AmplMed Corporation, 4380 N. Campbell Ave., Tucson, Arizona 85718, USA.
Curr Med Chem. 2012;19(33):5745-53. doi: 10.2174/092986712803988802.
Following the demonstration that addition of a 2-cyano group to aziridines prevented DNA alkylation and thus reduced toxicity, many novel 2-cyanoaziridines were synthesized and evaluated as immunomodulating and antitumor agents. They typically reacted with thiols such as cysteine, depleting them and allowing the accumulation of reactive oxygen species. Two of these compounds, azimexon and ciamexon, showed activity against tumors in clinical trials. Imexon was produced by cyclization of 2-cyanoaziridine-1- carboxamide in the presence of hydroxide ions. The two enantiomers were prepared by a process involving chiral chromatography. They were equipotent against cultured tumor cells. Imexon also reacts with thiols and it is especially potent against multiple myeloma in cell cultures. An efficient chemical synthesis and a lyophilization formulation of imexon as a water soluble, injectible drug, were developed. In Phase I and I/II clinical trials imexon showed hints of activity against a variety of tumors, but a randomized double-blind Phase II trial of imexon plus gemcitabine versus gemcitabine alone in pancreatic cancer showed no enhancement of activity above that of gemcitabine alone. This result was disappointing because in cell culture and mice the two compounds were synergistic. Based on a complete response in a Phase I trial, a new Phase II clinical trial of imexon is underway in non-Hodgkins lymphoma.
继证明将 2-氰基添加到氮丙啶中可以防止 DNA 烷基化从而降低毒性之后，许多新型 2-氰基氮丙啶被合成并评估为免疫调节和抗肿瘤药物。它们通常与半胱氨酸等巯基反应，耗尽这些巯基并允许活性氧物质的积累。其中两种化合物，azimexon 和 ciamexon，在临床试验中显示出对肿瘤的活性。Imexon 是通过在氢氧根离子存在下环化 2-氰基氮丙啶-1-羧酰胺产生的。两种对映异构体通过涉及手性色谱的过程制备。它们对培养的肿瘤细胞具有同等的活性。Imexon 还与巯基反应，在细胞培养物中对多发性骨髓瘤特别有效。开发了一种有效的化学合成和冻干制剂，使 imexon 成为水溶性可注射药物。在 I 期和 I/II 期临床试验中，imexon 对多种肿瘤显示出一定的活性迹象，但在胰腺癌中，imexon 加 gemcitabine 与 gemcitabine 单独治疗的随机双盲 II 期试验显示，活性增强并不超过 gemcitabine 单独治疗。这一结果令人失望，因为在细胞培养和小鼠中，这两种化合物具有协同作用。基于 I 期试验的完全缓解，正在进行非霍奇金淋巴瘤中 imexon 的新 II 期临床试验。
