- Dibenzofuran derivatives inspired from cercosporamide as dual inhibitors of pim and CLK1 kinases
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Pim kinases (proviral integration site for Moloney murine leukemia virus kinases) are overexpressed in various types of hematological malignancies and solid carcinomas, and promote cell proliferation and survival. Thus, Pim kinases are validated as targets for antitumor therapy. In this context, our combined efforts in natural product-inspired library generation and screening furnished very promising dibenzo[b, d]furan derivatives derived from cercosporamide. Among them, lead compound 44 was highlighted as a potent Pim-1/2 kinases inhibitor with an additional nanomolar IC50 value against CLK1 (cdc2-like kinases 1) and displayed a low micromolar anticancer potency towards the MV4-11 (AML) cell line, expressing high endogenous levels of Pim-1/2 kinases. The design, synthesis, structure-activity relationship, and docking studies are reported herein and supported by enzyme, cellular assays, and Galleria mellonella larvae testing for acute toxicity.
- Bach, Stéphane,Baratte, Blandine,Bazin, Marc-Antoine,Brachet-Botineau, Marie,Dao, Viet Hung,Denevault-Sabourin, Caroline,Gouilleux, Fabrice,Logé, Cédric,Marchand, Pascal,McCarthy, Florence O.,Ourliac-Garnier, Isabelle,Robert, Thomas,Thiéfaine, Jér?me,da Silva, Teresinha Gon?alves
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- COMPOUND
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The present invention provides compounds of the formula Formula I or a salt thereof: and the uses of such compounds for the treatment of a disease or disorder involving oxidative damage, for preventing UV damage to the skin of a mammal and for preventing or reversing the effects of ageing, or for treating or preventing dry skin.
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- TRICYCLIC COMPOUNDS AS mPGES-1 INHIBITORS
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The present invention relates to tricyclic compounds of formula (I) or pharmaceutically acceptable salt thereof as mPGES-1 inhibitors. These compounds are inhibitors of the microsomal prostaglandin E synthase-1 (mPGES-1) enzyme and are therefore useful in the treatment of pain and/or inflammation from a variety of diseases or conditions, such as asthama, osteoarthritis, rheumatoid arthritis, acute or chronic pain and neurodegenerative diseases. (I)
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- Potential therapeutic antioxidants that combine the radical scavenging ability of myricetin and the lipophilic chain of vitamin E to effectively inhibit microsomal lipid peroxidation
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The flavonol myricetin, reacts with oxygen-centred galvinoxyl radicals 28 times faster than d-α-tocopherol (vitamin E), the main lipid-soluble antioxidant in biological membranes. Moreover, each myricetin molecule reduces twice as many such radicals as vitamin E. However, myricetin fails to protect vitamin E-deficient microsomes from lipid peroxidation as assessed by the formation of thiobarbituric acid reactive substances (TBARS). Novel and potentially therapeutic antioxidants have been prepared that combine the radical-scavenging ability of a myricetin-like head group with a lipophilic chain similar to that of vitamin E. C6-C12 alkyl chains are attached to the A-ring of either a 3,3′,4 ′,5′-tetrahydroxyflavone or a 3,2 ′,4′,5′-tetrahydroxyflavone head group to give lipophilic flavonoids (ClogP=4 to 10) that markedly inhibit iron-ADP catalysed oxidation of microsomal preparations. Orientation of the head group as well as total lipophilicity are important determinants of antioxidant efficacy. MM2 models indicate that our best straight chain 7-alkylflavonoids embed to the same depth in the membrane as vitamin E. The flavonoid head groups are prepared by aldol condensation followed by Algar-Flynn-Oyamada (AFO) oxidation or by Baker-Venkataraman rearrangement. The alkyl tails are introduced by Suzuki or Negishi palladium-catalysed cross-coupling or by cross-metathesis catalysed by first generation Grubbs catalyst, which tolerate phenolic hydroxyl and ketone groups.
- Bennett, Christopher J.,Caldwell, Stuart T.,McPhail, Donald B.,Morrice, Philip C.,Duthie, Garry G.,Hartley, Richard C.
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p. 2079 - 2098
(2007/10/03)
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- FLAVONOID COMPOUNDS AS THERAPEUTIC ANTIOXIDANTS
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Novel flavonoid compounds having anti-oxidant activity are described. The compounds have been shown to exhibit anti-oxidative properties in biological systems and their utility in a sunscreen or skincare composition or to treat conditions involving oxidative damage, especially curative or prophylactic treatment of Alzheimer's disease or ischaemia-reperfusion injury, is described.
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