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From ligand to complexes: inhibition of human immunodeficiency virus type 1 integrase by beta-diketo acid metal complexes.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2006 Jul 13; Vol. 49 (14), pp. 4248-60. - Publication Year :
- 2006
-
Abstract
- beta-Diketo acid-containing compounds are a promising class of human immunodeficiency virus type 1 (HIV-1) integrase (IN) inhibitors. Starting from the hypothesis that these inhibitors are able to coordinate ions in solution before interacting on the active site, a series of potentiometric measurements have been performed to understand the coordination ability of the diketo acid pharmacophore toward the biologically relevant Mg(2+). Moreover, by using beta-diketo acid/ester as model ligands with a set of divalent metal ions (Mg, Mn, Ni, Co, Cu, and Zn), we obtained a series of complexes and tested them for anti-HIV-1 IN activity. Results demonstrate that the diketo acid functionality chelates divalent metal ions in solution, and complexes with metals in different stoichiometric ratios are isolated. We postulate that the diketo acids act as complexes in their active form. In particular, they predominantly form species such as Mg(2)L(2+) and Mg(2)L(2) (derived from diketo acids, H(2)L), and MgL(+) and MgL(2) (derived from diketo esters, HL) at physiological pH. Furthermore, the synthesized mono- and dimetallic complexes inhibited IN at a high nanomolar to low micromolar range, with metal dependency in the phenyl diketo acid series. Retrospective analysis suggests that the electronic properties of the aromatic framework influence the metal-chelating ability of the diketo acid system. Therefore, the difference in activities is related to the complexes they preferentially form in solution, and these findings are important for the design of a new generation of IN inhibitors.
- Subjects :
- Chelating Agents chemistry
Cobalt chemistry
Copper chemistry
Crystallography, X-Ray
HIV Integrase Inhibitors chemistry
Keto Acids chemistry
Ligands
Magnesium chemistry
Manganese chemistry
Nickel chemistry
Organometallic Compounds chemistry
Stereoisomerism
Zinc chemistry
Cations, Divalent chemistry
Chelating Agents chemical synthesis
HIV Integrase chemistry
HIV Integrase Inhibitors chemical synthesis
Keto Acids chemical synthesis
Organometallic Compounds chemical synthesis
Subjects
Details
- Language :
- English
- ISSN :
- 0022-2623
- Volume :
- 49
- Issue :
- 14
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 16821784
- Full Text :
- https://doi.org/10.1021/jm060193m