Potential radiosensitizing antiviral and anticancer pyrimidine nucleosides. Final report, June 1, 1974--May 31, 1978

Technical Report · Fri Sep 01 04:00:00 UTC 1978

DOI:https://doi.org/10.2172/6400611· OSTI ID:6400611

Prusoff, W H

The synthesis of a variety of novel nucleosides as potential antiviral, antineoplastic, and radiation sensitizing agents was investigated. The most significant accomplishment of this period was the development of 5-Iodo-5'-amino-2',5'-dideoxyuridine (AIU, AIdUrd) which is the first compound to require unequivocally, for antiviral activity, a unique activation by an enzyme (thymidine kinase) encoded by the Herpes virus genome. This unusual requirement for activation prevents toxicity to uninfected cells or tissues. The major conceptual contribution is that a non-toxic drug for established viral infections can indeed be developed. Although AIU is not a substrate for E. coli thymidine- or thymidylate kinase, it does bind to these enzymes and has a K/sub i/ of 240 ..mu..M and 59 ..mu..M respectively. Both enzymes are sensitized to uv radiations, and the concentrations required for 50 percent enhancement is roughly equivalent to their respective K/sub i/. Various other halogenated nucleoside analogs were prepared and evaluated for radiation sensitization potential. Mammalian enzymes appear to be less sensitive to uv radiations than bacterial enzymes. In an attempt to overcome this problem 5'-azido nucleoside analogs were prepared, but these were not effective.

• Research Organization: Yale Univ., New Haven, CT (USA). School of Medicine
• OSTI ID: 6400611
• Report Number(s): COO-2468-4
• Country of Publication: United States
• Language: English

Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
400301* -- Organic Chemistry-- Chemical & Physicochemical Properties-- (-1987)
550200 -- Biochemistry
550600 -- Medicine
560112 -- Radiation Effects on Biochemicals-- In Microorganisms-- (-1987)
59 BASIC BIOLOGICAL SCIENCES
62 RADIOLOGY AND NUCLEAR MEDICINE
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
ANTIMETABOLITES
ANTIMITOTIC DRUGS
ANTINEOPLASTIC DRUGS
AZINES
BIOCHEMICAL REACTION KINETICS
CHEMICAL PREPARATION
DISEASES
DRUGS
ELECTROMAGNETIC RADIATION
ENZYMES
HETEROCYCLIC COMPOUNDS
HYDROXY COMPOUNDS
INFECTIOUS DISEASES
IODODEOXYURIDINE
IODOURACILS
KINETICS
MICROORGANISMS
NUCLEOSIDES
NUCLEOTIDES
ORGANIC COMPOUNDS
ORGANIC HALOGEN COMPOUNDS
ORGANIC IODINE COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
PARASITES
PYRIMIDINES
RADIATIONS
RADIOSENSITIVITY
RADIOSENSITIVITY EFFECTS
RADIOSENSITIZERS
REACTION KINETICS
RESPONSE MODIFYING FACTORS
RIBOSIDES
SYNTHESIS
ULTRAVIOLET RADIATION
URACILS
VIRUSES