5-Iodoacetamidomethyl-2'-deoxyuridine 5'-phosphate. A selective inhibitor of mammalian thymidylate synthetases

Barfknecht, Roxane L.; Huet-Rose, Rocio; Kampf, Arieh; Mertes, Mathias P.

doi:10.1021/ja00432a069

Cited by 15 publications

(4 citation statements)

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“…The enzyme was activated by dialysis for 4 days at 4 °C against 0.1 M potassium phosphate (pH 6.8) containing 40 mM mercaptoethanol. The substrate 2'-deoxy[5-3H]uridine 5'-phosphate at a specific activity above 15 Ci/mmol was purchased from Moravek Biochemicals, Industry, Calif., and diluted with cold substrate purchased from Sigma Chemical Co., St. Louis, to give a specific activity of 500 µ /µ . The cofactor, dhtetrahydrofolic acid, was also purchased from Sigma Chemical Co.…”

Section: Methodsmentioning

confidence: 99%

“…Another inhibitor that has been examined for the rate of inactivation of thymidylate synthetase from Ehrlich ascites tumor is 5-[(iodoacetamido)methyl]-2'-deoxyuridine 5'-phosphate. 15 It is a reasonably weak competitive inhibitor of the enzyme; however, it irreversibly inactivates the tumor enzyme at one-fourth the rate that 1 inactivates the bacterial enzyme.…”

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confidence: 99%

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5-(.alpha.-Bromoacetyl)-2'-deoxyuridine 5'-phosphate: an affinity label for thymidylate synthetase

Brouillette¹,

Chang²,

Mertes³

1979

J. Med. Chem.

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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

5-(.alpha.-Bromoacetyl)-2'-deoxyuridine 5'-phosphate: an affinity label for thymidylate synthetase

Brouillette¹,

Chang²,

Mertes³

1979

J. Med. Chem.

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“…More recently, similarly selective irreversible inhibitors have distinguished between tumor and thymus thymidylate synthetases (36) and between rabbit, pig, and carp adenylate kinases (37).…”

Section: Some New Tools Of Organic Chemistrymentioning

confidence: 99%

Comparative Biochemistry and Drug Design for Infectious Disease

Cohen

1979

Science

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In the past two decades, biochemistry and molecular biology have demonstrated the existence of potentially exploitable biochemical differences between etiologic agents of disease and their hosts. Known differences between organism and host with respect to metabolism and polymer structure point to the detailed characterization of key proteins as the focus for the development of potential inhibitors. In the last decade, the methodology of the isolation, characterization, and inactivation of proteins and enzymes has been advanced. The present scientific and technological base suggests that new efforts toward the development of selective chemotherapeutic agents for infections caused by bacteria, viruses, protozoa, and higher eukaryotes should exploit the known differences in proteins or other specific biopolymers serving crucial structural or metabolic roles in the economy of the parasite.

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“…Thus, the action of ribonucleoside diphosphate reductase In the above scheme the folate moiety serves as the alkylating as well as the reducing agent (reductive alkylation). Thymidylate synthetase is a target enzyme for cancer chemotherapy; indeed, enzyme inhibitors are based on 5-substituted uracil derivatives, e.g., F, CF3, SH, CHO, and CH2NHCOCH2I (135). Inhibition mechanisms are thought to be related to irreversible enzyme alkylation at the 6 position of the substituted uracil derivative (98) thus preventing thymine synthesis which leads to "thymineless death" (136).…”

Section: Related Biochemicals Based On Uracil (Uridine)mentioning

confidence: 99%

Uracil. A Perspective

Pasquale¹

1978

Ind. Eng. Chem. Prod. Res. Dev.

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The RNA component, uracil, is reviewed from structural, spectroscopic, synthetic, chemical reactivity, biochemical, and application viewpoints. This fascinating molecule undergoes a plethora of reactions at nine different sites; the specificity of these is considered in some detail. The review contains 189 literature citations.Uracil, a major component of nucleic acid, has aroused the interest of numerous experimentalists. The properties and reactions of this molecule gain significance when one considers their relationship to the chemical modification of biologically active nucleic acids and, consequently, living organisms. An understanding of this interplay simultaneously nourishes biomedical applications and instills the awareness of potential hazards. This report highlights the properties and chemistry of uracil with the intention of hopefully stimulating future applications. PropertiesUracil [2,4(lH,3H)-pyrimidinedione, C4H4N202], a white crystalline solid, melts with decomposition at 335-338 °C. This pyrimidine derivative is essentially insoluble in cold water (pH 7) and typical organic solvents. It dissolves in boiling water (ca. 2 g/100 mL) and dipolar aprotic solvents, e.g., Me2SO (1) (5.6 g/100 mL at 23 °C). Due to its amphoteric nature it is soluble in acids, i.e., 35% H2S04 (ca. 1.5 g/100 mL at 25 °C), CF3C02H (2), HF (3), and bases. With regard to its weakly basic properties uracil has been used as an indicator to extend the acidity function Ha (4) up to 17% by weight S03 in H2S04, As acidity increases, uracil first protonates at the more basic site (0 at C4), then doubly protonates (0 at C4 and C2). In basic solution uracil behaves as a weak dibasic (5) acid with ionization first at N3 (pKa = 9.7) and then at N4 (pKa = 14.2), The ability of nucleic acid bases, including uracil, to associate by hydrogen bonding ( 6) is essential to their role in biological evolution. StructureAfter considerable difficulty, a single crystal of uracil was obtained (twinning is prevalent) and analyzed (7) by X-ray crystallography. The space group is P24/a; there are four molecules in the unit cell which are essentially parallel and held together by NH-0 hydrogen bonds. The molecule is planar in the solid state with the two sets of C-C and C-0 bonds being of similar length and exists in its lactam form.

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5-Iodoacetamidomethyl-2'-deoxyuridine 5'-phosphate. A selective inhibitor of mammalian thymidylate synthetases

Cited by 15 publications

References 1 publication

5-(.alpha.-Bromoacetyl)-2'-deoxyuridine 5'-phosphate: an affinity label for thymidylate synthetase

5-(.alpha.-Bromoacetyl)-2'-deoxyuridine 5'-phosphate: an affinity label for thymidylate synthetase

Comparative Biochemistry and Drug Design for Infectious Disease

Uracil. A Perspective

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