title: HIV-1 IN strand transfer chelating inhibitors: a focus on metal binding.
abstract: Most active and selective strand transfer HIV-1 integrase (IN) inhibitors contain chelating functional groups that are crucial feature for the inhibition of the catalytic activities of the enzyme. In particular, diketo acids and their derivatives can coordinate one or two metal ions within the catalytic core of the enzyme. The present work is intended as a contribution to elucidate the mechanism of action of the HIV-IN inhibitors by studying the coordinative features of H₂L¹ (L-708,906), an important member of the diketo acids family of inhibitors, and H₂L₂, a model for S-1360, another potent IN inhibitor. Magnesium(II) and manganese(II) complexes of H₂L¹ and H₂L² were isolated and fully characterized in solution and in the solid state. The crystal structures of the manganese complex [Mn(HL₂)₂(CH₃OH)₂]·2CH₃OH were solved by X-ray diffraction analysis. Moreover, the speciation models for H₂L₂ with magnesium(II) and manganese(II) ions were performed and the formation constants of the complexes were measured. M(HL₂)₂ (M = Mg²+, Mn²+) was the most abundant species in solution at physiological pH. All the synthesized compounds were tested for their anti-IN activity, showing good results both for the ligand and the corresponding complexes. From analysis of the speciation models and of the biological data we can conclude that coordination of both metal cofactors could not be strictly necessary and that inhibitors can act as complexes and not only as free ligands.
authors.affiliation: Dipartimento di Chimica Generale ed Inorganica, Chimica Analitica, Chimica Fisica, Università di Parma, Parco Area delle Scienze 17/A, 43124 Parma, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Bacchi
authors.forename: Mauro
authors.initials: M
authors.lastname: Carcelli
authors.forename: Carlotta
authors.initials: C
authors.lastname: Compari
authors.forename: Emilia
authors.initials: E
authors.lastname: Fisicaro
authors.forename: Nicolino
authors.initials: N
authors.lastname: Pala
authors.forename: Gabriele
authors.initials: G
authors.lastname: Rispoli
authors.forename: Dominga
authors.initials: D
authors.lastname: Rogolino
authors.forename: Tino W
authors.initials: TW
authors.lastname: Sanchez
authors.forename: Mario
authors.initials: M
authors.lastname: Sechi
authors.forename: Nouri
authors.initials: N
authors.lastname: Neamati
mesh_terms: D002614:Chelating Agents / Q000737:chemistry / Q000378:metabolism*; D018360:Crystallography, X-Ray; D019427:HIV Integrase / Q000737:chemistry*; D019428:HIV Integrase Inhibitors / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008274:Magnesium / Q000737:chemistry / Q000378:metabolism*; D008345:Manganese / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000737:chemistry / Q000378:metabolism*; D013237:Stereoisomerism
chemical_list: D002614:Chelating Agents; D019428:HIV Integrase Inhibitors; D009942:Organometallic Compounds; D008345:Manganese; D019427:HIV Integrase; D008274:Magnesium