Gary B Evans1, Scott A Cameron2, Andreas Luxenburger1, Rong Guan3, Javier Suarez3, Keisha Thomas3, Vern L Schramm3, Peter C Tyler1. 1. Ferrier Research Institute, Victoria University of Wellington, 69 Gracefield Rd, Lower Hutt 5010, New Zealand. 2. Ferrier Research Institute, Victoria University of Wellington, 69 Gracefield Rd, Lower Hutt 5010, New Zealand; Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461, USA. 3. Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461, USA.
Abstract
MTDIA is a picomolar transition state analogue inhibitor of human methylthioadenosine phosphorylase and a femtomolar inhibitor of Escherichia coli methylthioadenosine nucleosidase. MTDIA has proven to be a non-toxic, orally available pre-clinical drug candidate with remarkable anti-tumour activity against a variety of human cancers in mouse xenografts. The structurally similar compound MTDIH is a potent inhibitor of human and malarial purine nucleoside phosphorylase (PNP) as well as the newly discovered enzyme, methylthioinosine phosphorylase, isolated from Pseudomonas aeruginosa. Since the enantiomers of some pharmaceuticals have revealed surprising biological activities, the enantiomers of MTDIH and MTDIA, compounds 1 and 2, respectively, were prepared and their enzyme binding properties studied. Despite binding less tightly to their target enzymes than their enantiomers compounds 1 and 2 are nanomolar inhibitors.
MTDIA is a picomolar transition state analogue inhibitor of n class="Species">humanmethylthioadenosine phosphorylase and a femtomolar inhibitor of Escherichia colimethylthioadenosine nucleosidase. MTDIA has proven to be a non-toxic, orally available pre-clinical drug candidate with remarkable anti-tumour activity against a variety of humancancers in mouse xenografts. The structurally similar compound MTDIH is a potent inhibitor of human and malarialpurine nucleoside phosphorylase (PNP) as well as the newly discovered enzyme, methylthioinosine phosphorylase, isolated from Pseudomonas aeruginosa. Since the enantiomers of some pharmaceuticals have revealed surprising biological activities, the enantiomers of MTDIH and MTDIA, compounds 1 and 2, respectively, were prepared and their enzyme binding properties studied. Despite binding less tightly to their target enzymes than their enantiomers compounds 1 and 2 are nanomolar inhibitors.
Authors: Jemy A Gutierrez; Minkui Luo; Vipender Singh; Lei Li; Rosemary L Brown; Gillian E Norris; Gary B Evans; Richard H Furneaux; Peter C Tyler; Gavin F Painter; Dirk H Lenz; Vern L Schramm Journal: ACS Chem Biol Date: 2007-11-20 Impact factor: 5.100
Authors: Gary B Evans; Richard H Furneaux; Andrzej Lewandowicz; Vern L Schramm; Peter C Tyler Journal: J Med Chem Date: 2003-07-17 Impact factor: 7.446
Authors: Keith Clinch; Gary B Evans; Richard H Furneaux; Dirk H Lenz; Jennifer M Mason; Simon P H Mee; Peter C Tyler; Sarah J Wilcox Journal: Org Biomol Chem Date: 2007-07-20 Impact factor: 3.876
Authors: Jennifer M Mason; Hongling Yuan; Gary B Evans; Peter C Tyler; Quan Du; Vern L Schramm Journal: Eur J Med Chem Date: 2016-10-27 Impact factor: 6.514
Authors: Lawrence D Harris; Rajesh K Harijan; Rodrigo G Ducati; Gary B Evans; Brett M Hirsch; Vern L Schramm Journal: ACS Chem Biol Date: 2017-12-14 Impact factor: 5.100
Authors: Hilda A Namanja-Magliano; Gary B Evans; Rajesh K Harijan; Peter C Tyler; Vern L Schramm Journal: Biochemistry Date: 2017-09-07 Impact factor: 3.162
Authors: Rajesh K Harijan; Oskar Hoff; Rodrigo G Ducati; Ross S Firestone; Brett M Hirsch; Gary B Evans; Vern L Schramm; Peter C Tyler Journal: J Med Chem Date: 2019-03-28 Impact factor: 7.446