Viktoriya M. Alpatova

In this work meso -aryl-substituted BODIPYs (Ar = Ph, p -Br-C ₆ H ₄ , C ₆ F ₅ ) were used as starting compounds for modification of their boron atoms with carborane O -nucleophiles to afford novel boron-substituted carborane BODIPY derivatives. This type of reactions has not been used previously to prepare carborane structures. The reactions proceeded via the cleavage of boron–fluorine bonds in BODIPYs under the action of AlCl ₃ followed by the treatment with carborane O -nucleophiles such as 1-hydroxymethyl- o -carborane or 1,2-dihydroxymethyl- o -carborane. While reactions of meso -aryl-substituted BODIPYs with 1-hydroxymethyl- o -carborane proceeded selectively, forming mono- or dicarborane-substituted BODIPYs, the reactions of 1,2-bis(hydroxymethyl)- o -carborane were not selective yielding a mixture of products. The structures of novel compounds were confirmed by ¹ H and ¹¹ B NMR and mass spectrometry. The structures of some prepared carborane BODIPY compounds were further supported by their single X-ray crystal structures.

New carbon- and boron-substituted carborane isothiocyanates were obtained under neutral conditions and their reactivity towards N -nucleophiles was investigated.

The tetrapyrrolic macrocycle as a scaffold for various chemical modifications provides broad opportunities for the preparation of complex multifunctional conjugates suitable for binary antitumor therapies. Typically, illumination with monochromatic light triggers the photochemical generation of reactive oxygen species (ROS) (photodynamic effect). However, more therapeutically valuable effects can be achieved upon photoactivation of tetrapyrrole derivatives. Herein we report the novel porphyrin-based complexes of transition metals with isocyanide and carbonyl ligands. Synthesis of complexes presumed the use of 5-(p-isocyanophenyl)-10,15,20-triphenylporphyrin as a ligand in reactions with metal carbonyl complexes, M(CO)₆ (M = Cr, Mo, W), Re₂(CO)₁₀ and Re(CO)₅Cl. Based on these complexes and isocyanocarborane, the heteroleptic carbonyl complexes with porphyrin and carborane isocyanide ligands were prepared. In cell-free systems, the new compounds retained photochemical characteristics of the parental porphyrin derivative, such as triplet state formation and ROS generation, upon light-induced activation. In the cell culture, the carborane-containing derivatives demonstrated a more pronounced intracellular accumulation than their nonboronated counterparts. As expected, illumination at the Soret band (405 nm) of cells loaded with the new complexes caused photodynamic cell damage. In contrast, illumination at 530 nm instead initiated the release of carbon oxide (CO) followed by cell death independently of the photodynamic effect. Light-induced CO release was analyzed using second derivatives of UV-Vis spectra and our originally developed Spectrophotometric elimiNAtion of Photoinduced Side reactions (SNAPS) method. The yield of CO release decreased in the raw depending on metals in the carbonyl moiety: Mo ≥ Cr > W > Re ≥ Re₂. Overall, our novel metal carbonyl complexes with porphyrin and carborane isocyanide ligands emerge as potent bi-functional conjugates for combined photodynamic and photoinducible CO-releasing antitumor agents.

A carboranylporphyrin of A₃B-type bearing a single pentafluorophenyl ring was prepared through the regioselective nucleophilic aromatic substitution reaction of the p-fluorine atoms in 5,10,15,20-tetrakis(pentafluorophenyl)porphyrin with 9-mercapto-m-carborane. The reaction of this porphyrin with sodium azide led to the selective substitution of the p-fluorine atom in the pentafluorophenyl substituent with an azide functionality which upon reduction with SnCl₂ resulted in the formation of the corresponding porphyrin with an amino group. Pentafluorophenyl-substituted A₃B-porphyrins were studied and transformed to thiol and amino-substituted compounds allowing for the preparation of porphyrins with different reactive groups such as hydroxy and amino derivatives capable for further functionalization and conjugation of these porphyrins to other substrates. In addition, conjugates containing maleimide or biotin entities in the structure of carborane A₃B-porphyrin were also synthesized based on the amino-substituted A₃B-porphyrin. The structures of the prepared carboranylporphyrins were determined by UV–vis, IR, ¹H, ¹⁹F, ¹¹B NMR spectroscopic data and MALDI mass spectrometry.

Copper–organic compounds have gained momentum as potent antitumor drug candidates largely due to their ability to generate an oxidative burst upon the transition of Cu²⁺ to Cu¹⁺ triggered by the exogenous-reducing agents. We have reported the differential potencies of a series of Cu(II)–organic complexes that produce reactive oxygen species (ROS) and cell death after incubation with N-acetylcysteine (NAC). To get insight into the structural prerequisites for optimization of the organic ligands, we herein investigated the electrochemical properties and the cytotoxicity of Cu(II) complexes with pyridylmethylenethiohydantoins, pyridylbenzothiazole, pyridylbenzimidazole, thiosemicarbazones and porphyrins. We demonstrate that the ability of the complexes to kill cells in combination with NAC is determined by the potential of the Cu⁺² → Cu⁺¹ redox transition rather than by the spatial structure of the organic ligand. For cell sensitization to the copper–organic complex, the electrochemical potential of the metal reduction should be lower than the oxidation potential of the reducing agent. Generally, the structural optimization of copper–organic complexes for combinations with the reducing agents should include uncharged organic ligands that carry hard electronegative inorganic moieties.

2,4,6-Trichloro-1,3,5-triazine (cyanuric chloride) is an excellent coupling reagent for the preparation of highly structured multifunctional molecules. Three component systems based on porphyrin, cyanuric chloride and carborane clusters were prepared by a one-pot stepwise amination of cyanuric chloride with 5-(4-aminophenyl)-10,15,20-triphenylporphyrin, followed by replacement of the remaining chlorine atoms with carborane S- or N-nucleophiles. Some variants of 1,3,5-triazine derivatives containing porphyrin, carborane and residues of biologically active compounds such as maleimide, glycine methyl ester as well as thioglycolic acid, mercaptoethanol and hexafluoroisopropanol were also prepared. A careful control of the reaction temperature during the substitution reactions will allow the synthesis of desired compounds in a good to high yields. The structures of synthesized compounds were determined with UV-vis, IR, ¹H NMR, ¹¹B NMR, MALDI-TOF or LC-MS spectroscopic data. The dark and photocytotoxicity as well as intracellular localization and photoinduced cell death for compounds 8, 9, 17, 18 and 24 were evaluated.

Triton B-catalyzed Michael reaction as a green chemistry process was used for the functionalization of carbon- and boron-substituted carboranes with α,β-unsaturated nitriles and esters.

Copper-containing agents are promising antitumor pharmaceuticals due to the ability of the metal ion to react with biomolecules. In the current study, we demonstrate that inorganic Cu²⁺ in the form of oxide nanoparticles (NPs) or salts, as well as Cu ions in the context of organic complexes (oxidation states +1, +1.5 and +2), acquire significant cytotoxic potency (2–3 orders of magnitude determined by IC₅₀ values) in combinations with N-acetylcysteine (NAC), cysteine, or ascorbate. In contrast, other divalent cations (Zn, Fe, Mo, and Co) evoked no cytotoxicity with these combinations. CuO NPs (0.1–1 µg/mL) together with 1 mM NAC triggered the formation of reactive oxygen species (ROS) within 2–6 h concomitantly with perturbation of the plasma membrane and caspase-independent cell death. Furthermore, NAC potently sensitized HCT116 colon carcinoma cells to Cu–organic complexes in which the metal ion coordinated with 5-(2-pyridylmethylene)-2-methylthio-imidazol-4-one or was present in the coordination sphere of the porphyrin macrocycle. The sensitization effect was detectable in a panel of mammalian tumor cell lines including the sublines with the determinants of chemotherapeutic drug resistance. The components of the combination were non-toxic if added separately. Electrochemical studies revealed that Cu cations underwent a stepwise reduction in the presence of NAC or ascorbate. This mechanism explains differential efficacy of individual Cu–organic compounds in cell sensitization depending on the availability of Cu ions for reduction. In the presence of oxygen, Cu⁺¹ complexes can generate a superoxide anion in a Fenton-like reaction Cu⁺¹L + O₂ → O₂^−. + Cu⁺²L, where L is the organic ligand. Studies on artificial lipid membranes showed that NAC interacted with negatively charged phospholipids, an effect that can facilitate the penetration of CuO NPs across the membranes. Thus, electrochemical modification of Cu ions and subsequent ROS generation, as well as direct interaction with membranes, represent the mechanisms of irreversible membrane damage and cell death in response to metal reduction in inorganic and organic Cu-containing compounds.

Carborane maleimides were prepared in good yields through the thermal cyclization of maleamic acids prepared by the reaction of 3-amino-o-carborane with maleic or 3-bromomaleic anhydrides, respectively. The selective reactivity of synthesized maleimides towards S-nucleophiles was demonstrated. As a result a series of boronated thiosuccinimide- or thiomaleimide-substituted compounds including boron rich ones was obtained and fully characterized. Furthermore the opportunity of variation with substitution patterns may lead to the development of potential candidates for biological applications or the development of new materials.

The present review highlights the state-of-the-art in the synthesis of carborane derivatives of meso-arylporphyrins/chlorins and dipyrromethenes (BODIPY) for the application in photodynamic and boron neutron capture therapies of cancer. The main methods for the functionalization of porphyrins/chlorins and BODIPYs by boron polyhedra and the approaches to optimization of the properties of these compounds as antitumor agents are considered. The results of investigations on the photophysical and biological properties of carboranyl-containing porphyrins/chlorins and BODIPYs are presented.