2′-Deoxy-2′-methylenecytidine and 2′-Deoxy-2′,2′-difluorocytidine 5′-Diphosphates: Potent Mechanism-Based Inhibitors of Ribonucleotide Reductase

C. H. Baker, J. Banzon, J. M. Bollinger, J. Stubbe, V. Samano, M. J. Robins, B. Lippert, E. Jarvi, R. Resvick

Research output: Contribution to journalArticle

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Abstract

It has been found that 2′-deoxy-2′-methyleneuridine (MdUrd), 2′-deoxy-2′-methylenecytidine (MdCyd), and 2′- deoxy-2′,2′-difluorocytidine (dFdCyd) 5′-diphosphates (MdUDP (1) MdCDP (2) and dFdCDP (3), respectively) function as irreversible inactivators of the Escherichia coli ribonucleoside diphosphate reductase (RDPR). 2 is a much more potent inhibitor than its uridine analogue 1. It is proposed that 2 undergoes abstraction of H3′ to give an allylic radical that captures a hydrogen atom and decomposes to an active alkylating furanone species. RDPR also accepts 3 as an alternative substrate analogue and presumably executes an initial abstraction of H3′ to initiate formation of a suicide species. Both 2 and 3 give inactivation results that differ from those of previously studied inhibitors. The potent anticancer activities of MdCyd find dFdCyd indicate a significant chemotherapeutic potential. The analogous RDPR of mammalian cells should be regarded as a likely target and/or activating enzyme for these novel mechanism-based inactivators.

Original languageEnglish (US)
Pages (from-to)1879-1884
Number of pages6
JournalJournal of Medicinal Chemistry
Volume34
Issue number6
DOIs
StatePublished - Jun 1 1991

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gemcitabine
Ribonucleoside Diphosphate Reductase
Ribonucleotide Reductases
Diphosphates
Uridine
Suicide
Hydrogen
Escherichia coli
Enzymes
2'-methyl-2'-deoxyidenecytidine

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

Baker, C. H. ; Banzon, J. ; Bollinger, J. M. ; Stubbe, J. ; Samano, V. ; Robins, M. J. ; Lippert, B. ; Jarvi, E. ; Resvick, R. / 2′-Deoxy-2′-methylenecytidine and 2′-Deoxy-2′,2′-difluorocytidine 5′-Diphosphates : Potent Mechanism-Based Inhibitors of Ribonucleotide Reductase. In: Journal of Medicinal Chemistry. 1991 ; Vol. 34, No. 6. pp. 1879-1884.
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abstract = "It has been found that 2′-deoxy-2′-methyleneuridine (MdUrd), 2′-deoxy-2′-methylenecytidine (MdCyd), and 2′- deoxy-2′,2′-difluorocytidine (dFdCyd) 5′-diphosphates (MdUDP (1) MdCDP (2) and dFdCDP (3), respectively) function as irreversible inactivators of the Escherichia coli ribonucleoside diphosphate reductase (RDPR). 2 is a much more potent inhibitor than its uridine analogue 1. It is proposed that 2 undergoes abstraction of H3′ to give an allylic radical that captures a hydrogen atom and decomposes to an active alkylating furanone species. RDPR also accepts 3 as an alternative substrate analogue and presumably executes an initial abstraction of H3′ to initiate formation of a suicide species. Both 2 and 3 give inactivation results that differ from those of previously studied inhibitors. The potent anticancer activities of MdCyd find dFdCyd indicate a significant chemotherapeutic potential. The analogous RDPR of mammalian cells should be regarded as a likely target and/or activating enzyme for these novel mechanism-based inactivators.",
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2′-Deoxy-2′-methylenecytidine and 2′-Deoxy-2′,2′-difluorocytidine 5′-Diphosphates : Potent Mechanism-Based Inhibitors of Ribonucleotide Reductase. / Baker, C. H.; Banzon, J.; Bollinger, J. M.; Stubbe, J.; Samano, V.; Robins, M. J.; Lippert, B.; Jarvi, E.; Resvick, R.

In: Journal of Medicinal Chemistry, Vol. 34, No. 6, 01.06.1991, p. 1879-1884.

Research output: Contribution to journalArticle

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T2 - Potent Mechanism-Based Inhibitors of Ribonucleotide Reductase

AU - Baker, C. H.

AU - Banzon, J.

AU - Bollinger, J. M.

AU - Stubbe, J.

AU - Samano, V.

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AU - Lippert, B.

AU - Jarvi, E.

AU - Resvick, R.

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N2 - It has been found that 2′-deoxy-2′-methyleneuridine (MdUrd), 2′-deoxy-2′-methylenecytidine (MdCyd), and 2′- deoxy-2′,2′-difluorocytidine (dFdCyd) 5′-diphosphates (MdUDP (1) MdCDP (2) and dFdCDP (3), respectively) function as irreversible inactivators of the Escherichia coli ribonucleoside diphosphate reductase (RDPR). 2 is a much more potent inhibitor than its uridine analogue 1. It is proposed that 2 undergoes abstraction of H3′ to give an allylic radical that captures a hydrogen atom and decomposes to an active alkylating furanone species. RDPR also accepts 3 as an alternative substrate analogue and presumably executes an initial abstraction of H3′ to initiate formation of a suicide species. Both 2 and 3 give inactivation results that differ from those of previously studied inhibitors. The potent anticancer activities of MdCyd find dFdCyd indicate a significant chemotherapeutic potential. The analogous RDPR of mammalian cells should be regarded as a likely target and/or activating enzyme for these novel mechanism-based inactivators.

AB - It has been found that 2′-deoxy-2′-methyleneuridine (MdUrd), 2′-deoxy-2′-methylenecytidine (MdCyd), and 2′- deoxy-2′,2′-difluorocytidine (dFdCyd) 5′-diphosphates (MdUDP (1) MdCDP (2) and dFdCDP (3), respectively) function as irreversible inactivators of the Escherichia coli ribonucleoside diphosphate reductase (RDPR). 2 is a much more potent inhibitor than its uridine analogue 1. It is proposed that 2 undergoes abstraction of H3′ to give an allylic radical that captures a hydrogen atom and decomposes to an active alkylating furanone species. RDPR also accepts 3 as an alternative substrate analogue and presumably executes an initial abstraction of H3′ to initiate formation of a suicide species. Both 2 and 3 give inactivation results that differ from those of previously studied inhibitors. The potent anticancer activities of MdCyd find dFdCyd indicate a significant chemotherapeutic potential. The analogous RDPR of mammalian cells should be regarded as a likely target and/or activating enzyme for these novel mechanism-based inactivators.

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