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.
The amide moiety of peptides can be replaced for example by a triazole moiety, which is considered to be bioisosteric. Therefore, the carbonyl moiety of an amino acid has to be replaced by an alkyne in order to provide a precursor of such peptidomimetics. As most amino acids have a chiral center at Cα, such amide bond surrogates need a chiral moiety. Here the asymmetric synthesis of a set of 24 N-sulfinyl propargylamines is presented. The condensation of various aldehydes with Ellman’s chiral sulfinamide provides chiral N-sulfinylimines, which were reacted with (trimethylsilyl)ethynyllithium to afford diastereomerically pure N-sulfinyl propargylamines. Diverse functional groups present in the propargylic position resemble the side chain present at the Cα of amino acids. Whereas propargylamines with (cyclo)alkyl substituents can be prepared in a direct manner, residues with polar functional groups require suitable protective groups. The presence of particular functional groups in the side chain in some cases leads to remarkable side reactions of the alkyne moiety. Thus, electron-withdrawing substituents in the Cα-position facilitate a base induced rearrangement to α,β-unsaturated imines, while azide-substituted propargylamines form triazoles under surprisingly mild conditions. A panel of propargylamines bearing fluoro or chloro substituents, polar functional groups, or basic and acidic functional groups is accessible for the use as precursors of peptidomimetics.
A family of dinuclear complexes based on 2,7-disubstituted 1,8-naphthalenediol-ligands has been designed to bind covalently to two neighboring phosphate diester groups in the backbone of DNA. The dinuclear CuII and...
We have rationally designed a family of dinuclear transition-metal complexes to bind two neighboring phosphate diester groups of DNA. The two metal ions are positioned at the distance of two neighboring phosphate diesters in DNA of 6−7 Å by a 1,8-naphthalenediol backbone. Two sterically demanding dipicolylamine pendant arms in the 2 and 7 positions stabilize coordination of the metal ions and prevent coordination to the less exposed nucleobases of DNA. Although the dinuclear Ni II 2 and Cu II 2 bind to DNA, inhibit DNA synthesis, and preferentially kill human cancer cells over fast proliferating human stem cells, the DNA binding mode was elusive. Here, we prove the principle phosphate diester binding ability of this family of dinuclear complexes by a new dinuclear Ni II 2 complex with dibenzimidazolamine pendant arms. The distance of the oxygen atoms of the coordinated phosphate diesters of 6.5 Å confirms the initial design and binding ability to two neighboring phosphate diesters of the DNA backbone. Moreover, the facile exchange of coordinated acetates by phosphate diesters indicates a preferential binding to phosphate diesters.
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