Identification of Platinum(II) Sulfide Complexes Suitable as Intramuscular Cyanide Countermeasures.
Identification of Platinum(II) Sulfide Complexes Suitable as Intramuscular Cyanide Countermeasures.
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DOI：
10.1021/acs.chemrestox.2c00157
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发表时间：
2022-11-21
影响因子：
4.1
通讯作者：
Davisson, Vincent Jo
中科院分区：
文献类型：
--
作者：
Behymer, Matthew M.;Mo, Huaping;Fujii, Naoaki;Suresh, Vallabh;Chan, Adriano;Lee, Jangweon;Nath, Anjali K.;Saha, Kusumika;Mahon, Sari B.;Brenner, Matthew;MacRae, Calum A.;Peterson, Randall;Boss, Gerry R.;Knipp, Gregory T.;Davisson, Vincent Jo
使用肌内注射（IM）的快速作用氰化物对策的发展代表了在大规模伤亡环境中减轻毒物暴露的未满足的医疗需求。以前的工作确定，顺铂和其他铂（II）或铂（IV）为基础的代理有效地减轻斑马鱼的氰化物毒性。氰化物与含铂材料的体内反应被提议用于降低急性毒性的风险。然而，氰化物解毒剂活性取决于铂氯化物盐与二甲基亚砜（DMSO）的制剂，然后在磷酸盐缓冲盐水（PBS）中稀释。解释DMSO要求的一个工作假设是铂-亚砜络合物的形成激活了铂的氰化物清除性能。在不存在过量DMSO的情况下，分离的NaPtCl 5-DMSO和Na（NH3）2 PtCl-DMSO复合物的制备提供了在体外对氰化物具有增强的反应性的试剂，并且在斑马鱼和小鼠模型中完全再现了体内氰化物拯救。DMSO配体的氰化物清除效果的增强可以归因于用硫配体活化铂（IV）和（II）。不幸的是，当IM给药时，DMSO复合物的功效并不稳健。在双齿配合物中含有硫化物和胺配体的替代Pt（II）材料显示出对氰化物加成的增强的反应性。氰化物加成产物产生四氰基铂酸盐（II），转化为1：4 Pt/每种氰化物清除剂的化学计量。在氰化物毒性的小鼠和兔模型中，使用IM给药，这些新药物表现出比含DMSO的复合物更强的效力。使用这些铂（II）配合物的斑马鱼模型，没有检测到急性心脏毒性，达到致死所需的剂量水平超过有效剂量的100倍。数据支持一般的化学设计方法，可以扩展一个新的铅候选人系列开发下一代氰化物对策。
The development of rapidly acting cyanide countermeasures using intramuscular injection (IM) represents an unmet medical need to mitigate toxicant exposures in mass casualty settings. Previous work established that cisplatin and other platinum(II) or platinum(IV)-based agents effectively mitigate cyanide toxicity in zebrafish. Cyanide’s in vivo reaction with platinum-containing materials was proposed to reduce the risk of acute toxicities. However, cyanide antidote activity depended on a formulation of platinum-chloride salts with dimethyl sulfoxide (DMSO) followed by dilution in phosphate-buffered saline (PBS). A working hypothesis to explain the DMSO requirement is that the formation of platinum–sulfoxide complexes activates the cyanide scavenging properties of platinum. Preparations of isolated NaPtCl5–DMSO and Na (NH3)2PtCl–DMSO complexes in the absence of excess DMSO provided agents with enhanced reactivity toward cyanide in vitro and fully recapitulated in vivo cyanide rescue in zebrafish and mouse models. The enhancement of the cyanide scavenging effects of the DMSO ligand could be attributed to the activation of platinum(IV) and (II) with a sulfur ligand. Unfortunately, the efficacy of DMSO complexes was not robust when administered IM. Alternative Pt(II) materials containing sulfide and amine ligands in bidentate complexes show enhanced reactivity toward cyanide addition. The cyanide addition products yielded tetracyanoplatinate(II), translating to a stoichiometry of 1:4 Pt to each cyanide scavenger. These new agents demonstrate a robust and enhanced potency over the DMSO-containing complexes using IM administration in mouse and rabbit models of cyanide toxicity. Using the zebrafish model with these Pt(II) complexes, no acute cardiotoxicity was detected, and dose levels required to reach lethality exceeded 100 times the effective dose. Data are presented to support a general chemical design approach that can expand a new lead candidate series for developing next-generation cyanide countermeasures.
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影响因子：
4.4
作者：
Bojesen, G;Hvelplund, P;Nielsen, SB
通讯作者：
Nielsen, SB
影响因子：
3.4
作者：
Fischer, Stephanie J.;Benson, Linda M.;Windebank, Anthony J.
通讯作者：
Windebank, Anthony J.
影响因子：
14.8
作者：
Burns, CG;Milan, DJ;Fishman, MC
通讯作者：
Fishman, MC
影响因子：
7.3
作者：
Chan, Adriano;Jiang, Jingjing;Boss, Gerry R.
通讯作者：
Boss, Gerry R.
影响因子：
2.4
作者：
Fleischman, Ross J.;Lundquist, Mark;Warden, Craig
通讯作者：
Warden, Craig