BIOMAT Database Logo BIOMAT Database Logo

Synthesis and anti-HIV activity of (-)-beta-D-(2R,4R)-1,3-dioxolane-2,6-diamino purine (DAPD) (amdoxovir) and (-)-beta-D-(2R,4R)-1,3-dioxolane guanosine (DXG) prodrugs. 2007

Janarthanan Narayanasamy, and Manik R Pullagurla, and Ashoke Sharon, and Jianing Wang, and Raymond F Schinazi, and Chung K Chu
The University of Georgia College of Pharmacy, Athens, GA 30602, United States.

Prodrugs of (-)-beta-D-(2R,4R)-1,3-dioxolane-2,6-diamino purine (DAPD), organic salts of DAPD, 5'-L-valyl DAPD and N-1 substituted (-)-beta-D-(2R,4R)-1,3-dioxolane guanosine (DXG) have been synthesized with the objective of finding molecules which might be superior to DAPD and DXG in solubility as well as pharmacologic profiles. Synthesized prodrugs were evaluated for anti-HIV activity against HIV-1(LAI) in primary human lymphocytes (PBM cells) as well as their cytotoxicity in PBM, CEM and Vero cells. DAPD prodrugs, modified at the C6 position of the purine ring, demonstrated several folds of enhanced anti-HIV activity in comparison to the parent compound DAPD without increasing the toxicity. The presence of alkyl amino groups at the C6 position of the purine ring increased the antiviral potency several folds, and the most potent compound (-)-beta-D-(2R,4R)-1,3-dioxolane-2-amino-6-aminoethyl purine (8) was 17 times more potent than that of DAPD. 5'-L-Valyl DAPD 20 and organic acid salts 21-24 also exhibited enhanced anti-HIV activity in comparison to DAPD, while DXG prodrugs 16 and 17 exhibited lower potency than that of DXG or DAPD.

UI MeSH Term Description Entries
D007963 Leukocytes, Mononuclear Mature LYMPHOCYTES and MONOCYTES transported by the blood to the body's extravascular space. They are morphologically distinguishable from mature granulocytic leukocytes by their large, non-lobed nuclei and lack of coarse, heavily stained cytoplasmic granules. Mononuclear Leukocyte,Mononuclear Leukocytes,PBMC Peripheral Blood Mononuclear Cells,Peripheral Blood Human Mononuclear Cells,Peripheral Blood Mononuclear Cell,Peripheral Blood Mononuclear Cells,Leukocyte, Mononuclear
D011355 Prodrugs A compound that, on administration, must undergo chemical conversion by metabolic processes before becoming the pharmacologically active drug for which it is a prodrug. Drug Precursor,Drug Precursors,Pro-Drug,Prodrug,Pro-Drugs,Precursor, Drug,Precursors, Drug,Pro Drug,Pro Drugs
D011684 Purine Nucleosides Purines with a RIBOSE attached that can be phosphorylated to PURINE NUCLEOTIDES. Purine Nucleoside,Nucleoside, Purine,Nucleosides, Purine
D002460 Cell Line Established cell cultures that have the potential to propagate indefinitely. Cell Lines,Line, Cell,Lines, Cell
D004148 Dioxolanes
D004355 Drug Stability The chemical and physical integrity of a pharmaceutical product. Drug Shelf Life,Drugs Shelf Lives,Shelf Life, Drugs,Drug Stabilities,Drugs Shelf Life,Drugs Shelf Live,Life, Drugs Shelf,Shelf Life, Drug,Shelf Live, Drugs,Shelf Lives, Drugs
D006151 Guanosine A purine nucleoside that has guanine linked by its N9 nitrogen to the C1 carbon of ribose. It is a component of ribonucleic acid and its nucleotides play important roles in metabolism. (From Dorland, 28th ed)
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

Janarthanan Narayanasamy, and Manik R Pullagurla, and Ashoke Sharon, and Jianing Wang, and Raymond F Schinazi, and Chung K Chu
Phosphoramidate and phosphate prodrugs of (-)-beta-D-(2R,4R)-dioxolane-thymine: synthesis, anti-HIV activity and stability studies.
April 2006, Bioorganic & medicinal chemistry,
Janarthanan Narayanasamy, and Manik R Pullagurla, and Ashoke Sharon, and Jianing Wang, and Raymond F Schinazi, and Chung K Chu
Scaleable processes for the synthesis of (-)-β-D-2,6-diaminopurine dioxolane (Amdoxovir, DAPD) and (-)-β-D-2-aminopurine dioxolane (APD).
July 2012, Tetrahedron,
Janarthanan Narayanasamy, and Manik R Pullagurla, and Ashoke Sharon, and Jianing Wang, and Raymond F Schinazi, and Chung K Chu
PAMAM dendrimers and branched polyethyleneglycol (nanoparticles) prodrugs of (-)-beta-D-(2R, 4R)-dioxolane-thymine (DOT) and their anti-HIV activity.
January 2006, Antiviral chemistry & chemotherapy,
Janarthanan Narayanasamy, and Manik R Pullagurla, and Ashoke Sharon, and Jianing Wang, and Raymond F Schinazi, and Chung K Chu
Phosphoramidate prodrugs of (-)-β-D-(2R,4R)-dioxolane-thymine (DOT) as potent anti-HIV agents.
May 2012, Antiviral chemistry & chemotherapy,
Janarthanan Narayanasamy, and Manik R Pullagurla, and Ashoke Sharon, and Jianing Wang, and Raymond F Schinazi, and Chung K Chu
5'-O-Aliphatic and amino acid ester prodrugs of (-)-beta-D-(2R,4R)-dioxolane-thymine (DOT): synthesis, anti-HIV activity, cytotoxicity and stability studies.
February 2009, Bioorganic & medicinal chemistry,
Janarthanan Narayanasamy, and Manik R Pullagurla, and Ashoke Sharon, and Jianing Wang, and Raymond F Schinazi, and Chung K Chu
Anti-HIV-1 activities of 1,3-dioxolane guanine and 2,6-diaminopurine dioxolane.
January 1999, Nucleosides & nucleotides,
Janarthanan Narayanasamy, and Manik R Pullagurla, and Ashoke Sharon, and Jianing Wang, and Raymond F Schinazi, and Chung K Chu
1,3-dioxolanylpurine nucleosides (2R,4R) and (2R,4S) with selective anti-HIV-1 activity in human lymphocytes.
January 1993, Journal of medicinal chemistry,
Janarthanan Narayanasamy, and Manik R Pullagurla, and Ashoke Sharon, and Jianing Wang, and Raymond F Schinazi, and Chung K Chu
Asymmetric synthesis of 1,3-dioxolane-pyrimidine nucleosides and their anti-HIV activity.
May 1992, Journal of medicinal chemistry,
Janarthanan Narayanasamy, and Manik R Pullagurla, and Ashoke Sharon, and Jianing Wang, and Raymond F Schinazi, and Chung K Chu
[DIAMINO SUGARS. VI. THE SYNTHESIS OF 2,6-DIAMINO-2,6-DIDESOXY-BETA-D-MANNOSE. A DERIVATIVE OF 2,6-IMINO-2,6-DIDESOXY-ALPHA-D-ALTROSE].
January 1965, Chemische Berichte,
Janarthanan Narayanasamy, and Manik R Pullagurla, and Ashoke Sharon, and Jianing Wang, and Raymond F Schinazi, and Chung K Chu
Mechanism of action of 1-beta-D-2,6-diaminopurine dioxolane, a prodrug of the human immunodeficiency virus type 1 inhibitor 1-beta-D-dioxolane guanosine.
January 2001, Antimicrobial agents and chemotherapy,
Copied contents to your clipboard!