BIOMAT Database Logo BIOMAT Database Logo

Differential patterns of intracellular metabolism of 2',3'-didehydro-2',3'-dideoxythymidine and 3'-azido-2',3'-dideoxythymidine, two potent anti-human immunodeficiency virus compounds. 1989

J Balzarini, and P Herdewijn, and E De Clercq
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.

3'-Azido-2',3'-dideoxythymidine (AZT) and 2',3'-didehydro-2',3'-dideoxythymidine (D4T) are potent and selective inhibitors of human immunodeficiency virus replication in MT-4 and ATH8 cells. They are also inhibitory to the replication of murine retroviruses, i.e. Moloney murine sarcoma virus-induced transformation of C3H cells. In MT-4 cells AZT is readily phosphorylated to its 5'-monophosphate, while the 5'-di- and 5'-triphosphates are generated to a 200-600-fold lower extent than the 5'-monophosphate. D4T is phosphorylated in MT-4 cells to its 5'-monophosphate at a 300-600-fold lower extent than AZT. The phosphorylation of AZT in the thymidine kinase-deficient cell line (Raji/TK-) is severely depressed, while D4T phosphorylation is only slightly diminished in Raji/TK- as compared to Raji/0 cells. D4T has a 10-fold lower affinity for phosphorylation by crude MT-4 cell extracts than AZT (Km, 142 and 14 microM, respectively), and the Vmax for phosphorylation of D4T is only 5% that of AZT. D4T is phosphorylated by MT-4 cell extracts about 180-fold less efficiently than AZT (Vmax/Km, 0.06 for D4T, as compared to 11 for AZT), and this is consistent with the differences found in the amounts of phosphorylated products of D4T and AZT formed in intact MT-4 cells. The 5'-triphosphates of AZT and D4T are equipotent in their inhibitory effects on the reverse transcriptases from human immunodeficiency virus and Moloney murine leukemia virus.

UI MeSH Term Description Entries
D009053 Sarcoma Viruses, Murine A group of replication-defective viruses, in the genus GAMMARETROVIRUS, which are capable of transforming cells, but which replicate and produce tumors only in the presence of Murine leukemia viruses (LEUKEMIA VIRUS, MURINE). Finkel-Biskis-Jinkins murine sarcoma virus,Mouse Sarcoma Viruses,FBJ-MSV,FBR-MSV,Finkel-Biskis-Reilly murine sarcoma virus,Finkel Biskis Jinkins murine sarcoma virus,Finkel Biskis Reilly murine sarcoma virus,Murine Sarcoma Viruses,Sarcoma Viruses, Mouse
D010766 Phosphorylation The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. Phosphorylations
D002460 Cell Line Established cell cultures that have the potential to propagate indefinitely. Cell Lines,Line, Cell,Lines, Cell
D002470 Cell Survival The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability. Cell Viability,Cell Viabilities,Survival, Cell,Viabilities, Cell,Viability, Cell
D003841 Deoxycytidine A nucleoside component of DNA composed of CYTOSINE and DEOXYRIBOSE. Cytosine Deoxyribonucleoside,Cytosine Deoxyriboside,Deoxyribonucleoside, Cytosine,Deoxyriboside, Cytosine
D003854 Deoxyribonucleotides A purine or pyrimidine base bonded to a DEOXYRIBOSE containing a bond to a phosphate group. Deoxyribonucleotide
D004305 Dose-Response Relationship, Drug The relationship between the dose of an administered drug and the response of the organism to the drug. Dose Response Relationship, Drug,Dose-Response Relationships, Drug,Drug Dose-Response Relationship,Drug Dose-Response Relationships,Relationship, Drug Dose-Response,Relationships, Drug Dose-Response
D006678 HIV Human immunodeficiency virus. A non-taxonomic and historical term referring to any of two species, specifically HIV-1 and/or HIV-2. Prior to 1986, this was called human T-lymphotropic virus type III/lymphadenopathy-associated virus (HTLV-III/LAV). From 1986-1990, it was an official species called HIV. Since 1991, HIV was no longer considered an official species name; the two species were designated HIV-1 and HIV-2. AIDS Virus,HTLV-III,Human Immunodeficiency Viruses,Human T-Cell Lymphotropic Virus Type III,Human T-Lymphotropic Virus Type III,LAV-HTLV-III,Lymphadenopathy-Associated Virus,Acquired Immune Deficiency Syndrome Virus,Acquired Immunodeficiency Syndrome Virus,Human Immunodeficiency Virus,Human T Cell Lymphotropic Virus Type III,Human T Lymphotropic Virus Type III,Human T-Cell Leukemia Virus Type III,Immunodeficiency Virus, Human,Immunodeficiency Viruses, Human,Virus, Human Immunodeficiency,Viruses, Human Immunodeficiency,AIDS Viruses,Human T Cell Leukemia Virus Type III,Lymphadenopathy Associated Virus,Lymphadenopathy-Associated Viruses,Virus, AIDS,Virus, Lymphadenopathy-Associated,Viruses, AIDS,Viruses, Lymphadenopathy-Associated
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia

Related Publications

J Balzarini, and P Herdewijn, and E De Clercq
Intracellular metabolism of CycloSaligenyl 3'-azido-2', 3'-dideoxythymidine monophosphate, a prodrug of 3'-azido-2', 3'-dideoxythymidine (zidovudine).
December 1999, Molecular pharmacology,
J Balzarini, and P Herdewijn, and E De Clercq
Intracellular metabolism and pharmacokinetics of 5'-hydrogenphosphonate of 3'-azido-2',3'-dideoxythymidine, a prodrug of 3'-azido-2',3'-dideoxythymidine.
August 2004, Antiviral research,
J Balzarini, and P Herdewijn, and E De Clercq
Metabolism and activities of 3'-azido-2',3'-dideoxythymidine and 2',3'-didehydro-2',3'-dideoxythymidine in herpesvirus thymidine kinase transduced T-lymphocytes.
August 1997, Antiviral research,
J Balzarini, and P Herdewijn, and E De Clercq
Treatment of human immunodeficiency virus-related polyneuropathy with 3'-azido-2',3'-dideoxythymidine.
January 1988, Annals of neurology,
J Balzarini, and P Herdewijn, and E De Clercq
Synthesis and anti-HIV activity of some novel arylphosphate and H-phosphonate derivatives of 3'-azido-2',3'-dideoxythymidine and 2',3'-didehydro-2',3'-dideoxythymidine.
July 1999, Antiviral research,
J Balzarini, and P Herdewijn, and E De Clercq
Selective action of 2',3'-didehydro-2',3'-dideoxythymidine triphosphate on human immunodeficiency virus reverse transcriptase and human DNA polymerases.
February 1992, The Journal of biological chemistry,
J Balzarini, and P Herdewijn, and E De Clercq
Cyclosaligenyl-2',3'-didehydro-2',3'-dideoxythymidine monophosphate: efficient intracellular delivery of d4TMP.
November 2000, Molecular pharmacology,
J Balzarini, and P Herdewijn, and E De Clercq
Metabolism and DNA interaction of 2',3'-didehydro-2',3'-dideoxythymidine in human bone marrow cells.
November 1991, Molecular pharmacology,
J Balzarini, and P Herdewijn, and E De Clercq
Intracellular metabolism and persistence of the anti-human immunodeficiency virus activity of 2',3'-didehydro-3'-deoxy-4'-ethynylthymidine, a novel thymidine analog.
November 2007, Antimicrobial agents and chemotherapy,
J Balzarini, and P Herdewijn, and E De Clercq
In vitro toxicity of 3'-azido-3'-deoxythymidine, carbovir and 2',3'-didehydro-2',3'-dideoxythymidine to human and murine haematopoietic progenitor cells.
April 1992, British journal of haematology,
Copied contents to your clipboard!