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

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 (1H, 13C, 31P, and 2D NMR methods, including 1H15N 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.

Synthesis and reactivity of cyclobutadiene nickel bromide.

NiBr2 reacts with 3-hexyne in the presence of Mg and EtOH to give the cyclobutadiene bromide complex [(C4Et4)NiBr2]2, which serves as a general precursor for various cyclobutadiene nickel compounds. In particular, complexes with 2-electron ligands (C4Et4)Ni(L)Br2 (L = PPh3, P(OMe)3, pyridine), complexes with bidentate ligands [(C4Et4)Ni(L2)Br]PF6 (L2 = bipyridine, phenanthroline), and nickelacarborane (C4Et4)NiC2B9H11 were obtained from [(C4Et4)NiBr2]2 in 70-95% yields. The reactions of [(C4Et4)NiBr2]2 with an excess of strong ligands, such as tBuNC or dppe, led to the displacement of cyclobutadiene. The structures of the five compounds have been established by X-ray diffraction analysis. The previously reported data on cyclobutadiene nickel complexes have been also reviewed.