Design of a Fluoro-olefin Cytidine Nucleoside as a Bioprecursor of a Mechanism-Based Inhibitor of Ribonucleotide Reductase

James R. McCarthy; Prasad S. Sunkara; Donald P. Matthews; Alan J. Bitonti; Esa T. Jarvi; Jeffrey S. Sabol; Robert J. Resvick; Edward W. Huber; Wilfred Adrianus van der Donk; Guixue Yu; Joanne Stubbe

Design of a Fluoro-olefin Cytidine Nucleoside as a Bioprecursor of a Mechanism-Based Inhibitor of Ribonucleotide Reductase

James R. McCarthy, Prasad S. Sunkara, Donald P. Matthews, Alan J. Bitonti, Esa T. Jarvi, Jeffrey S. Sabol, Robert J. Resvick, Edward W. Huber, Wilfred Adrianus van der Donk, Guixue Yu, Joanne Stubbe

Research output: Contribution to journal › Article › peer-review

Abstract

MDL 101,731 (3) is a fluoro olefin cytidine nucleoside designed as a bioprecursor of a mechanism-based inhibitor of ribonucleotide diphosphate reductase (RDPR) targeted for the treatment of tumors. The rationale for the use of a fluoro olefin in the design of 3 are discussed. A new stereospecific method to fluoro olefins was developed as a key step in the synthesis of MDL 101,731. Studies showing inactivation of both the R1 and R2 subunits of RDPR from E. coli by the diphosphate of MDL 101,731 are presented, and a proposed mechanism for the process is discussed. In addition, the antitumor profile of the drug is outlined. MDL 101,731 has recently entered clinical trials for the treatment of solid tumors in the US and Japan.

Original language	English (US)
Pages (from-to)	244-264
Number of pages	21
Journal	ACS Symposium Series
Volume	639
State	Published - 1996
Externally published	Yes

ASJC Scopus subject areas

Chemistry(all)
Chemical Engineering(all)

Library availability

Discover UIUC Full Text

Cite this

@article{38c3c4e6e9794827ba1076f0b77df2a6,

title = "Design of a Fluoro-olefin Cytidine Nucleoside as a Bioprecursor of a Mechanism-Based Inhibitor of Ribonucleotide Reductase",

abstract = "MDL 101,731 (3) is a fluoro olefin cytidine nucleoside designed as a bioprecursor of a mechanism-based inhibitor of ribonucleotide diphosphate reductase (RDPR) targeted for the treatment of tumors. The rationale for the use of a fluoro olefin in the design of 3 are discussed. A new stereospecific method to fluoro olefins was developed as a key step in the synthesis of MDL 101,731. Studies showing inactivation of both the R1 and R2 subunits of RDPR from E. coli by the diphosphate of MDL 101,731 are presented, and a proposed mechanism for the process is discussed. In addition, the antitumor profile of the drug is outlined. MDL 101,731 has recently entered clinical trials for the treatment of solid tumors in the US and Japan.",

author = "McCarthy, {James R.} and Sunkara, {Prasad S.} and Matthews, {Donald P.} and Bitonti, {Alan J.} and Jarvi, {Esa T.} and Sabol, {Jeffrey S.} and Resvick, {Robert J.} and Huber, {Edward W.} and {van der Donk}, {Wilfred Adrianus} and Guixue Yu and Joanne Stubbe",

year = "1996",

language = "English (US)",

volume = "639",

pages = "244--264",

journal = "ACS Symposium Series",

issn = "0097-6156",

publisher = "American Chemical Society",

}

TY - JOUR

T1 - Design of a Fluoro-olefin Cytidine Nucleoside as a Bioprecursor of a Mechanism-Based Inhibitor of Ribonucleotide Reductase

AU - McCarthy, James R.

AU - Sunkara, Prasad S.

AU - Matthews, Donald P.

AU - Bitonti, Alan J.

AU - Jarvi, Esa T.

AU - Sabol, Jeffrey S.

AU - Resvick, Robert J.

AU - Huber, Edward W.

AU - van der Donk, Wilfred Adrianus

AU - Yu, Guixue

AU - Stubbe, Joanne

PY - 1996

Y1 - 1996

N2 - MDL 101,731 (3) is a fluoro olefin cytidine nucleoside designed as a bioprecursor of a mechanism-based inhibitor of ribonucleotide diphosphate reductase (RDPR) targeted for the treatment of tumors. The rationale for the use of a fluoro olefin in the design of 3 are discussed. A new stereospecific method to fluoro olefins was developed as a key step in the synthesis of MDL 101,731. Studies showing inactivation of both the R1 and R2 subunits of RDPR from E. coli by the diphosphate of MDL 101,731 are presented, and a proposed mechanism for the process is discussed. In addition, the antitumor profile of the drug is outlined. MDL 101,731 has recently entered clinical trials for the treatment of solid tumors in the US and Japan.

AB - MDL 101,731 (3) is a fluoro olefin cytidine nucleoside designed as a bioprecursor of a mechanism-based inhibitor of ribonucleotide diphosphate reductase (RDPR) targeted for the treatment of tumors. The rationale for the use of a fluoro olefin in the design of 3 are discussed. A new stereospecific method to fluoro olefins was developed as a key step in the synthesis of MDL 101,731. Studies showing inactivation of both the R1 and R2 subunits of RDPR from E. coli by the diphosphate of MDL 101,731 are presented, and a proposed mechanism for the process is discussed. In addition, the antitumor profile of the drug is outlined. MDL 101,731 has recently entered clinical trials for the treatment of solid tumors in the US and Japan.

UR - http://www.scopus.com/inward/record.url?scp=1842525830&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=1842525830&partnerID=8YFLogxK

M3 - Article

AN - SCOPUS:1842525830

SN - 0097-6156

VL - 639

SP - 244

EP - 264

JO - ACS Symposium Series

JF - ACS Symposium Series

ER -

Design of a Fluoro-olefin Cytidine Nucleoside as a Bioprecursor of a Mechanism-Based Inhibitor of Ribonucleotide Reductase

Abstract

ASJC Scopus subject areas

Library availability

Related links

Fingerprint

Cite this