Phosphorylation of “tricyclic nucleoside” by adenosine kinases from L1210 cells and HEp-2 cells

Bennett, L. Lee; Allan, Paula W.; Chang, C H

doi:10.1016/0006-2952(83)90026-6

Cited by 9 publications

(3 citation statements)

References 8 publications

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“…In addition, a decline in intracellular ATP is observed in cells treated with 8-Cl-Ado, however, by unknown mechanisms. Studies using cell lines that are proficient or deficient in adenosine kinase and in vitro kinase assays demonstrated that 8-Cl-Ado is monophosphorylated (8-Cl-AMP) by adenosine kinase [6, 9]. 8-Cl-AMP is further metabolized to 8-Cl-ADP and 8-Cl-ATP, which are presumed to be catalyzed by monophospho-kinase and diphospho-kinase, respectively.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of ATP synthase by chlorinated adenosine analogue

Chen

Nowak

Ayres

et al. 2009

Biochemical Pharmacology

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8-Chloroadenosine (8-Cl-Ado) is a ribonucleoside analogue that is currently in clinical trial for chronic lymphocytic leukemia. Based on the decline in cellular ATP pool following 8-Cl-Ado treatment, we hypothesized that 8-Cl-ADP and 8-Cl-ATP may interfere with ATP synthase, a key enzyme in ATP production. Mitochondrial ATP synthase is composed of two major parts; FO intermembrane base and F1 domain, containing α and β subunits. Crystal structures of both α and β subunits that bind to the substrate, ADP, are known in tight binding (αdpβdp) and loose binding (αtpβtp) states. Molecular docking demonstrated that 8-Cl-ADP/8-Cl-ATP occupied similar binding modes as ADP/ATP in the tight and loose binding sites of ATP synthase, respectively, suggesting that the chlorinated nucleotide metabolites may be functional substrates and inhibitors of the enzyme. The computational predictions were consistent with our whole cell biochemical results. Oligomycin, an established pharmacological inhibitor of ATP synthase, decreased both ATP and 8-Cl-ATP formation from exogenous substrates, however, did not affect pyrimidine nucleoside analogue triphosphate accumulation. Synthesis of ATP from ADP was inhibited in cells loaded with 8-Cl-ATP. These biochemical studies are in consent with the computational modeling; in the αtpβtp state 8-Cl-ATP occupies similar binding as ANP, a non-hydrolyzable ATP mimic that is a known inhibitor. Similarly, in the substrate binding site (αdpβdp) 8-Cl-ATP occupies a similar position as ATP mimic ADP-BeF3 −. Collectively, our current work suggests that 8-Cl-ADP may serve as a substrate and the 8-Cl-ATP may be an inhibitor of ATP synthase.

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Section: Introductionmentioning

confidence: 99%

Inhibition of ATP synthase by chlorinated adenosine analogue

Chen

Nowak

Ayres

et al. 2009

Biochemical Pharmacology

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“…Initial testing of triciribine and the water-soluble prodrug, triciribine-5‘-monophosphate (TCN-P), against murine leukemic L1210 cells revealed their potential as antineoplastic agents. This discovery led to extensive in vitro − and in vivo − studies of TCN and TCN-P as novel antineoplastic agents. Phase I clinical trials were completed with TCN-P, − and it was advanced to phase II studies as a potential antineoplastic agent. ,− …”

Section: Introductionmentioning

confidence: 99%

Deoxy Sugar Analogues of Triciribine: Correlation of Antiviral and Antiproliferative Activity with Intracellular Phosphorylation

et al. 2000

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Triciribine (TCN) and triciribine monophosphate (TCN-P) have antiviral and antineoplastic activity at low micromolar or submicromolar concentrations. In an effort to improve and better understand this activity, we have conducted a structure-activity relationship study to explore requirements for the number of hydroxyl groups on the ribosyl moiety for biological activity. 2'-Deoxytriciribine (2'-dTCN), 3'-deoxytriciribine (3'-dTCN), 2', 3'-epoxytriciribine (2',3'-epoxyTCN), 2',3'-dideoxy-2', 3'-didehydrotriciribine (2',3'-d4TCN), and 2',3'-dideoxytriciribine (2',3'-ddTCN) were synthesized and evaluated for activity against human immunodeficiency virus (HIV-1), herpes simplex virus type 1 (HSV-1), and human cytomegalovirus (HCMV). Antiproliferative activity of the compounds also was tested in murine L1210 cells and three human tumor cell lines. All compounds were either less active than TCN and TCN-P or inactive at the highest concentration tested (100 microM) in both antiviral and antiproliferative assays. Reverse-phase HPLC of extracts from uninfected cells treated with the deoxytriciribine analogues only detected the conversion of 3'-dTCN and 2',3'-ddTCN to their respective monophosphates. Therefore, either the deoxytriciribine analogues were not transported across the cell membrane or, more likely, they were not substrates for a nucleoside kinase or phosphotransferase. We have concluded that the hydroxyl groups on the ribosyl ring system of TCN and TCN-P must be intact in order to obtain significant antiviral and antineoplastic activity.

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“…As an antiviral, we have found that TCN is active against laboratory and clinical isolates of HIV type 1 (HIV-1) and HIV-2, including strains that are resistant to the reverse transcriptase (RT) inhibitors zidovudine (AZT) and 4,5,6,7-tetrahydro-5-methylimidazo [4,5,1-jk] [1,4]benzodiazepin-2(1H)-one (TIBO) (37). Those studies were performed with a variety of cell lines, including macrophage and human peripheral blood lymphocytes.…”

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confidence: 99%

Inhibition of Human Immunodeficiency Virus Type 1 by Triciribine Involves the Accessory Protein Nef

Ptak

Gentry

Hartman

et al. 2010

Antimicrob Agents Chemother

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Triciribine (TCN) is a tricyclic nucleoside that inhibits human immunodeficiency virus type 1 (HIV-1The virally encoded accessory proteins (Vpr, Vpu, Vif, Nef) are not required for replication in certain cell lines in vitro, but they are important factors causing the clinical manifestations of the pathogenesis of human immunodeficiency virus (HIV) (59). Viral protein R (Vpr) plays an important role in regulating nuclear import for the preintegration complex (PIC), is required for integration/replication in nondividing cells, induces cell cycle arrest in proliferating cells, stimulates viral transcription, and regulates apoptosis in infected cells (9). Viral protein U (Vpu) is an integral membrane phosphoprotein responsible for the degradation of CD4 in the endoplasmic reticulum and enhances virion release from the cell surface by antagonizing the cellular protein tetherin (41, 57). The viral infectivity factor (Vif) is required for replication in nonpermissive cell lines that express APOBE3G but is dispensable for replication in permissive cell lines that do not express APOBEC3G (26, 58). The "negative" factor (Nef) actually enhances viral replication and is necessary for pathogenesis to AIDS (32). Nef is the first viral protein to accumulate to detectable levels in cells following infection and is the most versatile of the accessory proteins (53). It interacts with several cellular pathways that influence HIV replication and immune evasion, resulting in the downregulation of CD4 and major histocompatibility complex class I molecules (25, 38, 51), promotion of the synthesis of FasL (a proapoptotic ligand that initiates apoptosis in nearby cells) (67), and the inhibition of both p53 (a regulator of apoptosis) and ASK-1 (the kinase involved in the initiation of apoptosis) (16,20,24). Nef also binds to several signaling proteins, including the Src family of tyrosine kinases (Erk-1, Raf1, and PKC theta), resulting in the activation of the cellular pathways responsible for proliferation and survival (22, 50). As important factors for the manifestation of HIV pathogenesis, these proteins are potential targets for antiretroviral therapy.Triciribine (TCN; Fig. 1) is a tricyclic nucleoside originally synthesized by Schram and Townsend as a potential anticancer drug (56). It is unique compared to naturally occurring purine nucleosides, in that it contains a tricyclic base instead of a bicyclic base. It has been studied broadly both as an antineoplastic agent and as an antiviral active against HIV (37, 65). Recent reports have provided new and unique insight into the antineoplastic activity of TCN. The studies described in those reports demonstrated that inhibition of the kinase activity and the level of phosphorylation of protein kinase B (Akt) are factors that result in the suppression of cell growth and the induction of apoptosis in human cancer cells that harbor constitutively overexpressed levels of Akt (68). Both the antineoplastic and antiviral activities of TCN require that the compound be phosphorylated to its cor...

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Phosphorylation of “tricyclic nucleoside” by adenosine kinases from L1210 cells and HEp-2 cells

Cited by 9 publications

References 8 publications

Inhibition of ATP synthase by chlorinated adenosine analogue

Inhibition of ATP synthase by chlorinated adenosine analogue

Deoxy Sugar Analogues of Triciribine: Correlation of Antiviral and Antiproliferative Activity with Intracellular Phosphorylation

Inhibition of Human Immunodeficiency Virus Type 1 by Triciribine Involves the Accessory Protein Nef

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