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Chemical Compound Review

manoalide     (5R)-5-hydroxy-4-[(2R,6R)-6- hydroxy-5-[(E)...

Synonyms: CHEMBL463914, CHEBI:66666, CHEBI:562520, AC1O5NJS, DNC004112, ...
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Disease relevance of manoalide

  • We, thus, studied the effect of manoalide (MLD), a PLA(2) inhibitor, on the toxin catalytic activity and its central and peripheral toxicity [1].
  • Modulation of superoxide anion generation by manoalide, arachidonic acid and staurosporine in liver infiltrated neutrophils in a rat model of endotoxemia [2].
  • The intracellular Ca2+ release and apoptosis induced by glibenclamide were significantly suppressed by treatment with phospholipase C (PLC) inhibitors (U-73122 and manoalide) or by pretreatment with pertussis toxin (PTx) [3].
  • In conclusion, concomitant administration of BSO and manoalide induces renal tubular damage and acute renal failure in rats, similar in characteristics to gentamicin-induced nephrotoxicity, whereas administration of BSO or manoalide alone did not [4].
  • To data, manoalide has been clinically evaluated in man and a new Bristol-Myers Squibb retenoid derivative may enter clinical trials for psoriasis (BMS-181162 (XVI)); however, there are no PLA2 inhibitors on the market or significantly advanced in clinical development (Table III) [5].

High impact information on manoalide

  • To evaluate the effects of the phospholipase A2 (PLA2) inhibitor manoalide on cartilage degradation, stromelysin expression, and inflammatory cell accumulation in rabbits treated intraarticularly with recombinant human interleukin-1 alpha (rHuIL-1 alpha) [6].
  • Pretreatment with manoalide (0.3 mg/joint) significantly inhibited PLA2 activity in the synovial fluid, prevented the loss of proteoglycan from the condylar cartilage, and reduced proteoglycan levels in lavage fluids [6].
  • The effects of the phospholipase A2 inhibitor, manoalide, on cartilage degradation, stromelysin expression, and synovial fluid cell count induced by intraarticular injection of human recombinant interleukin-1 alpha in the rabbit [6].
  • Functional assays also demonstrate that MLD and SLD block MAC-1-dependent adhesion of activated neutrophils to keyhole limpet hemocyanin at concentrations that block the surface expression of MAC-1 [7].
  • Addition of phospholipase A2 (PLA2) inhibitors (quinacrine, 4-bromophenacyl bromide, manoalide) to the perfusion medium inhibited K(+)-stimulated [3H]ACh and [3H]AA release in a dose-dependent manner [8].

Biological context of manoalide

  • A synthetic manoalide analogue 3(cis,cis,-7,10)hexadecadienyl-4-hydroxy-2-butenolide inhibited the enzyme with half-inhibition (IC50) at about 160 microM [9].
  • The PL inhibitors bromophenacyl bromide and manoalide abolished the release of 3H and inhibited phagocytosis of EIgG in parallel [10].
  • Manoalide inhibited hydrolysis of all three phosphoinositides by purified PI-PLC I [11].
  • The substrate kinetics of PI-PLC I suggest that manoalide does not inhibit purified PI-PLC I by simple competitive or noncompetitive inhibition [11].
  • These structure-activity relationship studies suggest that the closed ring form of manoalide is the predominant molecular species that accounts for the selective and potent inhibition of PLA2 by manoalide [12].

Anatomical context of manoalide


Associations of manoalide with other chemical compounds


Gene context of manoalide

  • Scalaradial and to some extent manoalide were capable of blocking the IL-1 beta-induced expression of PHGS-2 [18].
  • This conclusion is supported by the following findings: (1) ET-1-evoked AA release was inhibited by the PLA2 inhibitors dexamethasone, mepacrine and manoalide in a concentration-dependent manner [19].
  • Inhibition of other PLA2 isoforms, secretory PLA2 and calcium-independent PLA2, by manoalide and haloenol-lactone suicide substrate, respectively, does not affect this effect of AGEs relative to inhibitor-treated controls [20].
  • In A431 cells the increase in epidermal growth factor receptor-mediated Ca2+ entry and release from intracellular Ca2+ stores were blocked by manoalide in a time-dependent manner with an IC50 of 0.4 microM [15].
  • The phospholipase A2 (PLA2) inhibitors quinacrine, manoalide and scalaradial inhibit the carbachol-stimulated secretion of the amyloid precursor protein (APP) from cells transfected with the human m1 muscarinic receptor [21].

Analytical, diagnostic and therapeutic context of manoalide


  1. Inhibition of crotoxin phospholipase A(2) activity by manoalide associated with inactivation of crotoxin toxicity and dissociation of the heterodimeric neurotoxic complex. Dorandeu, F., Hesters, R., Girard, F., Four, E., Foquin, A., Bon, C., Lallement, G., Faure, G. Biochem. Pharmacol. (2002) [Pubmed]
  2. Modulation of superoxide anion generation by manoalide, arachidonic acid and staurosporine in liver infiltrated neutrophils in a rat model of endotoxemia. Mayer, A.M., Spitzer, J.A. J. Pharmacol. Exp. Ther. (1993) [Pubmed]
  3. Role of pertussis toxin-sensitive G-proteins in intracellular Ca2+ release and apoptosis induced by inhibiting cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channels in HepG2 human hepatoblastoma cells. Kim, J.A., Kang, Y.S., Lee, S.H., Lee, E.H., Lee, Y.S. J. Cell. Biochem. (2001) [Pubmed]
  4. Simultaneous inhibition of renal phospholipase A(2) and glutathione synthesis by manoalide and DL-buthionine sulfoximine induces acute tubular dysfunction in rats. Soejima, A., Ishizuka, S., Miyake, N., Fukuoka, K., Suzuki, M., Kamiya, Y., Nagasawa, T. Exp. Nephrol. (2000) [Pubmed]
  5. Regulation of phospholipase A2 enzymes: selective inhibitors and their pharmacological potential. Glaser, K.B. Adv. Pharmacol. (1995) [Pubmed]
  6. The effects of the phospholipase A2 inhibitor, manoalide, on cartilage degradation, stromelysin expression, and synovial fluid cell count induced by intraarticular injection of human recombinant interleukin-1 alpha in the rabbit. Schrier, D.J., Flory, C.M., Finkel, M., Kuchera, S.L., Lesch, M.E., Jacobson, P.B. Arthritis Rheum. (1996) [Pubmed]
  7. Regulation of CD11b/CD18 expression in human neutrophils by phospholipase A2. Jacobson, P.B., Schrier, D.J. J. Immunol. (1993) [Pubmed]
  8. Botulinum toxin inhibits arachidonic acid release associated with acetylcholine release from PC12 cells. Ray, P., Berman, J.D., Middleton, W., Brendle, J. J. Biol. Chem. (1993) [Pubmed]
  9. Purification and characterization of a lysophospholipase from a macrophage-like cell line P388D1. Zhang, Y.Y., Dennis, E.A. J. Biol. Chem. (1988) [Pubmed]
  10. Arachidonic acid is essential for IgG Fc receptor-mediated phagocytosis by human monocytes. Lennartz, M.R., Brown, E.J. J. Immunol. (1991) [Pubmed]
  11. Inhibition of phosphoinositide-specific phospholipase C by manoalide. Bennett, C.F., Mong, S., Wu, H.L., Clark, M.A., Wheeler, L., Crooke, S.T. Mol. Pharmacol. (1987) [Pubmed]
  12. Manoalide: structure-activity studies and definition of the pharmacophore for phospholipase A2 inactivation. Glaser, K.B., de Carvalho, M.S., Jacobs, R.S., Kernan, M.R., Faulkner, D.J. Mol. Pharmacol. (1989) [Pubmed]
  13. Phospholipase activation during monocyte adherence and spreading. Lefkowith, J.B., Lennartz, M.R., Rogers, M., Morrison, A.R., Brown, E.J. J. Immunol. (1992) [Pubmed]
  14. The inhibition of release of endothelium-derived relaxant factor by manoalide, a potent inhibitor of phospholipase A2. Long, C.J., Sarau, H.M., Berkowitz, B.A. Br. J. Pharmacol. (1987) [Pubmed]
  15. Manoalide, a natural sesterterpenoid that inhibits calcium channels. Wheeler, L.A., Sachs, G., De Vries, G., Goodrum, D., Woldemussie, E., Muallem, S. J. Biol. Chem. (1987) [Pubmed]
  16. Manoalide. Soriente, A., De Rosa, M.M., Scettri, A., Sodano, G., Terencio, M.C., Payá, M., Alcaraz, M.J. Current medicinal chemistry. (1999) [Pubmed]
  17. Regulation of eicosanoid biosynthesis in vitro and in vivo by the marine natural product manoalide: a potent inactivator of venom phospholipases. Mayer, A.M., Glaser, K.B., Jacobs, R.S. J. Pharmacol. Exp. Ther. (1988) [Pubmed]
  18. Regulation of prostaglandin H synthase 2 expression in human monocytes by the marine natural products manoalide and scalaradial. Novel effects independent of inhibition of lipid mediator production. Glaser, K.B., Lock, Y.W. Biochem. Pharmacol. (1995) [Pubmed]
  19. Endothelin-1 stimulates the release of arachidonic acid and prostaglandins in cultured human ciliary muscle cells: activation of phospholipase A2. Yousufzai, S.Y., Abdel-latif, A.A. Exp. Eye Res. (1997) [Pubmed]
  20. Advanced glycation end products stimulate an enhanced neutrophil respiratory burst mediated through the activation of cytosolic phospholipase A2 and generation of arachidonic Acid. Wong, R.K., Pettit, A.I., Quinn, P.A., Jennings, S.C., Davies, J.E., Ng, L.L. Circulation (2003) [Pubmed]
  21. Phospholipase A2 activation influences the processing and secretion of the amyloid precursor protein. Emmerling, M.R., Moore, C.J., Doyle, P.D., Carroll, R.T., Davis, R.E. Biochem. Biophys. Res. Commun. (1993) [Pubmed]
  22. The effects of two phospholipase A2 inhibitors on the neuromuscular blocking activities of homologous phospholipases A2 from the venom of Pseudechis australis, the Australian king brown snake. Fatehi, M., Rowan, E.G., Harvey, A.L. Toxicon (1995) [Pubmed]
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