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Tunable Stability of Imidazotetrazines Leads to a Potent Compound for Glioblastoma.
ACS Chemical Biology ( IF 4 ) Pub Date : 2018-11-08 , DOI: 10.1021/acschembio.8b00864
Riley L Svec , Lucia Furiassi , Christine G Skibinski 1 , Timothy M Fan , Gregory J Riggins 1 , Paul J Hergenrother
Affiliation  

Even in the era of personalized medicine and immunotherapy, temozolomide (TMZ), a small molecule DNA alkylating agent, remains the standard-of-care for glioblastoma (GBM). TMZ has an unusual mode-of-action, spontaneously converting to its active component via hydrolysis in vivo. While TMZ has been FDA approved for two decades, it provides little benefit to patients whose tumors express the resistance enzyme MGMT and gives rise to systemic toxicity through myelosuppression. TMZ was first synthesized in 1984, but certain key derivatives have been inaccessible due to the chemical sensitivity of TMZ, precluding broad exploration of the link between imidazotetrazine structure and biological activity. Here, we sought to discern the relationship between the hydrolytic stability and anticancer activity of imidazotetrazines, with the objectives of identifying optimal timing for prodrug activation and developing suitable compounds with enhanced efficacy via increased blood-brain barrier penetrance. This work necessitated the development of new synthetic methods to provide access to previously unexplored functionality (such as aliphatic, ketone, halogen, and aryl groups) at the C8 position of imidazotetrazines. Through synthesis and evaluation of a suite of compounds with a range of aqueous stabilities (from 0.5 to 40 h), we derive a predictive model for imidazotetrazine hydrolytic stability based on the Hammett constant of the C8 substituent. Promising compounds were identified that possess activity against a panel of GBM cell lines, appropriate hydrolytic and metabolic stability, and brain-to-serum ratios dramatically elevated relative to TMZ, leading to lower hematological toxicity profiles and superior activity to TMZ in a mouse model of GBM. This work points a clear path forward for the development of novel and effective anticancer imidazotetrazines.

中文翻译:

咪唑四嗪的可调稳定性导致胶质母细胞瘤的有效化合物。

即使在个性化医学和免疫疗法的时代,替莫唑胺(TMZ),一种小分子DNA烷基化剂,仍然是胶质母细胞瘤(GBM)的护理标准。TMZ具有异常的作用方式,可通过体内水解自发转化为其活性成分。尽管TMZ已获得FDA批准长达20年之久,但对于肿瘤表达抗性酶MGMT并通过骨髓抑制引起全身毒性的患者,TMZ几乎没有益处。TMZ于1984年首次合成,但由于TMZ的化学敏感性,无法获得某些关键衍生物,这排除了对咪唑四嗪结构与生物活性之间联系的广泛探索。在这里,我们试图辨别咪唑并四嗪的水解稳定性和抗癌活性之间的关系,目的是确定前药激活的最佳时机,并通过增加血脑屏障的渗透性来开发具有增强功效的合适化合物。这项工作需要开发新的合成方法,以便在咪唑并四嗪的C8位上获得以前未开发的功能(例如脂族,酮,卤素和芳基)。通过合成和评估一系列具有一定范围水稳定性(0.5至40 h)的化合物,我们基于C8取代基的Hammett常数得出了咪唑四嗪水解稳定性的预测模型。鉴定出具有潜力的化合物,它们具有针对一组GBM细胞系的活性,适当的水解和代谢稳定性,并且相对于TMZ而言脑与血清的比例显着提高,在GBM小鼠模型中导致较低的血液学毒性特征和比TMZ更好的活性。这项工作为新型和有效的抗癌咪唑并四嗪类药物的开发指明了一条清晰的道路。
更新日期:2018-10-08
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