Sechi Mario, Bacchi Alessia, Carcelli Mauro, Compari Carlotta, Duce Elenia, Fisicaro Emilia, Rogolino Dominga, Gates Paul, Derudas Marco, Al-Mawsawi Laith Q, Neamati Nouri
Dipartimento Farmaco Chimico Tossicologico, Università di Sassari, Via Muroni 23/A, 07100 Sassari, Italy.
J Med Chem. 2006 Jul 13;49(14):4248-60. doi: 10.1021/jm060193m.
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.
含β - 二酮酸的化合物是一类很有前景的1型人类免疫缺陷病毒（HIV - 1）整合酶（IN）抑制剂。基于这些抑制剂在与活性位点相互作用之前能够在溶液中配位离子的假设，已进行了一系列电位测量，以了解二酮酸药效基团与生物学相关的Mg(2+)的配位能力。此外，通过使用β - 二酮酸/酯作为与一组二价金属离子（Mg、Mn、Ni、Co、Cu和Zn）的模型配体，我们获得了一系列配合物，并测试了它们的抗HIV - 1 IN活性。结果表明，二酮酸官能团在溶液中螯合二价金属离子，并分离出了与金属具有不同化学计量比的配合物。我们推测二酮酸以其活性形式作为配合物起作用。特别是，它们在生理pH下主要形成诸如Mg(2)L(2+)和Mg(2)L(2)（源自二酮酸，H(2)L）以及MgL(+)和MgL(2)（源自二酮酯，HL）的物种。此外，合成的单金属和双金属配合物在高纳摩尔到低微摩尔范围内抑制整合酶，在苯基二酮酸系列中具有金属依赖性。回顾性分析表明，芳环骨架的电子性质影响二酮酸体系的金属螯合能力。因此，活性差异与它们在溶液中优先形成的配合物有关，这些发现对于新一代整合酶抑制剂的设计很重要。
