Dinuclear complex-induced DNA melting

Biere N, Kreft D, Walhorn V, Schwarzbich S, Glaser T, Anselmetti D. Dinuclear complex-induced DNA melting. Journal of Nanobiotechnology. 2023;21(1): 26.Dinuclear copper complexes have been designed for molecular recognition in order to selectively bind to two neighboring phosphate moieties in the backbone of double strand DNA. Associated biophysical, biochemical and cytotoxic effects on DNA were investigated in previous works, where atomic force microscopy (AFM) in ambient conditions turned out to be a particular valuable asset, since the complexes influence the macromechanical properties and configurations of the strands. To investigate and scrutinize these effects in more depth from a structural point of view, cutting-edge preparation methods and scanning force microscopy under ultra-high vacuum (UHV) conditions were employed to yield submolecular resolution images. DNA strand mechanics and interactions could be resolved on the single base pair level, including the amplified formation of melting bubbles. Even the interaction of singular complex molecules could be observed. To better assess the results, the appearance of treated DNA is also compared to the behavior of untreated DNA in UHV on different substrates. Finally, we present data from a statistical simulation reasoning about the nanomechanics of strand dissociation. This sort of quantitative experimental insights paralleled by statistical simulations impressively shade light on the rationale for strand dissociations of this novel DNA interaction process, that is an important nanomechanistic key and novel approach for the development of new chemotherapeutic agents. © 2023. The Author(s)

Cationic, Methylene-Bridged, Intramolecular Donor-Acceptor Systems Based on Zirconium and Hafnium and Phosphino-methanides

Pieper M, Auer P, Schwarzbich S, et al. Cationic, Methylene-Bridged, Intramolecular Donor-Acceptor Systems Based on Zirconium and Hafnium and Phosphino-methanides. ZEITSCHRIFT FUER ANORGANISCHE UND ALLGEMEINE CHEMIE. 2017;643(14):909-915.A new access to cationic zirconium and hafnium compounds [L2MCH2PR2][MeB(C6F5)(3)] (L = Cp, Ind; R = iso-Pr, tert-Bu; M = Zr, Hf) exhibiting an intramolecular donor-acceptor system was established by treating the precursors L2M(Me)CH2PR2 with B(C6F5)(3) (BCF). Precursors 1-6 [L2M(Me)CH2PR2 with L = Cp, Ind; R = iso-Pr, tert-Bu; M = Zr, Hf] were fully characterized. The crystal structures of these compounds revealed large M-CH2-P bond angles with values of about 134 degrees indicating the absence of interactions between the Lewis-acid and Lewis-base. The cationic compounds [L2MCH2PR2][MeB(C6F5)(3)] (7-12) were obtained by treatment of 1-6 with BCF. They were characterized by NMR spectroscopy, mass spectrometry, and elemental analyses; in H/D-scrambling experiments with H-2/D-2 mixtures 7-12 disclosed their reactivity towards cleavage of hydrogen

Binding Modes of a Cytotoxic Dinuclear Copper(II) Complex with Phosphate Ligands Probed by Vibrational Photodissociation Ion Spectroscopy

Giampa M, Corinti D, Maccelli A, et al. Binding Modes of a Cytotoxic Dinuclear Copper(II) Complex with Phosphate Ligands Probed by Vibrational Photodissociation Ion Spectroscopy. Inorganic Chemistry . 2023.The dinuclear copper complex bearing a 2,7-disubstituted-1,8-naphthalenediol ligand, [(HtomMe){Cu(OAc)}2](OAc), a potential anticancer drug able to bind to two neighboring phosphates in the DNA backbone, is endowed with stronger cytotoxic effects and inhibition ability of DNA synthesis in human cancer cells as compared to cisplatin. In this study, the intrinsic binding ability of the charged complex [(HtomMe){Cu(OAc)}2]+ is investigated with representative phosphate diester ligands with growing chemical complexity, ranging from simple inorganic phosphate up to mononucleotides. An integrated method based on high-resolution mass spectrometry (MS), tandem MS, and infrared multiple photon dissociation (IRMPD) spectroscopy in the 600-1800 cm-1 spectral range, backed by quantum chemical calculations, has been used to characterize complexes formed in solution and delivered as bare species by electrospray ionization. The structural features revealed by IRMPD spectroscopy have been interpreted by comparison with linear IR spectra of the lowest-energy structures, revealing diagnostic signatures of binding modes of the dinuclear copper(II) complex with phosphate groups, whereas the possible competitive interaction with the nucleobase is silenced in the gas phase. This result points to the prevailing interaction of [(HtomMe){Cu(OAc)}2]+ with phosphate diesters and mononucleotides as a conceivable contribution to the observed anticancer activity

Stronger Cytotoxicity for Cancer Cells Than for Fast Proliferating Human Stem Cells by Rationally Designed Dinuclear Complexes

Schwarzbich S, Horstmann Nee Gruschka C, Simon J, et al. Stronger Cytotoxicity for Cancer Cells Than for Fast Proliferating Human Stem Cells by Rationally Designed Dinuclear Complexes. Inorganic chemistry. 2020;59(19):14464–14477.Cytostatic metallo-drugs mostly bind to the nucleobases of DNA. A new family of dinuclear transition metal complexes was rationally designed to selectively target the phosphate diesters of the DNA backbone by covalent bonding. The synthesis and characterization of the first dinuclear NiII2 complex of this family are presented, and its DNA binding and interference with DNA synthesis in polymerase chain reaction (PCR) are investigated and compared to those of the analogous CuII2 complex. The NiII2 complex also binds to DNA but forms fewer intermolecular DNA cross-links, while it interferes with DNA synthesis in PCR at lower concentrations than CuII2. To simulate possible competing phosphate-based ligands in vivo, these effects have been studied for both complexes with 100-200-fold excesses of phosphate and ATP, which provided no disturbance. The cytotoxicity of both complexes has been studied for human cancer cells and human stem cells with similar rates of proliferation. CuII2 shows the lowest IC50 values and a remarkable preference for killing the cancer cells. Three different assays show that the CuII2 complex induces apoptosis in cancer cells. These results are discussed to gain insight into the mechanisms of action and demonstrate the potential of this family of dinuclear complexes as anticancer drugs acting by a new binding target