A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, ul. Vavilova 28, Moscow 119991, Russia.
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, ul. Vavilova 28, Moscow 119991, Russia.
J Inorg Biochem. 2022 Oct;235:111908. doi: 10.1016/j.jinorgbio.2022.111908. Epub 2022 Jun 24.
Following a recent trend on the application of different pincer scaffolds for the development of new metal-based antitumor agents, in this work, dipeptides and dipeptide surrogates based on picolinyl- and 4-chloropicolinylamides with S-donor amino acid residues (cysteine, homocysteine, or methionine) bearing glycinate, alaninate, or phosphonate moieties either at the C-terminus or in the S-donor side arm have been designed as nonclassical pincer ligands with central amide units and shown to smoothly undergo site-selective direct cyclopalladation under mild conditions, affording the target Pd(II) pincer complexes in good to high yields. The realization of S,N,N-coordination through the sulfur atom of the thioether group and nitrogen atoms of the pyridine and deprotonated amide units was unambiguously confirmed using different NMR techniques (H, C, P, and 2D NMR methods, including HN HMBC) and IR spectroscopy; the structure of one representative was elucidated by X-ray crystallography. The resulting pincer-(pseudo)dipeptide conjugates were screened for cytotoxicity against several cancer cell lines and noncancerous human embryonic kidney cells and at least some of them provided an appreciable level of activity comparable to that of cisplatin. The S-modified homocysteine-based derivatives exhibited also significant antiproliferative effects against doxorubicin-resistant transformed breast cells HBL100/Dox, implying the possibility of overcoming drug resistance. The complexes can induced apoptosis but did not affect mitochondria. The comparative DNA/protein binding studies of one of the most active pincer-(pseudo)dipeptide conjugates with the monoamino acid-based prototype revealed certain advantages of the former and gave further insights into the potential of this type of palladium-based antitumor agents.
受近期不同钳形配体在新型金属抗肿瘤试剂开发中应用的启发，本工作设计了一系列基于吡啶基和 4-氯吡啶基酰胺的二肽及其二肽类似物，作为非经典钳形配体，其结构中含有 S 供体氨基酸残基（半胱氨酸、高半胱氨酸或蛋氨酸），且在 C 末端或 S 供体侧臂上分别连有甘氨酰基、丙氨酰基或膦酸酯基。这些配体含有中心酰胺单元，在温和条件下可顺利进行位点选择性直接环钯化反应，以较高至很好的产率得到目标 Pd(II)钳形配合物。通过硫醚基团的硫原子以及吡啶和去质子化酰胺单元的氮原子实现 S，N，N 配位，这一点通过不同的 NMR 技术（H、C、P 和 2D NMR 方法，包括 HN HMBC）和红外光谱得到明确证实；通过 X 射线晶体学解析了一个代表性配合物的结构。对这些钳形（拟）二肽缀合物进行了针对几种癌细胞系和非癌细胞系人胚肾细胞的细胞毒性筛选，其中至少一些表现出与顺铂相当的可观活性。S 修饰的高半胱氨酸基衍生物对多柔比星耐药转化的乳腺癌细胞 HBL100/Dox 也表现出显著的增殖抑制作用，这意味着可能克服耐药性。这些配合物可以诱导细胞凋亡，但不影响线粒体。对一种最活跃的钳形（拟）二肽缀合物与基于单氨基酸的原型进行的比较 DNA/蛋白结合研究表明了前者的某些优势，并进一步深入了解了这种类型的钯基抗肿瘤试剂的潜力。
