Isostructural Series of Ni(II), Pd(II), Pt(II), and Au(III) Azido Complexes with a N

An isoelectronic and isostructural series of cyclometalated azido complexes [M(N3)(dpb)] with M = Ni(II), Pd(II), Pt(II), and Au(III) based on the N^C^N pincer ligand 1,3-di(2-pyridyl)phenide (dpb) was characterized by X-ray diffraction analysis and investigated for reactivity in the iClick reaction with a wide range of internal and terminal alkynes by using 1H and 19F NMR spectroscopy. Reaction rate constants were found to increase with greater charge density in the order Ni(II) > Pd(II) > Pt(II) > Au(III). Terminal alkynes R-C≡C-R' with strongly electron-withdrawing groups R and R' exhibited faster kinetics than those with electron-donating substituents in the order CF3 > ketone > ester > H > phenyl ≫ amide, while R = CH3 resulted in complete loss of reactivity. Four symmetrical triazolato complexes [M(triazolatoCOOCH3,COOCH3)(dpb)] with M = Ni(II), Pd(II), Pt(II), and Au(III) as well as four nonsymmetrically substituted triazolato complexes [Pt(triazolatoR,R')(dpb)] originating from terminal and internal alkynes were shown by X-ray crystal structure analysis to exclusively feature N2-coordination of the five-membered ring ligand. However, the Pt(II) triazolato complexes exist as a mixture of N1- and N2-coordinated species in solution. Torsion angles between the mean planes of the N^C^N pincer and the triazolato ligand increase from a nearly coplanar to a perpendicular arrangement when going from Au(III)/Pt(II)/Pd(II) to Ni(II), while different substituents R and R' on the alkyne have no influence on the torsion angle and were rationalized by DFT calculations. Finally, a carbohydrate derivative obtained by glucuronic acid conjugation to methyl propiolate demonstrates the facile biofunctionalization of metal complexes via the iClick reaction.

Taming the Biological Activity of Pd(II) and Pt(II) Complexes with Triazolato "Protective" Groups: 1H, 77Se Nuclear Magnetic Resonance and X-ray Crystallographic Model Studies with Selenocysteine to Elucidate Differential Thioredoxin Reductase Inhibition.

The biological activity of Pd(II) and Pt(II) complexes toward three different cancer cell lines as well as inhibition of selenoenzyme thioredoxin reductase (TrxR) was modulated in an unexpected way by the introduction of triazolate as a "protective group" to the inner metal coordination sphere using the iClick reaction of [M(N3)(terpy)]PF6 [M = Pd(II) or Pt(II) and terpy = 2,2':6',2″-terpyridine] with an electron-poor alkyne. In a cell proliferation assay using A549, HT-29, and MDA-MB-231 human cancer cell lines, the palladium compound was significantly more potent than the isostructural platinum analogue and exhibited submicromolar activity on the most responsive cell line. This difference was also reflected in the inhibitory efficiency toward TrxR with IC50 values of 0.1 versus 5.4 µM for the Pd(II) and Pt(II) complexes, respectively. UV/Vis kinetic studies revealed that the Pt compound binds to selenocysteine faster than to cysteine [k = (22.9 ± 0.2)·10-3 vs (7.1 ± 0.2)·10-3 s-1]. Selective triazolato ligand exchange of the title compounds with cysteine (Hcys) and selenocysteine (Hsec)─but not histidine (His) and 9-ethylguanine (9EtG)─was confirmed by 1H, 77Se, and 195Pt NMR spectroscopy. Crystal structures of three of the four ligand exchange products were obtained, including [Pt(sec)(terpy)]PF6 as the first metal complex of selenocysteine to be structurally characterized.