Carbon-Substituted Amines of the Cobalt Bis(dicarbollide) Ion: Stereochemistry and Acid-Base Properties.

Organic amines are found to be abundant in natural living systems. They also constitute an inestimable family of building blocks available in drug design. Considering the man-made cluster [(1,2-C2B9H11)2-3,3'-Co(III)]- ion (1-) and its application as an emerging unconventional pharmacophore, the availability of the corresponding amines has been limited and those with amino groups attached directly to carbon atoms have remained unknown. This paper describes the synthesis of compounds containing one or two primary amino groups attached to the carbon atoms of the cobaltacarborane cage that are accessible via the reduction of newly synthesized azides or via the Curtius rearrangement of the corresponding acyl azide. This substitution represents the first members of the series of azides and primary amines with functional groups bound directly to the carbon atoms of the cage. As expected, the absence of the linker along with the presence of the bulky anionic polyhedral ion leads to a significant alteration of the chemical and physicochemical properties. On a broader series of amines of the ion 1- we have thus observed significant differences in the acidity of the amino groups, depending on whether these are attached to the carbon or boron atoms of the cage, or the C-substituted amines contain an aliphatic linker of variable length. The compounds are relevant for potential use as cobalt bis(dicarbollide) structural blocks in medicinal chemistry and material science. Our study includes single-crystal X-ray diffraction (XRD) structures of both amines and a discussion of their stereochemical and structural features.

Chemistry of Carbon-Substituted Derivatives of Cobalt Bis(dicarbollide)(1-) Ion and Recent Progress in Boron Substitution.

The cobalt bis(dicarbollide)(1-) anion (1-), [(1,2-C2B9H11)2-3,3'-Co(III)](1-), plays an increasingly important role in material science and medicine due to its high chemical stability, 3D shape, aromaticity, diamagnetic character, ability to penetrate cells, and low cytotoxicity. A key factor enabling the incorporation of this ion into larger organic molecules, biomolecules, and materials, as well as its capacity for "tuning" interactions with therapeutic targets, is the availability of synthetic routes that enable easy modifications with a wide selection of functional groups. Regarding the modification of the dicarbollide cage, syntheses leading to substitutions on boron atoms are better established. These methods primarily involve ring cleavage of the ether rings in species containing an oxonium oxygen atom connected to the B(8) site. These pathways are accessible with a broad range of nucleophiles. In contrast, the chemistry on carbon vertices has remained less elaborated over the previous decades due to a lack of reliable methods that permit direct and straightforward cage modifications. In this review, we present a survey of methods based on metalation reactions on the acidic C-H vertices, followed by reactions with electrophiles, which have gained importance in only the last decade. These methods now represent the primary trends in the modifications of cage carbon atoms. We discuss the scope of currently available approaches, along with the stereochemistry of reactions, chirality of some products, available types of functional groups, and their applications in designing unconventional drugs. This content is complemented with a report of the progress in physicochemical and biological studies on the parent cobalt bis(dicarbollide) ion and also includes an overview of recent syntheses and emerging applications of boron-substituted compounds.

Cross-Bridged Cyclam with Phosphonate and Phosphinate Pendant Arms: Chelators for Copper Radioisotopes with Fast Complexation.

Cross-bridged cyclam derivatives bearing two phosphonate (H4L1), bis(phosphinate) (H4L2), or phosphinate (H2L3) pendant arms were synthesized and studied with respect to their application as copper radioisotope carriers in nuclear medicine. The ligands show high macrocycle basicity (pK1 > 14) and high Cu(II) complex stability (log K = 20-24). The complexation and dissociation kinetics of the Cu(II) complexes were studied by ultraviolet-visible spectroscopy. Phosphonate Cu(II)-H4L1 and bis(phosphinate) Cu(II)-H4L2 complexes form very quickly, reaching quantitative formation within 1 s at pH ∼6 and millimolar concentrations. Conversely, the formation of the phosphinate complex Cu(II)-H2L3 is much slower (9 min at pH ∼6) due to the low stability of the out-of-cage reaction intermediate. All studied complexes are highly kinetically inert, showing half-lives of 120, 11, and 111 h for Cu(II)-H4L1, Cu(II)-H4L2, and Cu(II)-H2L3 complexes, respectively, in 1 M HClO4 at 90 °C. The high thermodynamic stability, fast formation, and extreme kinetic inertness of Cu(II) complexes indicate that phosphonate and bis(phosphinate) derivatives are promising ligands for nuclear medicine.

Structurally rigidified cobalt bis(dicarbollide) derivatives, a chiral platform for labelling of biomolecules and new materials.

We report the difunctional modification of an anionic cobalta bis(dicarbollide)(1-) cluster with a B(8,8')-oxygen bridging unit that provides structural rigidity and an organic alkylazide substituent(s) on the carbon atoms of the metallacarborane cage. These ions present a good binding motif for incorporation into organic molecules using Huisgen-Sharpless (2+3) cycloaddition reactions. In addition, the compounds are chiral, as verified by separation of enantiomers using HPLC on chiral stationary phases (CSPs) and provide a high electrochemical peak in the window located outside of typical signals of biomolecules.

Cyclam with a phosphinate-bis(phosphonate) pendant arm is a bone-targeting carrier of copper radionuclides.

Ligands combining a bis(phosphonate) group with a macrocycle function as metal isotope carriers for radionuclide-based imaging and for treating bone metastases associated with several cancers. However, bis(phosphonate) pendant arms often slow down complex formation and decrease radiochemical yields. Nevertheless, their negative effect on complexation rates may be mitigated by using a suitable spacer between bis(phosphonate) and the macrocycle. To demonstrate the potential of bis(phosphonate) bearing macrocyclic ligands as a copper radioisotope carrier, we report the synthesis of a new cyclam derivative bearing a phosphinate-bis(phosphonate) pendant (H5te1PBP). The ligand showed a high selectivity to CuII over ZnII and NiII ions, and the bis(phosphonate) group was not coordinated in the CuII complex, strongly interacting with other metal ions in solution. The CuII complex formed quickly, in 1 s, at pH 5 and at a millimolar scale. The complexation rates significantly differed under a ligand or metal ion excess due to the formation of reaction intermediates differing in their metal-to-ligand ratio and protonation state, respectively. The CuII-te1PBP complex also showed a high resistance to acid-assisted hydrolysis (t1/2 2.7 h; 1 M HClO4, 25 °C) and was effectively adsorbed on the hydroxyapatite surface. H5te1PBP radiolabeling with [64Cu]CuCl2 was fast and efficient, with specific activities of approximately 30 GBq 64Cu per 1 µmol of ligand (pH 5.5, room temperature, 30 min). In a pilot experiment, we further demonstrated the excellent suitability of [64Cu]CuII-te1PBP for imaging active bone compartments by dedicated small animal PET/CT in healthy mice and subsequently in a rat femoral defect model, in direct comparison with [18F]fluoride. Moreover, [64Cu]CuII-te1PBP showed a higher uptake in critical bone defect regions. Therefore, our study highlights the potential of [64Cu]CuII-te1PBP as a PET radiotracer for evaluating bone healing in preclinical and clinical settings with a diagnostic value similar to that of [18F]fluoride, albeit with a longer half-life (12.7 h) than 18F (1.8 h), thereby enabling extended observation times.

Effects of cytotoxic cis- and trans-diammine monochlorido platinum(II) complexes on selenium-dependent redox enzymes and DNA.

Here we present the preparation of 14 pairs of cis- and trans-diammine monochlorido platinum(II) complexes, coordinated to heterocycles (i.e., imidazole, 2-methylimidazole and pyrazole) and linked to various acylhydrazones, which were designed as potential inhibitors of the selenium-dependent enzymes glutathione peroxidase 1 (GPx-1) and thioredoxin reductase 1 (TrxR-1). However, no inhibition of bovine GPx-1 and only weak inhibition of murine TrxR-1 was observed in in vitro assays. Nonetheless, the cis configured diammine monochlorido Pt(II) complexes exhibited cytotoxic and apoptotic properties on various human cancer cell lines, whereas the trans configured complexes generally showed weaker potency with a few exceptions. On the other hand, the trans complexes were generally more likely to lack cross-resistance to cisplatin than the cis analogues. Platinum was found bound to the nuclear DNA of cancer cells treated with representative Pt complexes, suggesting that DNA might be a possible target. Thus, detailed in vitro binding experiments with DNA were conducted. Interactions of the compounds with calf thymus DNA were investigated, including Pt binding kinetics, circular dichroism (CD) spectral changes, changes in DNA melting temperatures, unwinding of supercoiled plasmids and ethidium bromide displacement in DNA. The CD results indicate that the most active cis configured pyrazole-derived complex causes unique structural changes in the DNA compared to the other complexes as well as to those caused by cisplatin, suggesting a denaturation of the DNA structure. This may be important for the antiproliferative activity of this compound in the cancer cells.

Platinum(II) carboxylato complexes containing 7-azaindoles as N-donor carrier ligands showed cytotoxicity against cancer cell lines.

The platinum(II) malonato (Mal) and decanoato (Dec) complexes of the general formulas [Pt(Mal)(naza)2] (1-3) and cis-[Pt(Dec)2(naza)2] (4-7) were prepared, characterized and tested for their in vitro cytotoxicity against cisplatin-sensitive (A2780) and cisplatin-resistant (A2780R) human ovarian carcinoma cell lines and non-cancerous human lung fibroblasts (MRC-5); naza=halogeno-derivatives of 7-azaindole. Complexes 1-7 effectively overcome the acquired resistance of ovarian carcinoma cells to cisplatin. Complexes 2 (IC50=26.6±8.9µM against A2780 and 28.9±6.7µM against A2780R), 4 (IC50=14.5±0.6µM against A2780 and 14.5±3.8µM against A2780R) and 5 (IC50=13.0±1.1µM against A2780 and 13.6±4.9µM against A2780R) indicated decreased toxicity against healthy MRC-5 cells (IC50>50.0µM for 2 and >25.0µM for 4 and 5). The representative complexes 2 and 4 showed mutually different effect on the A2780 cell cycle at IC50 concentrations after 24h exposure. Concretely, the complex 2 caused cell cycle arrest at G0/G1 phase, while 4 induced cell death by apoptosis with high population of cells in sub-G1 cell cycle phase. The hydrolysis and interactions of the selected complexes with biomolecules (glutathione (GSH) and guanosine monophosphate (GMP)) were also studied by means of 1H NMR and ESI+ mass spectra.