Istituto CNR per la Sintesi Organica e Fotoreattività "I.S.O.F.", Bologna, Italy.
ChemMedChem. 2010 Dec 3;5(12):2006-15. doi: 10.1002/cmdc.201000369.
The instability of the hydroxylactone E ring represents a critical drawback of camptothecins, because the lactone ring is recognized to be essential for stabilization of topoisomerase I-mediated DNA cleavage. In an attempt to investigate the effect of the thiopyridone pharmacophofore on the molecular and pharmacological features of the drug, we prepared a series of novel 16 a-thiocamptothecin analogues. Due to the sulfur atom, a destabilization of the hydrogen bond between the hydroxy group in position 17 of the opened E ring and the carbonyl of the pyridone moiety is predicted, thus shifting the equilibrium toward the closed lactone form and increasing the lipophilic properties of the compounds. This feature was associated with superior antiproliferative potency, with reduced interaction with the human serum albumin and with substantial increase of the persistence of the topoisomerase I-DNA cleavable complex. These effects were prominent for thio-SN38, the most active compound of the series. The favorable interactions at the molecular and cellular level of the reported thiocamptothecins confer promising features, and these compounds warrant preclinical development.
羟基内酰胺 E 环的不稳定性是喜树碱类药物的一个关键缺陷，因为内酯环被认为是稳定拓扑异构酶 I 介导的 DNA 断裂所必需的。为了研究硫代吡啶酮药效团对药物的分子和药理学特征的影响，我们制备了一系列新型 16α-硫代喜树碱类似物。由于硫原子的存在，预测在打开的 E 环的 17 位的羟基与吡啶酮部分的羰基之间的氢键将被破坏，从而使平衡向闭环内酯形式移动，并增加化合物的亲脂性。这种特性与优越的抗增殖活性相关联，与人类血清白蛋白的相互作用降低，并且拓扑异构酶 I-DNA 可切割复合物的持久性显著增加。在该系列中，硫代-SN38 是最活跃的化合物。所报道的硫代喜树碱在分子和细胞水平上的有利相互作用赋予了其有前景的特性，这些化合物值得进行临床前开发。
