Gaudiano G, Koch T H
Department of Chemistry and Biochemistry, University of Colorado, Boulder 80309-0215.
Chem Res Toxicol. 1991 Jan-Feb;4(1):2-16. doi: 10.1021/tx00019a001.
The oxomorpholinyl radicals are unique materials in organic and medicinal chemistry. Their closest parallel lies in inorganic chemistry with dithionite, which exists in equilibrium with sulfur dioxide radical anion, also a one-electron reducing agent. However, dithionite is a more powerful reducing agent and is probably more toxic. The rate of release of the oxomorpholinyl radical from its dimer is medium and is structure dependent, which provides for some level of control. The oxomorpholinyl radicals TM-3 and DHM-3 are selective one-electron reducing agents for the anthracyclines, generating sequentially semiquinone and hydroquinone redox states. Formation of the reduced states of the anthracyclines is probably relevant to their cytotoxic activity. Semiquinones and hydroquinones react rapidly with molecular oxygen to yield superoxide. Hydroquinone redox states with anaerobic conditions in protic media at pH 7-8 undergo glycosidic cleavage to form quinone methides; in aprotic media or at pH less than 4, they tautomerize to leuco forms. Quinone methides react with protons from solvent to form 7-deoxyaglycons, with some nucleophiles to form adducts, and with molecular oxygen to form semiquinone methide. The reactivity of the quinone methide is a function of substitution; nucleophilic addition is facilitated by the absence of a hydroxyl group at the 11-position and by proper location of the nucleophile. Quinone methides and semiquinone methides are both viable transients for covalently linking anthracycline aglycons to biological macromolecules. DHM-3 dimer is of possible pharmaceutical value for the detoxification of quinone antitumor drugs and for the improvement of chemotherapy through modulating the redox chemistry of the quinone antitumor drugs.
氧代吗啉基自由基是有机化学和药物化学中的独特物质。与其最相似的物质存在于无机化学中的连二亚硫酸盐，它与二氧化硫自由基阴离子处于平衡状态，二氧化硫自由基阴离子也是一种单电子还原剂。然而，连二亚硫酸盐是一种更强的还原剂，可能毒性也更大。氧代吗啉基自由基从其二聚体中释放的速率适中且取决于结构，这提供了一定程度的控制。氧代吗啉基自由基TM - 3和DHM - 3是蒽环类药物的选择性单电子还原剂，依次产生半醌和对苯二酚氧化还原态。蒽环类药物还原态的形成可能与其细胞毒性活性有关。半醌和对苯二酚与分子氧迅速反应生成超氧化物。在pH 7 - 8的质子性介质中，对苯二酚氧化还原态在厌氧条件下会发生糖苷键断裂形成醌甲基化物；在非质子性介质中或pH小于4时，它们会互变异构为无色形式。醌甲基化物与溶剂中的质子反应形成7 - 脱氧糖苷配基，与一些亲核试剂反应形成加合物，与分子氧反应形成半醌甲基化物。醌甲基化物的反应活性是取代作用的函数；11位不存在羟基以及亲核试剂的适当位置有利于亲核加成。醌甲基化物和半醌甲基化物都是将蒽环类糖苷配基与生物大分子共价连接的可行中间体。DHM - 3二聚体对于醌类抗肿瘤药物的解毒以及通过调节醌类抗肿瘤药物的氧化还原化学来改善化疗可能具有药物价值。
