Design and synthesis of potent "sulfur-free" transition state analogue inhibitors of 5′-methylthioadenosine nucleosidase and 5′-methylthioadenosine phosphorylase

Alistair I. Longshaw, Florian Adanitsch, Jemy A. Gutierrez, Gary B. Evans, Peter C. Tyler, Vern L. Schramm

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

5′-Methylthioadenosine/S-adenosylhomocysteine nucleosidase (MTAN) is a dual substrate bacterial enzyme involved in S-adenosylmethionine (SAM) related quorum sensing pathways that regulates virulence in many bacterial species. MTANs from many bacteria are directly involved in the quorum sensing mechanism by regulating the synthesis of autoinducer molecules that are used by bacterial communities to communicate. In humans, 5′-methylthioadenosine phosphorylase (MTAP) is involved in polyamine biosynthesis as well as in purine and SAM salvage pathways and thus has been identified as an anticancer target. Previously we have described the synthesis and biological activity of several aza-C-nucleoside mimics with a sulfur atom at the 5′ position that are potent E. coli MTAN and human MTAP inhibitors. Because of the possibility that the sulfur may affect bioavailability, we were interested in synthesizing "sulfur-free" analogues. Herein we describe the preparation of a series of "sulfur-free" transition state analogue inhibitors of E. coli MTAN and human MTAP that have low nano-to picomolar dissociation constants and are potentially novel bacterial anti-infective and anticancer drug candidates.

Original languageEnglish (US)
Pages (from-to)6730-6746
Number of pages17
JournalJournal of Medicinal Chemistry
Volume53
Issue number18
DOIs
StatePublished - Sep 23 2010

Fingerprint

adenosylhomocysteine nucleosidase
Sulfur
Quorum Sensing
S-Adenosylmethionine
Escherichia coli
Polyamines
Nucleosides
Biological Availability
Virulence
Bacteria
5'-methylthioadenosine phosphorylase
5'-methylthioadenosine
Enzymes
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery
  • Medicine(all)

Cite this

Design and synthesis of potent "sulfur-free" transition state analogue inhibitors of 5′-methylthioadenosine nucleosidase and 5′-methylthioadenosine phosphorylase. / Longshaw, Alistair I.; Adanitsch, Florian; Gutierrez, Jemy A.; Evans, Gary B.; Tyler, Peter C.; Schramm, Vern L.

In: Journal of Medicinal Chemistry, Vol. 53, No. 18, 23.09.2010, p. 6730-6746.

Research output: Contribution to journalArticle

Longshaw, Alistair I. ; Adanitsch, Florian ; Gutierrez, Jemy A. ; Evans, Gary B. ; Tyler, Peter C. ; Schramm, Vern L. / Design and synthesis of potent "sulfur-free" transition state analogue inhibitors of 5′-methylthioadenosine nucleosidase and 5′-methylthioadenosine phosphorylase. In: Journal of Medicinal Chemistry. 2010 ; Vol. 53, No. 18. pp. 6730-6746.
@article{66b3ccfc2448428a91bdf0972827ef94,
title = "Design and synthesis of potent {"}sulfur-free{"} transition state analogue inhibitors of 5′-methylthioadenosine nucleosidase and 5′-methylthioadenosine phosphorylase",
abstract = "5′-Methylthioadenosine/S-adenosylhomocysteine nucleosidase (MTAN) is a dual substrate bacterial enzyme involved in S-adenosylmethionine (SAM) related quorum sensing pathways that regulates virulence in many bacterial species. MTANs from many bacteria are directly involved in the quorum sensing mechanism by regulating the synthesis of autoinducer molecules that are used by bacterial communities to communicate. In humans, 5′-methylthioadenosine phosphorylase (MTAP) is involved in polyamine biosynthesis as well as in purine and SAM salvage pathways and thus has been identified as an anticancer target. Previously we have described the synthesis and biological activity of several aza-C-nucleoside mimics with a sulfur atom at the 5′ position that are potent E. coli MTAN and human MTAP inhibitors. Because of the possibility that the sulfur may affect bioavailability, we were interested in synthesizing {"}sulfur-free{"} analogues. Herein we describe the preparation of a series of {"}sulfur-free{"} transition state analogue inhibitors of E. coli MTAN and human MTAP that have low nano-to picomolar dissociation constants and are potentially novel bacterial anti-infective and anticancer drug candidates.",
author = "Longshaw, {Alistair I.} and Florian Adanitsch and Gutierrez, {Jemy A.} and Evans, {Gary B.} and Tyler, {Peter C.} and Schramm, {Vern L.}",
year = "2010",
month = "9",
day = "23",
doi = "10.1021/jm100898v",
language = "English (US)",
volume = "53",
pages = "6730--6746",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "18",

}

TY - JOUR

T1 - Design and synthesis of potent "sulfur-free" transition state analogue inhibitors of 5′-methylthioadenosine nucleosidase and 5′-methylthioadenosine phosphorylase

AU - Longshaw, Alistair I.

AU - Adanitsch, Florian

AU - Gutierrez, Jemy A.

AU - Evans, Gary B.

AU - Tyler, Peter C.

AU - Schramm, Vern L.

PY - 2010/9/23

Y1 - 2010/9/23

N2 - 5′-Methylthioadenosine/S-adenosylhomocysteine nucleosidase (MTAN) is a dual substrate bacterial enzyme involved in S-adenosylmethionine (SAM) related quorum sensing pathways that regulates virulence in many bacterial species. MTANs from many bacteria are directly involved in the quorum sensing mechanism by regulating the synthesis of autoinducer molecules that are used by bacterial communities to communicate. In humans, 5′-methylthioadenosine phosphorylase (MTAP) is involved in polyamine biosynthesis as well as in purine and SAM salvage pathways and thus has been identified as an anticancer target. Previously we have described the synthesis and biological activity of several aza-C-nucleoside mimics with a sulfur atom at the 5′ position that are potent E. coli MTAN and human MTAP inhibitors. Because of the possibility that the sulfur may affect bioavailability, we were interested in synthesizing "sulfur-free" analogues. Herein we describe the preparation of a series of "sulfur-free" transition state analogue inhibitors of E. coli MTAN and human MTAP that have low nano-to picomolar dissociation constants and are potentially novel bacterial anti-infective and anticancer drug candidates.

AB - 5′-Methylthioadenosine/S-adenosylhomocysteine nucleosidase (MTAN) is a dual substrate bacterial enzyme involved in S-adenosylmethionine (SAM) related quorum sensing pathways that regulates virulence in many bacterial species. MTANs from many bacteria are directly involved in the quorum sensing mechanism by regulating the synthesis of autoinducer molecules that are used by bacterial communities to communicate. In humans, 5′-methylthioadenosine phosphorylase (MTAP) is involved in polyamine biosynthesis as well as in purine and SAM salvage pathways and thus has been identified as an anticancer target. Previously we have described the synthesis and biological activity of several aza-C-nucleoside mimics with a sulfur atom at the 5′ position that are potent E. coli MTAN and human MTAP inhibitors. Because of the possibility that the sulfur may affect bioavailability, we were interested in synthesizing "sulfur-free" analogues. Herein we describe the preparation of a series of "sulfur-free" transition state analogue inhibitors of E. coli MTAN and human MTAP that have low nano-to picomolar dissociation constants and are potentially novel bacterial anti-infective and anticancer drug candidates.

UR - http://www.scopus.com/inward/record.url?scp=77956789065&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77956789065&partnerID=8YFLogxK

U2 - 10.1021/jm100898v

DO - 10.1021/jm100898v

M3 - Article

VL - 53

SP - 6730

EP - 6746

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 18

ER -