D-3-Deoxy-3-substitutedmyo-inositol analogues as inhibitors of cell growth

Powis, Garth; Aksoy, Ibrahim A.; Melder, Deborah C.; Aksoy, Saime; Eichinger, H; Fauq, Abdul H.; Kozikowski, Alan P.

doi:10.1007/bf00687317

Cited by 56 publications

(24 citation statements)

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“…One class of drugs against Candida includes fluoro-nucleoside analogues such as 5-fluorocytosine (Georgopapadakou & Walsh, 1996). Moreover, fluorinated myo-inositol analogues such as 3-fluoro-3-deoxy-myoinositol have been reported to possess anti-proliferative activity in cancer cells through inhibition of phosphatidylinositol signalling (Powis et al, 1991;Offer et al, 1993;Johnson et al, 1993). Hence, our finding that 3-fluoro-3-deoxy-myo-inositol is recognized by the C. albicans myoinositol transporter with similar affinity as myo-inositol is particularly encouraging to further probe the Candida myo-inositol transporter as an attractive target for rational drug design and delivery of cytotoxic substrate analogues.…”

Section: Discussionmentioning

confidence: 99%

High-affinity myo-inositol transport in Candida albicans: substrate specificity and pharmacology

Jian

Seyfang

2003

Microbiology

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Inositol is considered a growth factor in yeast cells and it plays an important role in Candida as an essential precursor for phospholipomannan, a glycophosphatidylinositol (GPI)-anchored glycolipid on the cell surface of Candida which is involved in the pathogenicity of this opportunistic fungus and which binds to and stimulates human macrophages. In addition, inositol plays an essential role in the phosphatidylinositol signal transduction pathway, which controls many cell cycle events. Here, high-affinity myo-inositol uptake in Candida albicans has been characterized, with an apparent K m value of 240±15 μM, which appears to be active and energy-dependent as revealed by inhibition with azide and protonophores (FCCP, dinitrophenol). Candida myo-inositol transport was sodium-independent but proton-coupled with an apparent K m value of 11·0±1·1 nM for H+, equal pH 7·96±0·05, suggesting that the C. albicans myo-inositol–H+ transporter is fully activated at physiological pH. C. albicans inositol transport was not affected by cytochalasin B, phloretin or phlorizin, an inhibitor of mammalian sodium-dependent inositol transport. Furthermore, myo-inositol transport showed high substrate specificity for inositol and was not significantly affected by hexose or pentose sugars as competitors, despite their structural similarity. Transport kinetics in the presence of eight different inositol isomers as competitors revealed that proton bonds between the C-2, C-3 and C-4 hydroxyl groups of myo-inositol and the transporter protein play a critical role for substrate recognition and binding. It is concluded that C. albicans myo-inositol–H+ transport differs kinetically and pharmacologically from the human sodium-dependent myo-inositol transport system and constitutes an attractive target for delivery of cytotoxic inositol analogues in this pathogenic fungus.

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Section: Discussionmentioning

confidence: 99%

High-affinity myo-inositol transport in Candida albicans: substrate specificity and pharmacology

Jian

Seyfang

2003

Microbiology

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“…This mode of inhibition would prevent Akt translocation to the plasma membrane and activation [73]. The feasibility of this approach was suggested by the demonstration that D-3-deoxy-myo-inositols inhibited the growth of transformed cells [74]. It was subsequently found that the inositol derivative DPI (6) had an IC 50 of 35 µM against H-29 colon cancer growth [75].…”

Section: B Phosphatidylinositol Analog Inhibitorsmentioning

confidence: 97%

The Akt/PKB Family of Protein Kinases: A Review of Small Molecule Inhibitors and Progress Towards Target Validation

Barnett¹,

Bilodeau²,

Lindsley³

2005

CTMC

136

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This article describes recent advances in the development and biological evaluation of small molecule inhibitors for the serine/threonine kinase Akt (PKB). Akt plays a pivotal role in cell survival and proliferation through a number of downstream effectors. Recent studies indicate that unregulated activation of the PI3K/Akt pathway is a prominent feature of many human cancers and Akt is over-expressed or activated in all major cancers. Akt is considered an attractive target for chemotherapy and it has been postulated that inhibition of Akt alone or in combination with standard cancer chemotherapeutics will reduce the apoptotic threshold and preferentially kill cancer cells. The development of specific and potent inhibitors will allow this hypothesis to be tested in animals. The majority of small molecule inhibitors in this nascent field are classic ATP-competitive inhibitors which provide little specificity. Phosphatidylinositol (PI) analogs have been reported to inhibit Akt, but these inhibitors may also have specificity problems with respect to other PH domain containing proteins and may have poor bioavailability. None of the inhibitors in these classes have been reported to have Akt isozyme specificity. Recently, novel allosteric inhibitors have been reported which are pleckstrin homology domain dependent and exhibit Akt isozyme selectivity. Inhibitors in this class may have sufficient potency and specificity to test for tumor efficacy in animal models and recently reported preliminary experiments are reviewed.

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“…This mode of inhibition would prevent Akt translocation to the plasma membrane and activation. The feasibility of this approach was suggested by the demonstration that D-3-deoxy-myo-inositols inhibited the growth of transformed cells (Powis et al, 1991). It was subsequently found that the inositol derivative DPI had an IC 50 of 35 mM against H-29 colon cancer cell growth .…”

Section: Pi Analog Inhibitorsmentioning

confidence: 99%