biological testing of these analogues will give us a unique insight into how the molecule exerts its important biological effect. Ultimately, our studies may lead to new drugs and to improvements in the quality of life, worldwide.
Organisations
People |
ORCID iD |
David Procter (Principal Investigator) |
Publications
Collins KD
(2010)
Selective reductions of cyclic 1,3-diesters by using SmI(2) and H(2)O.
in Chemistry (Weinheim an der Bergstrasse, Germany)
Sautier B
(2012)
Recent advances in the chemistry of SmI(2)-H(2)O.
in Chimia
Sautier B
(2013)
Development of an additive-controlled, SmI2-mediated stereoselective sequence: Telescoped spirocyclisation, lactone reduction and Peterson elimination.
in Beilstein journal of organic chemistry
Sautier B
(2012)
Radical cyclization cascades of unsaturated Meldrum's acid derivatives.
in Organic letters
Szostak M
(2013)
Selective reduction of barbituric acids using SmI2/H2O: synthesis, reactivity, and structural analysis of tetrahedral adducts.
in Angewandte Chemie (International ed. in English)
Szostak M
(2014)
Electron transfer reduction of nitriles using SmI2-Et3N-H2O: synthetic utility and mechanism.
in Organic letters
Szostak M
(2014)
Switching between reaction pathways by an alcohol cosolvent effect: SmI2-ethylene glycol vs SmI2-H2O mediated synthesis of uracils.
in Organic letters
Szostak M
(2014)
Structural analysis and reactivity of unusual tetrahedral intermediates enabled by SmI2-mediated reduction of barbituric acids: vinylogous N-acyliminium additions to a-hydroxy-N-acyl-carbamides.
in Chemical communications (Cambridge, England)
Description | We have developed radically new routes for the synthesis of biologically significant molecular motifs and have applied them in an approach to an anticancer natural product. |
Exploitation Route | Others have used our technology in their our research. |
Sectors | Agriculture, Food and Drink,Chemicals,Healthcare |