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 NiII 2 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 CuII 2 complex. The NiII 2 complex also binds to DNA but forms fewer intermolecular DNA cross-links, while it interferes with DNA synthesis in PCR at lower concentrations than CuII 2. 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. CuII 2 shows the lowest IC50 values and a remarkable preference for killing the cancer cells. Three different assays show that the CuII 2 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.

As histone deacetylases (HDACs) play an important role in the treatment of cancer, their selective inhibition has been the subject of various studies. These continuous investigations have given rise to a large collection of pan- and selective HDAC inhibitors, containing diverse US Food and Drug Administration (FDA)-approved representatives. In previous studies, a class of alkyne-based HDAC inhibitors was presented. We modified this scaffold in two previously neglected regions and compared their cytotoxicity and affinity toward HDAC1, HDAC6, and HDAC8. We were able to show that R-configured propargylamines contribute to increased selectivity for HDAC6. Docking studies on available HDAC crystal structures were carried out to rationalize the observed selectivity of the compounds. Substitution of the aromatic portion by a thiophene derivative results in high affinity and low cytotoxicity, indicating an improved drug tolerance.

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.

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.

A new access to cationic zirconium and hafnium compounds [L 2 MCH 2 PR 2 ][MeB(C 6 F 5 ) 3 ] (L = Cp, Ind; R = iso-Pr, tert-Bu; M = Zr, Hf) exhibiting an intramolecular donor-acceptor system was established by treating the precursors L 2 M(Me)CH 2 PR 2 with B(C 6 F 5 ) 3 (BCF). Precursors 1-6 [L 2 M(Me)CH 2 PR 2 with L = Cp, Ind; R = iso-Pr, tert-Bu; M = Zr, Hf] were fully characterized. The crystal structures of these compounds revealed large M-CH 2 -P bond angles * Prof. Dr. N. W. Mitzel 909with values of about 134°indicating the absence of interactions between the Lewis-acid and Lewis-base. The cationic compounds [L 2 MCH 2 PR 2 ][MeB(C 6 F 5 ) 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.intramolecular Lewis pair geminally bonded to the central metal atom. Journal of Inorganic and General ChemistryZeitschrift für anorganische und allgemeine Chemie ARTICLEIn the NMR spectra the anticipated patterns of resonances could be observed. The 13 C NMR chemical shifts of the methylene group of the tert-butyl compounds 2, 4, and 6 are found between δ = 49.7 and 52.3 ppm, the corresponding 1 H NMR chemical shifts between δ = -0.73 ppm and 0.05 ppm. The 31 P NMR spectra of compounds 2, 4 and 6 show singlets with a strong low-field shift in the range between δ = 50.8 and 51.6 ppm. The corresponding NMR spectroscopic data for the iso-propyl-substituted compounds 1, 3 and 5 show 13 C NMR shifts between δ = 43.2 and 48.7 ppm and 1 H NMR shifts between -0.55 and 0.15 ppm. However, the 31 P NMR chemical shifts of 1, 3 and 5 are found between δ = 19.5 and 21.1 ppm, i.e. in a completely different range and high-field shifted compared to those of compounds 2, 4 and 6.Crystalline samples of compounds 1-6 were obtained upon cooling either n-hexane, n-pentane, or toluene solutions to -30°C. The compounds crystallize in the monoclinic space groups P2 1 /n (1, 3, 5, 6), P2 1 /c (2) as well as P2 1 (4), respectively. Figure 1 exemplarily depicts the molecular structures of 1 and 3.