Lavendustin B
(Synonyms: 薰草菌素B) 目录号 : GC45494An inhibitor of Glut1
Cas No.:125697-91-8
Sample solution is provided at 25 µL, 10mM.
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Lavendustin B is a competitive inhibitor of glucose transporter 1 (Glut1; Ki = 15 μM).1 It is also an inhibitor of the interaction between HIV-1 integrase and LEDGF/p75 (IC50 = 94.07 μM).2 Lavendustin B is a weak inhibitor of tyrosine kinases (IC50 = 0.49 μg/ml) and has been used as a negative control for the protein tyrosine kinase inhibitor lavendustin A .3,4,5
References
1. Vera, J.C., Reyes, A.M., VelÁsquez, F.V., et al. Direct inhibition of the hexose transporter GLUT1 by tyrosine kinase inhibitors. Biochemistry 40(3), 777-790 (2001).
2. De Luca, L., Morreale, F., Christ, F., et al. New scaffolds of natural origin as Integrase-LEDGF/p75 interaction inhibitors: Virtual screening and activity assays. Eur. J. Med. Chem. 68, 405-411 (2013).
3. Onoda, T., Iinuma, H., Sasaki, Y., et al. Isolation of a novel tyrosine kinase inhibitor, lavendustin A, from Streptomyces griseolavendus. J. Nat. Prod. 52(6), 1252-1257 (1989).
4. Hu, D.E., and Fan, T.-P.D. Suppression of VEGF-induced angiogenesis by the protein tyrosine kinase inhibitor, lavendustin A. Br. J. Pharmacol. 114(2), 262-268 (1995).
5. Alioua, A., Mahajan, A., Nishimaru, K., et al. Coupling of c-Src to large conductance voltage- and Ca2+-activated K+ channels as a new mechanism of agonist-induced vasoconstriction. Proc. Natl. Acad. Sci. USA 99(22), 14560-14565 (2002).
Cas No. | 125697-91-8 | SDF | |
别名 | 薰草菌素B | ||
Canonical SMILES | OC1=CC=CC=C1CN(C2=CC(C(O)=O)=C(O)C=C2)CC3=CC=CC=C3O | ||
分子式 | C21H19NO5 | 分子量 | 365.4 |
溶解度 | DMF: 10 mg/mL,DMSO: 10 mg/mL,Ethanol: 10 mg/mL | 储存条件 | Store at -20°C |
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10 mM | 0.2737 mL | 1.3684 mL | 2.7367 mL |
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Computational and synthetic approaches for developing Lavendustin B derivatives as allosteric inhibitors of HIV-1 integrase
Eur J Med Chem 2016 Nov 10;123:673-683.PMID:27517812DOI:10.1016/j.ejmech.2016.07.077.
Through structure-based virtual screening and subsequent activity assays of selected natural products, Lavendustin B was previously identified as an inhibitor of HIV-1 integrase (IN) interaction with its cognate cellular cofactor, lens epithelium-derived growth factor (LEDGF/p75). In order to improve the inhibitory potency we have employed in silico-based approaches. Particularly, a series of new analogues was designed and docked into the LEDGF/p75 binding pocket of HIV-1 IN. To identify promising leads we used the Molecular Mechanics energies combined with the Generalized Born and Surface Area continuum solvation (MM-GBSA) method, molecular dynamics simulations and analysis of hydrogen bond occupancies. On the basis of these studies, six analogues of Lavendustine B, containing the benzylamino-hydroxybenzoic scaffold, were selected for synthesis and structure activity-relationship (SAR) studies. Our results demonstrated a good correlation between computational and experimental data, and all six analogues displayed an improved potency for inhibiting IN binding to LEDGF/p75 in vitro to respect to the parent compound Lavendustin B. Additionally, these analogs show to inhibit weakly LEDGF/p75-independent IN catalytic activity suggesting a multimodal allosteric mechanism of action. Nevertheless, for the synthesized compounds similar profiles for HIV-1 inhibition and cytoxicity were highlighted. Taken together, our studies elucidated the mode of action of Lavendustin B analogs and provided a path for their further development as a new promising class of HIV-1 integrase inhibitors.
Suppression of VEGF-induced angiogenesis by the protein tyrosine kinase inhibitor, lavendustin A
Br J Pharmacol 1995 Jan;114(2):262-8.PMID:7533611DOI:10.1111/j.1476-5381.1995.tb13221.x.
1. Vascular endothelial growth factor (VEGF) is a heparin-binding angiogenic factor which specifically acts on endothelial cells via distinct membrane-spanning tyrosine kinase receptors. Here we used the rat sponge implant model to test the hypothesis that the angiogenic activity of VEGF can be suppressed by protein tyrosine kinase (PTK) inhibitors. 2. Neovascular responses in subcutaneous sponge implants were determined by measurements of relative sponge blood flow by use of a 133Xe clearance technique, and confirmed by histological studies and morphometric analysis. 3. Daily local administration of 250 ng VEGF165 accelerated the rate of 133Xe clearance from the sponges and induced an intense neovascularisation. This VEGF165-induced angiogenesis was inhibited by daily co-administration of the selective PTK inhibitor, lavendustin A (10 micrograms), but not its negative control, Lavendustin B (10 micrograms). Blood flow measurements and morphometric analysis of 8-day-old sponges showed that lavendustin A reduced the 133Xe clearance of VEGF165-treated sponges from 32.9 +/- 1.5% to 20.9 +/- 1.6% and the total fibrovascular growth area from 62.4 +/- 6.1% to 21.6 +/- 6.8% (n = 12, P < 0.05). 4. Co-injection of suramin (3 mg), an inhibitor of heparin-binding growth factors, also suppressed the VEGF165-elicited neovascular response. In contrast, neither lavendustin A nor suramin produced any effect on the basal sponge-induced angiogenesis. 5. When given alone, low doses of VEGF165 (25 ng) or basic fibroblast growth factor (bFGF; 10 ng) did not modify the basal sponge-induced neovascularisation. However, co-administration of these two peptides to a single sponge together caused a significant increase in the rate of 133Xe clearance and angiogenesis similar to that seen with the high dose of VEGF165 (250 ng) acting alone. This VEGF/bFGF neovascular response was also blocked by daily co-administration of lavendustin A (10 jig),suramin (3 mg) or a monoclonal anti-bFGF antibody (DG2, I jig), but not Lavendustin B (10 g).6 These results suggest that selective inhibition of PTK could have therapeutic potential in angiogenic diseases where VEGF plays a dominant role. Furthermore, blockade of the angiogenic activity of VEGF and VEGF,/bFGF by suramin reveals an alternative strategy in angio suppression.
Modulation of tyrosine kinase activity has multiple actions on insulin release from the pancreatic beta-cell: studies with lavendustin A
Jpn J Pharmacol 1997 Jun;74(2):203-8.PMID:9243329DOI:10.1254/jjp.74.203.
We investigated the role of tyrosine kinases in the regulation of insulin release from a hamster beta-cell line, HIT T15, using selective tyrosine kinase inhibitors. Genistein increased the insulin release induced by glucose, but herbimycin A, tyrphostins and the erbstatin analogue failed to change the release. Lavendustin A at 0.1 nM-1 microM caused a concave-shaped inhibition of the insulin release stimulated by 7 mM glucose. The inhibitory effect of lavendustin A was overcome by higher concentrations of glucose. Lavendustin B, the negative control analogue, had no effect on the release. Lavendustin A at a nanomolar range progressively inhibited insulin release by high K+ (50 mM)-depolarization, whereas the inhibitor did not change the insulin release by Ca2+ ionophore (A23187). On the contrary, lavendustin A at 10 nM significantly increased insulin release when glucose-induced insulin release was enhanced by either 5 microM forskolin or 162 nM 12-O-tetradecanoylphorbol 13-acetate. Lavendustin A failed to influence the Ca(2+)-induced insulin release from HIT cells permeabilized with streptolysin-O. These findings suggest that tyrosine kinases may play versatile roles in the control of insulin release from the pancreatic beta-cell.
Chloride efflux during the progesterone-initiated human sperm acrosome reaction is inhibited by lavendustin A, a tyrosine kinase inhibitor
J Androl 1996 Jul-Aug;17(4):327-30.PMID:8889693doi
Previous studies showed that progesterone (P) can initiate the mammalian sperm acrosome reaction (AR) in vitro and that a sperm GABAA-like receptor/Cl- channel is involved in an essential Cl- efflux mediated by P during the AR. Here, we show that lavendustin A, a potent, specific inhibitor of tyrosine kinase activity, strongly inhibits the P-initiated human AR and the essential P-mediated Cl- efflux. Lavendustin B, a weak tyrosine kinase inhibitor, had no significant effect. These results suggest that, as part of AR initiation, P mediates tyrosine phosphorylation of the sperm GABAA- like receptor/Cl- channel.
Tyrosine kinase inhibitors block sperm-induced egg activation in Xenopus laevis
Dev Biol 1999 Jan 1;205(1):171-80.PMID:9882505DOI:10.1006/dbio.1998.9042.
Fertilization of Xenopus laevis eggs triggers a wave of increased [Ca2+]i. The exact signal transduction pathway culminating in this Ca2+ wave remains unknown. To determine whether increases in tyrosine kinase activity are part of this pathway, we microinjected tyrosine kinase inhibitors into unfertilized eggs. Upon fertilization, signs of activation were monitored, such as fertilization envelope liftoff and the Ca2+ wave (for eggs microinjected with lavendustin A). Various concentrations of lavendustin A and tyrphostin B46 were microinjected, as well as inactive forms of these compounds (Lavendustin B and tyrphostin A1) to provide negative controls. Peptide A, a 20-amino-acid peptide derived from the SH2 region of pp60(v-src) tyrosine kinase, was also microinjected. Peptide A inhibits tyrosine kinase activity but not PKA or PKG activity. Dose-response curves for lavendustin A, tyrphostin B46, and peptide A show clear inhibition of vitelline envelope liftoff by these three compounds. Confocal imaging of eggs coinjected with lavendustin A and Oregon Green-dextran showed that the Ca2+ wave was inhibited under normal insemination conditions but that the block of the Ca2+ wave could be overcome with very high sperm densities. A phenomenon of small local Ca2+ increases termed "hot spots" seen in lavendustin A containing eggs is also described. Since this inhibition of egg activation by tyrosine kinase inhibitors can be overcome by Ca2+ microinjection, the inhibitors must act on a step in the signal transduction cascade that is upstream of the Ca2+ wave.