Publications by authors named "Leo M H Leung"

3 Publications

  • Page 1 of 1

2-Aminomethylene-5-sulfonylthiazole Inhibitors of Lysyl Oxidase (LOX) and LOXL2 Show Significant Efficacy in Delaying Tumor Growth.

J Med Chem 2020 03 4;63(5):2308-2324. Epub 2019 Sep 4.

Drug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester, Alderley Park, Macclesfield SK10 4TG, United Kingdom.

The lysyl oxidase (LOX) family of extracellular proteins plays a vital role in catalyzing the formation of cross-links in fibrillar elastin and collagens leading to extracellular matrix (ECM) stabilization. These enzymes have also been implicated in tumor progression and metastatic disease and have thus become an attractive therapeutic target for many types of invasive cancers. Following our recently published work on the discovery of aminomethylenethiophenes (AMTs) as potent, orally bioavailable LOX/LOXL2 inhibitors, we report herein the discovery of a series of dual LOX/LOXL2 inhibitors, as well as a subseries of LOXL2-selective inhibitors, bearing an aminomethylenethiazole (AMTz) scaffold. Incorporation of a thiazole core leads to improved potency toward LOXL2 inhibition via an irreversible binding mode of inhibition. SAR studies have enabled the discovery of a predictive 3DQSAR model. Lead AMTz inhibitors exhibit improved pharmacokinetic properties and excellent antitumor efficacy, with significantly reduced tumor growth in a spontaneous breast cancer genetically engineered mouse model.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.9b01112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073924PMC
March 2020

A linchpin carbacyclization approach for the synthesis of carbanucleosides.

J Org Chem 2008 Dec;73(23):9197-206

School of Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ, UK.

A convenient synthesis of carbanucleosides, with both enantiomers equally accessible, is reported. The key step is a tandem linchpin cyclization process to give access to substituted carbafuranose derivatives having the correct relative stereochemistry for subsequent nucleobase introduction with inversion of configuration at C1. This was illustrated by the synthesis of 2',3'-dideoxycarbathymidine via a convergent nucleobase introduction and of 2',3'-dideoxy-6'-hydroxycarbauridine via a linear nucleobase introduction. Both methods relied on Mitsunobu chemistry, and the first example of the Mukaiyama modification of the Mitsunobu reaction involving nucleobases as nucleophiles is reported.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jo801848hDOI Listing
December 2008

A stereoselective cyclization to carbafuranose derivatives starting from 1,4-bis-epoxides.

Org Lett 2005 Nov;7(23):5183-6

School of Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ, United Kingdom.

[reactions: see text] A concise synthesis of highly functionalized cyclopentane derivatives via a Brook rearrangement mediated stereoselective linchpin cyclization reaction involving tert-butyldimethylsilyl-1,3-dithianyllithium and homochiral 1,4-bis-epoxides is described.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/ol052009hDOI Listing
November 2005