Lambs L, Venturini M, Decock-Le Révérend B, Kozlowski H, Berthon G
INSERM U305, Université Paul Sabatier, Toulouse, France.
J Inorg Biochem. 1988 Jul;33(3):193-210. doi: 10.1016/0162-0134(88)80049-7.
Effects of metal ion-tetracycline (TC) interactions on both gastrointestinal absorption and pharmacological activity of these drugs are well documented. In particular, recent simulation studies based on newly determined complex stability constants have drawn attention to the potential influence of Ca2+ and Mg2+ ions on the bioavailability of various TC derivatives in blood plasma. Contrary to previous thoughts, it was demonstrated in these studies that the fraction of antibiotic not bound to proteins almost exclusively occurs as calcium and magnesium complexes. Among this fraction, predominant binuclear species are electrically charged, and as such cannot passively diffuse through cell membranes. It was thus postulated that the partial blocking of one of the potential coordination sites of the TC molecule, which would favor the formation of neutral mononuclear complexes, should result in a better tissue penetration of the drug. Such correlations were recently established for specific derivatives. Before possible modifications of the TC molecule can be envisaged, it is necessary that all the chelating sites involved in the relevant complexes be properly assigned. As tetracyclines are very complex ligands, the present paper first deals with the coordination of calcium and magnesium with two simpler parent substances, i.e., 4-dedimethylamino-tetracycline (DTC) and 6-desoxy-6-demethyl-tetracycline (DSC). After the quantitative investigation of the proton and metal complex equilibria involved, UV and circular dichroism spectroscopies are used to study the corresponding structural aspects. In DTC complexes, the BCD ring system acts as the exclusive coordination site for both metals. For DSC, however, the N4 atom plays a leading role in the metal binding and would be the only donor involved in 1:1 species; in ML2 complexes, the second ligand is thought to bind through the BCD ring system.
金属离子与四环素（TC）相互作用对这些药物胃肠道吸收和药理活性的影响已有充分记载。特别是，最近基于新测定的络合物稳定常数进行的模拟研究，使人们关注到Ca2+和Mg2+离子对各种TC衍生物在血浆中生物利用度的潜在影响。与先前的想法相反，这些研究表明，未与蛋白质结合的抗生素几乎完全以钙和镁络合物的形式存在。在这一部分中，主要的双核物种带有电荷，因此不能被动地扩散穿过细胞膜。因此推测，部分阻断TC分子的一个潜在配位位点，有利于形成中性单核络合物，应该会使药物在组织中的渗透更好。最近针对特定衍生物建立了这种相关性。在设想对TC分子进行可能的修饰之前，有必要正确确定相关络合物中所有的螯合位点。由于四环素是非常复杂的配体，本文首先研究钙和镁与两种较简单的母体物质，即4-去二甲氨基四环素（DTC）和6-脱氧-6-去甲基四环素（DSC）的配位情况。在对涉及的质子和金属络合物平衡进行定量研究之后，利用紫外光谱和圆二色光谱研究相应的结构方面。在DTC络合物中，BCD环系统是两种金属的唯一配位位点。然而，对于DSC，N4原子在金属结合中起主导作用，并且是1:1物种中唯一参与的供体；在ML2络合物中，第二个配体被认为是通过BCD环系统结合的。
