title: Tight binding enantiomers of pre-clinical drug candidates.
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.
authors.affiliation: Ferrier Research Institute, Victoria University of Wellington, 69 Gracefield Rd, Lower Hutt 5010, New Zealand.
authors.forename: Gary B
authors.initials: GB
authors.lastname: Evans
authors.affiliation: 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.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Cameron
authors.affiliation: Ferrier Research Institute, Victoria University of Wellington, 69 Gracefield Rd, Lower Hutt 5010, New Zealand.
authors.forename: Andreas
authors.initials: A
authors.lastname: Luxenburger
authors.affiliation: Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461, USA.
authors.forename: Rong
authors.initials: R
authors.lastname: Guan
authors.affiliation: Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461, USA.
authors.forename: Javier
authors.initials: J
authors.lastname: Suarez
authors.affiliation: Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461, USA.
authors.forename: Keisha
authors.initials: K
authors.lastname: Thomas
authors.affiliation: Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461, USA.
authors.forename: Vern L
authors.initials: VL
authors.lastname: Schramm
authors.affiliation: Ferrier Research Institute, Victoria University of Wellington, 69 Gracefield Rd, Lower Hutt 5010, New Zealand.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Tyler
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D055808:Drug Discovery; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology*; D011485:Protein Binding; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000201:enzymology*; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011759:Pyrrolidines / Q000737:chemistry* / Q000494:pharmacology*; D013237:Stereoisomerism
chemical_list: D011759:Pyrrolidines; C556837:methylthio-DADMe-immucillin-A; D011683:Purine-Nucleoside Phosphorylase; C021784:5'-methylthioadenosine phosphorylase; D000225:Adenine
keywords: Cancer; Drug; Enantiomer; Enzyme; Transition state analogue