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1.
Chirality ; 35(12): 937-951, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37461229

RESUMO

Derivatives of the nido-7,8-C2 B9 H12 (1-) (dicarbollide ion) and [3,3'-Co-(1,2-C2 B9 H11 )2 ](1-) cobalt sandwich (COSAN) ion represent groups of extremely chemically and thermally stable abiotic compounds. They are being investigated in many research areas, that is, medicinal chemistry, material sciences, analytical chemistry, and electrochemistry. The chirality of these compounds remains still grossly overlooked, what is also reflected in limited number of reports on their chiral separations. Continued progress depends on reliable, fast, and cost-effective methods for such separations. Recently, chiral separations of COSAN derivatives were achieved in liquid chromatography and supercritical fluid chromatography. Only five anionic derivatives of nido-7,8-C2 B9 H12 (1-) were successfully enantioseparated in liquid chromatography. Efforts to separate anionic nido-7,8-C2 B9 H12 (1-) in supercritical chromatography have failed, and only a few dicarbollide ions were separated using liquid chromatography. Generally, all chiral separations in liquid chromatography took about 30 min. Herein, we identify a versatile column capable of separating both COSAN and nido-7,8-C2 B9 H12 (1-) derivatives and achieve faster analyses times employing commercially available superficially porous chiral stationary phases. The semisynthetic hydroxypropyl ß-cyclodextrin-based column (CDShell-RSP) is identified as the column of choice from the tested columns by separating 19 of 27 compounds from each structural motifs tested mainly in less than 10 min. The dihydroxyalkyl, oxygen-bridged hydroxyalkyl, and bisphenylene-bridged COSAN derivatives were baseline separated in less than 5 min exceeding the results of supercritical fluid chromatography. Methods developed herein will aid synthetic chemists without the possession of a supercritical fluid chromatograph to achieve fast chiral separations of COSAN and derivatives of nido-7,8-C2 B9 H12 (1-) on a common liquid chromatograph without the need of dedicated instrumentation.

2.
RSC Adv ; 13(28): 19627-19637, 2023 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-37388141

RESUMO

Borane and heteroborane clusters have been known as neutral or anionic species. In contrast to them, several ten-vertex monocationic nido and closo dicarbaborane-based systems have recently emerged from the reaction of the parent bicapped-square antiprismatic dicarbaboranes with N-heterocyclic carbenes followed by the protonization of the corresponding nido intermediates. The expansion of these efforts has afforded the very first closo-dicationic octahedral phosphahexaborane along with new closo-monocationic pnictogenahexaboranes of the same shapes. All are the products of the one-pot procedure that consists in the reaction of the same carbenes with the parent closo-1,2-Pn2B4Br4 (Pn = As, P). Whereas in the case of phosphorus such a monocation appears to be a mixture of stable intermediates, and arsenahexaboranyl monocation has occurred as the final product, all of them without using any subsequent reaction. The well-established DFT/ZORA/NMR approach has unambiguously confirmed the existence of these species in solution, and computed electrostatic potentials have revealed the delocalization of the positive charge in these monocations and in the very first dication, namely within the octahedral shapes in both cases.

3.
ACS Omega ; 8(15): 13993-14004, 2023 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-37091389

RESUMO

Mössbauer and X-ray photoelectron spectroscopies (XPS) are complemented with high-level quantum-chemical computations in the study of the geometric and electronic structure of the paramagnetic salt of the metallacarborane sandwich complex [Fe(1,2-C2B9H11)2]Cs = FeSanCs. Experimental 57Fe isomer shifts and quadrupole splitting parameters are compared with the theoretical prediction, with good agreement. The appearance of two sets of Cs(3d) doublets in the XPS spectrum, separated by 2 eV, indicates that Cs has two different chemical environments due to ease of the Cs(+) cation moving around the sandwich complex with low-energy barriers, as confirmed by quantum-chemical computations. Several minimum-energy geometries of the FeSanCs structure with the corresponding energies and Mössbauer parameters are discussed, in particular the atomic charges and spin population and the surroundings of the Fe atom in the complex. The Mössbauer spectra were taken at different temperatures showing the presence of a low-spin Fe atom with S = 1/2 and thus confirming a paramagnetic FeIII species.

4.
Molecules ; 28(8)2023 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-37110879

RESUMO

Modern computational protocols based on the density functional theory (DFT) infer that polyhedral closo ten-vertex carboranes are key starting stationary states in obtaining ten-vertex cationic carboranes. The rearrangement of the bicapped square polyhedra into decaborane-like shapes with open hexagons in boat conformations is caused by attacks of N-heterocyclic carbenes (NHCs) on the closo motifs. Single-point computations on the stationary points found during computational examinations of the reaction pathways have clearly shown that taking the "experimental" NHCs into account requires the use of dispersion correction. Further examination has revealed that for the purposes of the description of reaction pathways in their entirety, i.e., together with all transition states and intermediates, a simplified model of NHCs is sufficient. Many of such transition states resemble in their shapes those that dictate Z-rearrangement among various isomers of closo ten-vertex carboranes. Computational results are in very good agreement with the experimental findings obtained earlier.

5.
Phys Chem Chem Phys ; 25(3): 1728-1733, 2023 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-36594655

RESUMO

Among non-covalent interactions, B-H⋯π and C-H⋯π hydrogen bonding is rather weak and less studied. Nevertheless, since both can affect the energetics of protein-ligand binding, their understanding is an important prerequisite for reliable predictions of affinities. Through a combination of high-resolution X-ray crystallography and quantum-chemical calculations on carbonic anhydrase II/carborane-based inhibitor systems, this paper provides the first example of B-H⋯π hydrogen bonding in a protein-ligand complex. It shows that the B-H⋯π interaction is stabilized by dispersion, followed by electrostatics. Furthermore, it demonstrates that the similar C-H⋯π interaction is twice as strong, with a slightly smaller contribution of dispersion and a slightly higher contribution of electrostatics. Such a detailed insight will facilitate the rational design of future protein ligands, controlling these types of non-covalent interactions.


Assuntos
Anidrase Carbônica II , Sulfonamidas , Ligantes , Sulfanilamida , Cristalografia por Raios X
6.
J Comput Chem ; 44(3): 256-260, 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-35612818

RESUMO

Closo-carborane anions are prominent, whereas the cations of the same are less abundant in the literature. As these ions have similar size and are weakly coordinating, the ionic liquids of these two ions could have important applications in many areas of chemistry. In view of limited number of polyhedral carborane cations available, we revisited the rearrangement of dicarboranyl methyl cation (7-CH2 7,9-nido-C2 B9 H10 + ) using ab initio molecular dynamics calculations with metadynamics. Our simulations confirmed the concerted mechanism of the rearrangement. We believe this work will resume the interest in its synthesis and carborane cations in general.

7.
J Chromatogr A ; 1672: 463051, 2022 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-35468566

RESUMO

The aspect of the different spatial arrangement of anionic cobalt bis(dicarbollides) and dicarba-nido-undecaboranes remains grossly overlooked despite increased scientific interest. Regarding their growing potential, which does not limit only to medicinal chemistry, suitable enantioseparation methods are needed. The presented paper explores the possibilities of chiral separations of anionic cobalt bis(dicarbollide) and dicarba-7,8-nido-undecaborane derivatives on four polysaccharide-based columns under reversed-phase conditions. The chromatographic behavior of anionic derivatives was evaluated and compared with that of zwitterionic clusters. The isocratic procedure for HPLC method development was suggested. The main parameters for the optimization of separations were described. Successful chiral separations were critically compared to previously reported results in normal phase and polar-organic mode. Reversed-phase separations are superior in resolution, lower consumption of organic solvents, and flexibility during the method development. Moreover, the first chiral discrimination of some hydroxyalkyl derivatives of anionic cobalt bis(dicarbollides) is reported. The outcomes of this work may be used for method development in any area, where the chirality of these interesting molecules is of concern.


Assuntos
Cromatografia de Fase Reversa , Polissacarídeos , Ânions , Cromatografia Líquida de Alta Pressão/métodos , Cobalto , Polissacarídeos/química , Estereoisomerismo
8.
Rev Cardiovasc Med ; 23(6): 210, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-39077194

RESUMO

Acute myocardial infarction is a manifestation of atherosclerosis which may be fatal. In-hospital and short-term mortality rates after an acute myocardial infarction have declined in the past few decades. However, although long-term mortality has decreased, it remains unacceptably high. This review paper summarises the non-pharmacological interventions (smoking cessation, physical activity, nutrition, and psychosocial intervention) and pharmacological approaches (antiplatelet and lipid-lowering therapy, renin-angiotensin-aldosterone system inhibitors, beta-blockers, and glucose-lowering drugs) to secondary prevention after a myocardial infarction. The provision of secondary prevention services is established through cardiac rehabilitation, which consists of several discussed components. Finally, we discuss the quality indicators for long-term care after an acute myocardial infarction.

9.
Nat Commun ; 12(1): 4971, 2021 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-34404809

RESUMO

Polyhedral boranes and heteroboranes appear almost exclusively as neutral or anionic species, while the cationic ones are protonated at exoskeletal heteroatoms or they are instable. Here we report the reactivity of 10-vertex closo-dicarbadecaboranes with one or two equivalents of N-heterocyclic carbene to 10-vertex nido mono- and/or bis-carbene adducts, respectively. These complexes easily undergo a reaction with HCl to give cages of stable and water soluble 10-vertex nido-type cations with protonation in the form of a BHB bridge or 10-vertex closo-type cations containing one carbene ligand when originating from closo-1,10-dicarbadecaborane. The reaction of a 10-vertex nido mono-carbene adduct with phosphorus trichloride gives nido-11-vertex 2-phospha-7,8-dicarbaundecaborane, which undergoes an oxidation of the phosphorus atom to P = O, while the product of a bis-carbene adduct reaction is best described as a distorted C2B6H8 fragment bridged by the (BH)2PCl2+ moiety.

10.
Inorg Chem ; 60(12): 8428-8431, 2021 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-34101456

RESUMO

The electrophilic substitution of icosahedral closo-1-SB11H11 with methyl iodide has resulted in two B-functionalized thiaboranes, 7,12-I2-2,3,4,5,6,8,9,10,11-(CH3)9-1-closo-SB11 and 7,8,12-I3-2,3,4,5,6,9,10,11-(CH3)8-closo-1-SB11, with the former being significantly predominant. These two icosahedral thiaboranes are the first cases of polysubstituted polyhedral boron clusters with another vertex that differs from B and C. Such polyfunctionalizations have increased the earlier observed thiaborane icosahedral barrier, not exhibiting any reactivity toward bases, unlike the parent thiaborane. The search for methylation pathways has revealed that the complete B11-methylation is impossible, like in the case of decaborane(14), where this seems to be a result of the positively charged upper parts of these two molecules.

11.
Chembiochem ; 22(18): 2741-2761, 2021 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-33939874

RESUMO

This review describes recent progress in the design and development of inhibitors of human carbonic anhydrase IX (CA IX) based on space-filling carborane and cobalt bis(dicarbollide) clusters. CA IX enzyme is known to play a crucial role in cancer cell proliferation and metastases. The new class of potent and selective CA IX inhibitors combines the structural motif of a bulky inorganic cluster with an alkylsulfamido or alkylsulfonamido anchor group for Zn2+ ion in the enzyme active site. Detailed structure-activity relationship (SAR) studies of a large series containing 50 compounds uncovered structural features of the cluster-containing inhibitors that are important for efficient and selective inhibition of CA IX activity. Preclinical evaluation of selected compounds revealed low toxicity, favorable pharmacokinetics and ability to reduce tumor growth. Cluster-containing inhibitors of CA IX can thus be considered as promising candidates for drug development and/or for combination therapy in boron neutron capture therapy (BNCT).


Assuntos
Compostos de Boro/química , Anidrase Carbônica IX/antagonistas & inibidores , Inibidores da Anidrase Carbônica/química , Sítios de Ligação , Compostos de Boro/metabolismo , Compostos de Boro/uso terapêutico , Anidrase Carbônica IX/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/metabolismo , Inibidores da Anidrase Carbônica/uso terapêutico , Humanos , Simulação de Dinâmica Molecular , Neoplasias/tratamento farmacológico , Compostos Organometálicos/química , Relação Estrutura-Atividade , Sulfonamidas/química
12.
Dalton Trans ; 50(35): 12098-12106, 2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-33656022

RESUMO

Reported herein are mutual rearrangements in the whole series of seven bicapped-square antiprismatic closo-C2B8H10 by means of high-quality computations that disprove the earlier postulated dsd (diamond-square-diamond) scheme for these isomerizations. The experimentally existing closo-1,2-C2B8H10 was able to be converted to 1,6-, and 1,10-isomers by pyrolysis, and the dsd (diamond-square-diamond) mechanism was offered as an explanation of these processes. However, these computations disprove the postulated dsd scheme for these isomerizations that take place in the ten-vertex closo series. Experimentally observed thermal rearrangements, both in the parent and substituted closo-1,2-C2B8H10, closo-1-CB9H10-, and closo-B10H102-, indirectly support these refined computations. All these processes are based on the new concept of the so-called Z-mechanism, being consistent with a transition state of a boat shape with an open hexagonal belt that results from the initial breakage of three bonds. Such bond breakings and the consequent bond formations bring to mind the shape of the letter Z. In effect, the pattern of multicenter bonding shifts from reactant through a transition state to product. The molecular rearrangements that are available experimentally favour either the axial or equatorial isomers, and this ratio depends on temperature and the type of cluster and its substitution.

13.
Electrophoresis ; 42(7-8): 910-919, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33405254

RESUMO

Capillary electrophoresis (CE) has been applied for determination of the thermodynamic acidity constants (pKa ) of the sulfamidoalkyl and sulfonamidoalkyl groups, the actual and limiting ionic mobilities and hydrodynamic radii of important compounds, eight carborane-based inhibitors of carbonic anhydrases, which are potential new anticancer drugs. Two types of carboranes were investigated, (i) icosahedral cobalt bis(dicarbollide)(1-) ion with sulfamidoalkyl moieties, and (ii) 7,8-nido-dicarbaundecaborate with sulfonamidoalkyl side chains. First, the mixed acidity constants, pKamix , of the sulfamidoalkyl and sulfonamidoalkyl groups of the above carboranes and their actual ionic mobilities were determined by nonlinear regression analysis of the pH dependences of their effective electrophoretic mobility measured by capillary electrophoresis in the pH range 8.00-12.25, at constant ionic strength (25 mM), and constant temperature (25°C). Second, the pKamix were recalculated to the thermodynamic pKa s using the Debye-Hückel theory. The sulfamidoalkyl and sulfonamidoalkyl groups were found to be very weakly acidic with the pKa s in the range 10.78-11.45 depending on the type of carborane cluster and on the position and length of the alkyl chain on the carborane scaffold. These pKa s were in a good agreement with the pKa s (10.67-11.27) obtained by new program AnglerFish (freeware at https://echmet.natur.cuni.cz), which provides thermodynamic pKa s and limiting ionic mobilities directly from the raw CE data. The absolute values of the limiting ionic mobilities of univalent and divalent carborane anions were in the range 18.3-27.8 TU (Tiselius unit, 1 × 10-9 m2 /Vs), and 36.4-45.9 TU, respectively. The Stokes hydrodynamic radii of univalent and divalent carborane anions varied in the range 0.34-0.52 and 0.42-0.52 nm, respectively.


Assuntos
Anidrases Carbônicas , Hidrodinâmica , Ácidos , Eletroforese Capilar , Concentração de Íons de Hidrogênio , Íons
14.
Chempluschem ; 86(3): 352-363, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32955786

RESUMO

Carbonic anhydrase IX (CAIX) is an enzyme expressed on the surface of cells in hypoxic tumors. It plays a role in regulation of tumor pH and promotes thus tumor cell survival and occurrence of metastases. Here, derivatives of the cobalt bis(dicarbollide)(1-) anion are reported that are based on substitution at the carbon sites of the polyhedra by two alkylsulfonamide groups differing in the length of the aliphatic connector (from C1 to C4, n=1-4), which were prepared by cobalt insertion into the 7-sulfonamidoalkyl-7,8-dicarba-nido-undecaborate ions. Pure meso- and rac-diastereoisomeric forms were isolated. The series is complemented with monosubstituted species (n=2). Synthesis by a direct method furnished similar derivatives (n=2, 3), which are chlorinated at the B(8,8') boron sites. All compounds inhibited CAIX with subnanomolar inhibition constants and showed high selectivity for CAIX. The best inhibitory properties were observed for the compound with n= 3 and two substituents present in rac-arrangement with Ki =20 pM and a selectivity index of 668. X-ray crystallography was used to study interactions of these compounds with the active site of CAIX on the structural level.


Assuntos
Anidrase Carbônica IX/antagonistas & inibidores , Inibidores da Anidrase Carbônica/química , Cobalto/química , Complexos de Coordenação/química , Sulfonamidas/química , Sítios de Ligação , Anidrase Carbônica IX/metabolismo , Inibidores da Anidrase Carbônica/metabolismo , Inibidores da Anidrase Carbônica/uso terapêutico , Domínio Catalítico , Complexos de Coordenação/metabolismo , Complexos de Coordenação/uso terapêutico , Cristalografia por Raios X , Humanos , Conformação Molecular , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Neoplasias/patologia
15.
Chempluschem ; 86(3): 351, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33369232

RESUMO

Invited for this month's cover is a collaboration from three institutes from the Czech Academy of Sciences: Institute of Inorganic Chemistry, Institute of Organic Chemistry and Biochemistry, and Institute of Molecular Genetics, and the University of Pardubice. The cover picture shows a family of potent and selective CA IX inhibitors that combines the structural motif of a bulky inorganic cobalt bis(dicarbollide) polyhedral ion with a propylsulfonamido anchor group. Read the full text of the article at 10.1002/cplu.202000574.


Assuntos
Inibidores da Anidrase Carbônica , Neoplasias , Anidrase Carbônica IX , Cobalto , Humanos
16.
Chempluschem ; 85(12): 2606-2610, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33029907

RESUMO

9-Br-closo-1,2-C2 B10 H11 has been prepared and its gas-phase structure has been examined by means of gas electron diffraction. The structure of the carbaborane core is similar to the structure of the parent compound, which is of C2v symmetry. A DFT-based search for the corresponding reaction pathway of the bromination of closo-1,2-C2 B10 H12 revealed that the catalytic amount of aluminum reduces the barrier of the initial attack of the bromination agent toward the negatively charged part of the icosahedral carbaborane, i. e., the first transition state, from about 40 to about 27 kcalmol-1 . The Br-Br bond is weakened by an intermediate binding to the large π-hole on the aluminum atom of AlBr3 , which is the driving force for the AlBr3 -catalyzed bromination.

17.
J Enzyme Inhib Med Chem ; 35(1): 1800-1810, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32962427

RESUMO

Human carbonic anhydrase IX (CA IX), a protein specifically expressed on the surface of solid tumour cells, represents a validated target both for anticancer therapy and diagnostics. We recently identified sulfonamide dicarbaboranes as promising inhibitors of CA IX with favourable activities both in vitro and in vivo. To explain their selectivity and potency, we performed detailed X-ray structural analysis of their interactions within the active sites of CA IX and CA II. Series of compounds bearing various aliphatic linkers between the dicarbaborane cluster and sulfonamide group were examined. Preferential binding towards the hydrophobic part of the active site cavity was observed. Selectivity towards CA IX lies in the shape complementarity of the dicarbaborane cluster with a specific CA IX hydrophobic patch containing V131 residue. The bulky side chain of F131 residue in CA II alters the shape of the catalytic cavity, disrupting favourable interactions of the spherical dicarbaborane cluster.


Assuntos
Antineoplásicos/química , Compostos de Boro/química , Anidrase Carbônica IX/antagonistas & inibidores , Inibidores da Anidrase Carbônica/química , Sulfonamidas/química , Sequência de Aminoácidos , Antígenos de Neoplasias/genética , Antineoplásicos/farmacologia , Anidrase Carbônica IX/genética , Inibidores da Anidrase Carbônica/farmacologia , Domínio Catalítico , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Células HEK293 , Humanos , Interações Hidrofóbicas e Hidrofílicas , Ligação Proteica , Relação Estrutura-Atividade , Sulfonamidas/farmacologia
18.
Chemistry ; 26(69): 16541-16553, 2020 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-32757220

RESUMO

Carbonic anhydrase IX (CA IX), a tumor-associated metalloenzyme, represents a validated target for cancer therapy and diagnostics. Herein, we report the inhibition properties of isomeric families of sulfonamidopropyl-dicarba-closo-dodecaboranes group(s) prepared using a new direct five-step synthesis from the corresponding parent cages. The protocol offers a reliable solution for synthesis of singly and doubly substituted dicarba-closo-dodecaboranes with a different geometric position of carbon atoms. The closo-compounds from the ortho- and meta-series were then degraded to corresponding 11-vertex dicarba-nido-undecaborate(1-) anions. All compounds show in vitro enzymatic activity against CA IX in the low nanomolar or subnanomolar range. This is accompanied by clear isomer dependence of the inhibition constant (Ki ) and selectivity towards CA IX. Decreasing trends in Ki and selectivity index (SI ) values are observed with increasing separation of the cage carbon atoms. Interactions of compounds with the active sites of CA IX were explored with X-ray crystallography, and eight high-resolution crystal structures uncovered the structural basis of inhibition potency and selectivity.


Assuntos
Antígenos de Neoplasias/química , Anidrase Carbônica IX/química , Anidrase Carbônica I/química , Inibidores da Anidrase Carbônica , Neoplasias , Antígenos de Neoplasias/metabolismo , Anidrase Carbônica I/metabolismo , Anidrase Carbônica IX/metabolismo , Inibidores da Anidrase Carbônica/farmacologia , Humanos , Isoenzimas , Relação Estrutura-Atividade
19.
Inorg Chem ; 59(15): 10540-10547, 2020 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-32662985

RESUMO

The paper reports specific syntheses of methylated decaborane(14), nido-B10H14 (1), derivatives. The reaction of 1 with an excess of neat MeI and AlCl3 yields 1,2,3,4-Me4-nido-B10H10 (2) essentially quantitatively when performed at room temperature. Heating the same mixture to 120 °C provides 1-I-2,3,4,5,7,8,10-Me7-nido-B10H6 (3a). The formation of analogous 1-CF3SO2O-2,3,4,5,7,8,10-Me7-nido-B10H6 (3b) is achieved by heating 1 or 2 with an excess of MeSO3CF3 in the presence of a catalytic amount of HOSO2CF3 to 120 °C. Compounds 2 and 3 can be deprotonated to yield the corresponding anions [1,2,3,4-Me4-nido-B10H9]- (2-), [1-I-2,3,4,5,7,8,10-Me7-nido-B10H5]- (3a-), and [1-CF3SO2O-2,3,4,5,7,8,10-Me7-nido-B10H5]- (3b-). The structure of all the compounds isolated has been unambiguously confirmed by multinuclear (11B and 1H) NMR measurements, and the structures of 2-, 3a, 3a-, and 3b have been established by X-ray diffraction analyses. The very high volatility of 2 has made it impossible to apply X-ray diffraction in this case; therefore, its structure has been derived computationally using the ab initio/GIAO/NMR tool. DFT-based computational protocols have also outlined the reason why it is impossible to obtain an octamethyl derivative of 1 experimentally.

20.
Eur J Med Chem ; 200: 112460, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32505851

RESUMO

Carbonic anhydrase IX (CA IX) is a transmembrane enzyme overexpressed in hypoxic tumors, where it plays an important role in tumor progression. Specific CA IX inhibitors potentially could serve as anti-cancer drugs. We designed a series of sulfonamide inhibitors containing carborane clusters based on prior structural knowledge of carborane binding into the enzyme active site. Two types of carborane clusters, 12-vertex dicarba-closo-dodecaborane and 11-vertex 7,8-dicarba-nido-undecaborate (dicarbollide), were connected to a sulfonamide moiety via aliphatic linkers of varying lengths (1-4 carbon atoms; n = 1-4). In vitro testing of CA inhibitory potencies revealed that the optimal linker length for selective inhibition of CA IX was n = 3. A 1-sulfamidopropyl-1,2-dicarba-closo-dodecaborane (3) emerged as the strongest CA IX inhibitor from this series, with a Ki value of 0.5 nM and roughly 1230-fold selectivity towards CA IX over CA II. X-ray studies of 3 yielded structural insights into their binding modes within the CA IX active site. Compound 3 exhibited moderate cytotoxicity against cancer cell lines and primary cell lines in 2D cultures. Cytotoxicity towards multicellular spheroids was also observed. Moreover, 3 significantly lowered the amount of CA IX on the cell surface both in 2D cultures and spheroids and facilitated penetration of doxorubicin. Although 3 had only a moderate effect on tumor size in mice, we observed favorable ADME properties and pharmacokinetics in mice, and preferential presence in brain over serum.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Anidrase Carbônica IX/antagonistas & inibidores , Inibidores da Anidrase Carbônica/farmacologia , Sulfonamidas/farmacologia , Animais , Antígenos de Neoplasias/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Neoplasias da Mama/metabolismo , Anidrase Carbônica IX/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Cães , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
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