Pincer-dipeptide and pseudodipeptide conjugates: Synthesis and bioactivity studies.

Autor: Churusova SG; A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, ul. Vavilova 28, Moscow 119991, Russia., Aleksanyan DV; A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, ul. Vavilova 28, Moscow 119991, Russia. Electronic address: aleksanyan.diana@ineos.ac.ru., Rybalkina EY; N. N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of the Russian Federation, Kashirskoe shosse 23, Moscow 115478, Russia., Gutsul EI; A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, ul. Vavilova 28, Moscow 119991, Russia., Peregudov AS; A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, ul. Vavilova 28, Moscow 119991, Russia., Klemenkova ZS; A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, ul. Vavilova 28, Moscow 119991, Russia., Nelyubina YV; A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, ul. Vavilova 28, Moscow 119991, Russia., Buyanovskaya AG; A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, ul. Vavilova 28, Moscow 119991, Russia., Kozlov VA; A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, ul. Vavilova 28, Moscow 119991, Russia.
Jazyk: angličtina
Zdroj: Journal of inorganic biochemistry [J Inorg Biochem] 2022 Oct; Vol. 235, pp. 111908. Date of Electronic Publication: 2022 Jun 24.
DOI: 10.1016/j.jinorgbio.2022.111908
Abstrakt: 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 ( 1 H, 13 C, 31 P, and 2D NMR methods, including 1 H 15 N 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.
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Databáze: MEDLINE
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