Pyrido[2,3-d]pyrimidines. III. Synthesis of some 8-.beta.-D-ribofuranosylprido[2,3-d]pyrimidines structurally related to the antibiotic sangivamycin

Rizkalla, Boshra H.; Broom, Arthur D.

doi:10.1021/jo00798a002

Cited by 43 publications

(14 citation statements)

References 2 publications

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“…Fig. 1A shows the chemical structure of API-1 (Cancer Chemotherapy National Service Center (NSC) 177223; pyrido [2,3-d]pyrimidines), which is structurally related to the antibiotic sangivamycin (30). Although the sangivamycin has been shown to have anti-tumor activity (31)(32)(33), NSC 177223/ API-1 has not been tested in cancer cells including NCI 60 cell lines (nih.gov).…”

Section: Identification Of a Small Molecule Akt/pkb Inhibitor-1 (Api-1)-mentioning

confidence: 99%

A Small Molecule Inhibits Akt through Direct Binding to Akt and Preventing Akt Membrane Translocation

Kim

Sun

et al. 2010

Journal of Biological Chemistry

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The Akt pathway is frequently hyperactivated in human cancer and functions as a cardinal nodal point for transducing extracellular and intracellular oncogenic signals and, thus, presents an exciting target for molecular therapeutics. Here we report the identification of a small molecule Akt/protein kinase B inhibitor, API-1. Although API-1 is neither an ATP competitor nor substrate mimetic, it binds to pleckstrin homology domain of Akt and blocks Akt membrane translocation. Furthermore, API-1 treatment of cancer cells results in inhibition of the kinase activities and phosphorylation levels of the three members of the Akt family. In contrast, API-1 had no effects on the activities of the upstream Akt activators, phosphatidylinositol 3-kinase, phosphatidylinositol-dependent kinase-1, and mTORC2. Notably, the kinase activity and phosphorylation (e.g. Thr(P) 308 and Ser(P) 473 ) levels of constitutively active Akt, including a naturally occurring mutant AKT1-E17K, were inhibited by API-1. API-1 is selective for Akt and does not inhibit the activation of protein kinase C, serum and glucocorticoid-inducible kinase, protein kinase A, STAT3, ERK1/2, or JNK. The inhibition of Akt by API-1 resulted in induction of cell growth arrest and apoptosis selectively in human cancer cells that harbor constitutively activated Akt. Furthermore, API-1 inhibited tumor growth in nude mice of human cancer cells in which Akt is elevated but not of those cancer cells in which it is not. These data indicate that API-1 directly inhibits Akt through binding to the Akt pleckstrin homology domain and blocking Akt membrane translocation and that API-1 has anti-tumor activity in vitro and in vivo and could be a potential anti-cancer agent for patients whose tumors express hyperactivated Akt.

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Section: Identification Of a Small Molecule Akt/pkb Inhibitor-1 (Api-1)-mentioning

confidence: 99%

A Small Molecule Inhibits Akt through Direct Binding to Akt and Preventing Akt Membrane Translocation

Kim

Sun

et al. 2010

Journal of Biological Chemistry

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“…ethanol, methanol and pyridine. However, most of these rely on multi-step reactions and complex synthetic pathways, long reaction times and yields are low [2][3][4][5][6][7][8][9][10][11][12][13].…”

Section: Introductionmentioning

confidence: 99%

Ionic Liquid Promoted Efficient and Rapid One-pot Synthesis of Pyran Annulated Heterocyclic Systems

et al. 2005

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“…Ht-terocyclic Chem., 23, 335 (1986).Condensed bicyclic systems, mostly pyrido[ 1,2-a]pyrimidines [ l ] or pyrido[2,3-d]pyrimidines [2] have been used as antibacterial agents. These systems are prepared from derivatives of 4-aminopyrimidine [2,3,4] and diethyl alkylmalonates Il,2,5]. The same reagents, have been recently used by Matsumoto et al [6] for the preparation of some pyrimido[1,6-~]pyrimidines.…”

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confidence: 99%

Synthesis of some new pyrimido[1,6‐a]pyrimidines

Pegiadou‐Koemtjopoulou

Tsatsaronis

1986

Journal of Heterocyclic Chem

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Pyrido[2,3-d]pyrimidines. III. Synthesis of some 8-.beta.-D-ribofuranosylprido[2,3-d]pyrimidines structurally related to the antibiotic sangivamycin

Cited by 43 publications

References 2 publications

A Small Molecule Inhibits Akt through Direct Binding to Akt and Preventing Akt Membrane Translocation

A Small Molecule Inhibits Akt through Direct Binding to Akt and Preventing Akt Membrane Translocation

Ionic Liquid Promoted Efficient and Rapid One-pot Synthesis of Pyran Annulated Heterocyclic Systems

Synthesis of some new pyrimido[1,6‐a]pyrimidines

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