Dharmasivam Mahendiran, Zhang Stanley, Zhao Xiao, Richardson Vera, Wijesinghe Tharushi P, Suleymanoglu Mediha, Gholam Azad Mahan, Bernhardt Paul V, Kaya Busra, Richardson Des R
Centre for Cancer Cell Biology and Drug Discovery, Institute for Biomedicine and Glycomics, Griffith University, Southport 4215 Queensland, Australia.
Department of Medical Biology, Istanbul Faculty of Medicine, Istanbul University, Istanbul 34093, Turkey.
J Med Chem. 2025 May 8;68(9):9594-9622. doi: 10.1021/acs.jmedchem.5c00374. Epub 2025 Apr 23.
Fe(III) complexes of clinically trialed thiosemicarbazones demonstrate deleterious oxy-myoglobin and oxy-hemoglobin oxidation. Therefore, the PPP4pSe selenosemicarbazone analogues were designed with several PPP4pSe Fe(III) complexes completely preventing deleterious oxy-myoglobin oxidation. This was ascribed to the decreased potentials of their Fe(III) complexes and steric hindrance effects. The Fe(III), Cu(II), and Zn(II) complexes of PPP4pSe demonstrated greater reactivity with physiological reductants/ligands (glutathione, l-cysteine, or l-ascorbate), than respective complexes of the isosteric thiosemicarbazone, PPP4pT. Considering this: (1) [Fe(PPP4pSe)] demonstrated increased reduction relative to [Fe(PPP4pT)] with glutathione and l-cysteine, while l-ascorbate led to comparable reduction; (2) glutathione led to complete dissociation of [Zn(PPP4pSe)], while incomplete dissociation of [Zn(PPP4pT)] occurred; and (3) [Cu(PPP4pSe)Cl] demonstrated complete coordinate sphere substitution with glutathione, l-cysteine, and l-ascorbate, whereas [Cu(PPP4pT)Cl] demonstrated partial substitution. The role of glutathione in all three latter reactions is significant, given the greater reactivity of the selenosemicarbazone, and glutathione's key role in selenosemicarbazone and thiosemicarbazone anticancer activity.
临床试用的硫代半卡巴腙的铁（III）配合物表现出有害的氧合肌红蛋白和氧合血红蛋白氧化。因此，设计了PPP4pSe硒代半卡巴腙类似物，其几种PPP4pSe铁（III）配合物能完全防止有害的氧合肌红蛋白氧化。这归因于其铁（III）配合物电位的降低和空间位阻效应。PPP4pSe的铁（III）、铜（II）和锌（II）配合物与生理还原剂/配体（谷胱甘肽、L-半胱氨酸或L-抗坏血酸）的反应性比等排硫代半卡巴腙PPP4pT的相应配合物更高。考虑到这一点：（1）相对于[Fe(PPP4pT)]，[Fe(PPP4pSe)]与谷胱甘肽和L-半胱氨酸反应时还原增加，而L-抗坏血酸导致的还原相当；（2）谷胱甘肽导致[Zn(PPP4pSe)]完全解离，而[Zn(PPP4pT)]发生不完全解离；（3）[Cu(PPP4pSe)Cl]与谷胱甘肽、L-半胱氨酸和L-抗坏血酸反应时表现出完全的配位球取代，而[Cu(PPP4pT)Cl]表现出部分取代。鉴于硒代半卡巴腙的更高反应性以及谷胱甘肽在硒代半卡巴腙和硫代半卡巴腙抗癌活性中的关键作用，谷胱甘肽在上述后三个反应中的作用很重要。
