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The PI3K signaling pathway is activated in a broad spectrum of human cancers, either directly by genetic mutation or indirectly via activation of receptor tyrosine kinases or inactivation of the PTEN tumor suppressor. The key nodes of this pathway have emerged as important therapeutic targets for the treatment of cancer. In this study, we show that (-)-epigallocatechin-3-gallate (EGCG), a major component of green tea, is an ATP-competitive inhibitor of both phosphoinositide-3-kinase (PI3K) and mammalian target of rapamycin (mTOR) with K(i) values of 380 and 320nM respectively. The potency of EGCG against PI3K and mTOR is within physiologically relevant concentrations. In addition, EGCG inhibits cell proliferation and AKT phosphorylation at Ser473 in MDA-MB-231 and A549 cells. Molecular docking studies show that EGCG binds well to the PI3K kinase domain active site, agreeing with the finding that EGCG competes for ATP binding. Our results suggest another important molecular mechanism for the anticancer activities of EGCG., (Copyright © 2011 Elsevier Inc. All rights reserved.)

A systematic study of tethering various groups on 6-phenyl ring of 4-hydroxy-6-phenyl-3-[(2-isopropylphenyl)thio]pyran-2-one was performed to increase the binding affinity with HIV protease. This tethering approach was aimed to fill S3 pocket of the enzyme. Thus, tethering hydrophilic groups resulted in more potent inhibitors. Similarly, various aromatic hydrophobic rings as well as heterocyclic rings were explored as tethering substituents to alter the physical properties as well as to enhance the binding affinity with HIV protease. Inhibitor 24, 4-hydroxy-3-[(2-isopropylphenyl)thio]-6-[4-(3-pyridinylmethoxy+ ++ ) phenyl]-2H-pyran-2-one, was evaluated as a prototypic lead structure to study various physical as well as pharmacological properties of this class of HIV protease inhibitors.

The oral anticoagulant warfarin (4-hydroxy-3-(3-oxo-1-phenylbutyl)- benzopyran-2-one) is a structurally novel low micromolar competitive inhibitor of HIV-1 protease in vitro. It was recently reported that warfarin inhibits HIV-1 infection in U-1 monocytes and viral production in ACH-2 lymphocytes (Bourinbaiar, A.S. et al., (1993) AIDS 7, 129-130). Our results demonstrate that warfarin and a series of structurally related analogs inhibit the viral protease, the most potent analog having an IC50 = 1.9 microM. Kinetic analysis reveals inhibition by warfarin occurs in a competitive manner, with Ki = 3.3 microM. While it is unclear whether the cellular inhibition previously reported is due to inhibition of HIV-1 protease, the warfarin analogs are a novel class of nonpeptide HIV-1 protease inhibitors.

The nonpeptide compounds C1 (4-hydroxy-3-(3-phenoxypropyl)-1-benzopyran-2-one) and P1 (4-hydroxy-6-phenyl-3-(phenylthio)pyran-2-one) are structurally novel low micromolar inhibitors of the protease of human immunodeficiency virus type 1 (HIV-1). Kinetic analysis revealed that both compounds are competitive inhibitors, with Ki values of 1.0 microM (C1) and 1.1 microM (P1), that act in a reversible fast-binding manner. Structural analogs of both compounds indicate that the pyran-2-one group, the 4-hydroxyl group and substitution at the 3 position are all necessary for inhibitory activity. These two pyranones provide excellent initial compounds in the development of therapeutically effective HIV-1 protease inhibitors, since they are small achiral nonpeptide molecules more easily synthesized and with potentially better pharmacological characteristics than peptide inhibitors of the protease.