For research use only. Not for therapeutic Use.
Lavendustin B is a Tyrosine Kinase Inhibitor amd an inhibitor of HIV-1 integrase (IN) interaction with its cognate cellular cofactor, lens epithelium-derived growth factor (LEDGF/p75).
| CAS Number | 125697-91-8 |
| Synonyms | 5-[Bis[(2-hydroxyphenyl)methyl]amino]-2-hydroxy-benzoic Acid; |
| Molecular Formula | C21H19NO5 |
| Purity | ≥95% |
| Target | Membrane Transporter/Ion Channel |
| Storage | Desiccate at -20C |
| IUPAC Name | 5-[bis[(2-hydroxyphenyl)methyl]amino]-2-hydroxybenzoic acid |
| InChI | InChI=1S/C21H19NO5/c23-18-7-3-1-5-14(18)12-22(13-15-6-2-4-8-19(15)24)16-9-10-20(25)17(11-16)21(26)27/h1-11,23-25H,12-13H2,(H,26,27) |
| InChIKey | RTYOLBQXFXYMKY-UHFFFAOYSA-N |
| SMILES | C1=CC=C(C(=C1)CN(CC2=CC=CC=C2O)C3=CC(=C(C=C3)O)C(=O)O)O |
| Reference | 1:Eur J Med Chem. 2016 Nov 10;123:673-83. doi: 10.1016/j.ejmech.2016.07.077. Epub 2016 Aug 3. Computational and synthetic approaches for developing Lavendustin B derivatives as allosteric inhibitors of HIV-1 integrase.Agharbaoui FE,Hoyte AC,Ferro S,Gitto R,Buemi MR,Fuchs JR,Kvaratskhelia M,De Luca L, PMID: 27517812 PMCID: PMC5283093 DOI: 10.1016/j.ejmech.2016.07.077 </br><span>Abstract:</span> 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. Copyright © 2016 Elsevier Masson SAS. All rights reserved. |
