Cisplatin (CisPt) and other platinum (Pt)-based antineoplastic drugs (e.g., carboplatin, oxaliplatin) are highly effective and widely used in the treatment of solid tumors in both pediatric and adult patients. Although considered to be life-saving as a cancer treatment, Pt-based drugs frequently result in dose-limiting toxicities such as chemotherapy-induced peripheral neuropathies (CIPN). Specifically, irreversible damage to outer hair cells and injury of sensory neurons are linked to profound sensorineural hearing loss (ototoxicity), which complicates tumor management and can lead to a poor clinical prognosis. Given the severity of CIPN, substantial effort has been devoted to the development of neuroprotective compounds, regardless clinical results have been underwhelming. It is noteworthy that Pt is a highly reactive electrophile (electron deficient) that causes toxicity by forming adducts with nucleophilic (electron rich) targets on macromolecules. In this regard, we have discovered a series of carbon-based enol nucleophiles; e.g., N-(4-acetyl-3,5-dihydroxyphenyl)-2-oxocytclopentane-1-carboxamide (Gavinol), that can prevent neurotoxicity by scavenging the platinum ion. The chemistry of enol compounds is well understood and mechanistic research has demonstrated the role of this chemistry in cytoprotection. Our cell-derived data were corroborated by calculations of hard and soft, acids and bases (HSAB) parameters that describe the electronic character of interacting electrophiles and nucleophiles. Together, these observations indicate that the respective mechanisms of Pt neurotoxicity and antitumor activity are separable and can therefore be affected independently.

中文翻译：

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形成烯醇化物的化合物可防止铂神经毒性。

顺铂（CisPt）和其他铂（Pt）基抗肿瘤药物（例如卡铂、奥沙利铂）非常有效，广泛用于治疗儿童和成人实体瘤。尽管铂基药物被认为是一种可以挽救生命的癌症治疗方法，但它经常导致剂量限制性毒性，例如化疗引起的周围神经病变 (CIPN)。具体来说，外毛细胞的不可逆损伤和感觉神经元的损伤与严重的感音神经性听力损失（耳毒性）有关，这使肿瘤治疗变得复杂并可能导致临床预后不良。鉴于 CIPN 的严重性，尽管临床结果并不理想，但人们还是投入了大量精力来开发神经保护化合物。值得注意的是，Pt 是一种高反应性亲电子试剂（缺电子），通过与大分子上的亲核（富电子）靶标形成加合物而引起毒性。对此，我们发现了一系列碳基烯醇亲核试剂；例如，N-(4-乙酰基-3,5-二羟基苯基)-2-氧代环戊烷-1-甲酰胺(Gavinol)，可以通过清除铂离子来预防神经毒性。烯醇化合物的化学性质已为人们所熟知，并且机理研究已经证明了这种化学性质在细胞保护中的作用。我们的细胞衍生数据通过描述相互作用的亲电试剂和亲核试剂的电子特性的硬、软、酸和碱 (HSAB) 参数的计算得到了证实。总之，这些观察结果表明 Pt 神经毒性和抗肿瘤活性各自的机制是可分离的，因此可以独立受到影响。