Thiocyanation of closo-dodecaborate B(12)H(12)(2-). A novel synthetic route and theoretical elucidation of the reaction mechanism.

Although vast experimental experience has been accumulated about the reactions of icosahedral B(12)H(12)(2-) borane cages, little is known about the mechanisms by which these reactions proceed. To address this issue, we have chosen the thiocyanation of B(12)H(12)(2-) and have studied this reaction using both experimental and theoretical methods. First, we present a novel and more convenient synthetic route using in situ generated thiocyanogen, (SCN)(2). The synthesized disubstituted product B(12)H(10)(SCN)(2)(2-) is exclusively the meta positional isomer, as confirmed by the X-ray crystallographic analysis. The quantum chemical calculations at the B3LYP/def2-TZVP//RI-PBE/def2-SVP level show that the free energy differences between the ortho, meta, and para disubstituted species are very small and as such cannot explain the observed positional preferences. The calculations of the kinetic aspects reveal that the reaction is best described as an electrophilic substitution. The calculated isomer preferences for the second SCN substituent are meta > para > ortho. The major outcome of this work is a clear and consistent picture of the electrophilic substitution reaction mechanism of the thiocyanation of B(12)H(12)(2-), thus contributing to our understanding of the general features of boron hydride reactivity.

Design of HIV protease inhibitors based on inorganic polyhedral metallacarboranes.

HIV protease (HIV PR) is a primary target for anti-HIV drug design. We have previously identified and characterized substituted metallacarboranes as a new class of HIV protease inhibitors. In a structure-guided drug design effort, we connected the two cobalt bis(dicarbollide) clusters with a linker to substituted ammonium group and obtained a set of compounds based on a lead formula [H(2)N-(8-(C(2)H(4)O)(2)-1,2-C(2)B(9)H(10))(1',2'-C(2)B(9)H(11))-3,3'-Co)(2)]Na. We explored inhibition properties of these compounds with various substitutions, determined the HIV PR:inhibitor crystal structure, and computationally explored the conformational space of the linker. Our results prove the capacity of linker-substituted dual-cage cobalt bis(dicarbollides) as lead compounds for design of more potent inhibitors of HIV PR.

Boron(8) substituted nitrilium and ammonium derivatives, versatile cobalt bis(1,2-dicarbollide) building blocks for synthetic purposes.

The reaction of the cobalt bis(dicarbollide)(1-)() ion in the presence of t-butylbromide, acting as a potent Lewis acid activator, leads to the clean substitution of by the N-atom of acetonitrile (or benzonitrile), thus resulting in the smooth formation of [(8-RCN)-1,2-C(2)B(9)H(10))(1',2'-C(2)B(9)H(11))-3,3'-Co(iii)](0) (R = CH(3) or C(6)H(5)) ( and ). These compounds can serve as versatile precursors for the generation of a variety of other synthetically useful functional groups. The nitrogen atom of the nitrile C[triple bond, length as m-dash]N- bond in and is prone to the facile addition of nucleophiles. Thus, alkaline hydrolysis of and in aqueous alcohols furnishes high yields of the corresponding B(8)-N-alkylamides [(8-RC(O)=NH)-1,2-C(2)B(9)H(10))(1',2'-C(2)B(9)H(11))-3,3'-Co(iii)](-), where R = CH(3) or C(6)H(5) ( and ). The reactions with butyl and diethyl amine result in the high-yield formation of 8-alkylamidine derivatives [(8-(3)R(2)RNH-(1)RC[double bond, length as m-dash]N)-1,2-C(2)B(9)H(10))(1',2'-C(2)B(9)H(11))-3,3'-Co(iii)](0), where (1)R = CH(3), (2)R = H, (3)R = C(4)H(9), (), (1)R = C(6)H(5), (2)R = (3)R = C(2)H(5) () or (1)R = C(6)H(5), (2)R = (3)R = C(2)H(5) (). Hydrazinolysis of provides a high yield of the zwitterionic [(8-H(3)N)-1,2-C(2)B(9)H(10))(1',2'-C(2)B(9)H(11))-3,3'-Co(iii)](0) (), whereas reduction of the nitrile group in and using BH(3).SMe(2) affords the respective alkylammonium derivatives [(8-RH(2)N)-1,2-C(2)B(9)H(10))(1',2'-C(2)B(9)H(11))-3,3'-Co(iii)](0), where R = -C(2)H(5) () or -CH(2)C(6)H(5) () in moderate yields. Compound can also be prepared by alkylation of along with dibenzylderivative (). A further example of alkylation is the ring cleavage of the 3-hydroxypropanesulfonic acid gamma-sultone producing a compound with alkyl ammonium sulfonic acid substitution [(8-O(3)SC(3)H(6)NH(2))-1,2-C(2)B(9)H(10))(1',2'-C(2)B(9)H(11))-3,3'-Co(iii)](-) () All new compounds were characterized by multinuclear NMR spectroscopy and mass spectrometry and the structures of compounds , , and were established by X-ray crystallography.

Inorganic polyhedral metallacarborane inhibitors of HIV protease: a new approach to overcoming antiviral resistance.

HIV protease (PR) is a prime target for rational anti-HIV drug design. We have previously identified icosahedral metallacarboranes as a novel class of nonpeptidic protease inhibitors. Now we show that substituted metallacarboranes are potent and specific competitive inhibitors of drug-resistant HIV PRs prepared either by site-directed mutagenesis or cloned from HIV-positive patients. Molecular modeling explains the inhibition profile of metallacarboranes by their unconventional binding mode.

Dimethylsulfide-dicarbaborane chemistry. Isolation and characterisation of isomers [9-(SMe2)-nido-7,8-C2B9H10-X-Me] (where X = 1, 2, 3 and 4) and some related compounds. An unusual skeletal rearrangement.

Oxidative coupling by FeCl(3) of the [nido-7,8-C(2)B(9)H(11)-9-Me](-) anion 1a with SMe(2) yields a mixture of four isomers of 9-(SMe(2))-nido-7,8-C(2)B(9)H(10)-X-Me, where X = 1, 2, 3 and 4 (compounds 2a, 2b, 2c and 2d respectively). On high dilution of the reaction mixture, the 9-(SMe(2))-nido-7,8-C(2)B(9)H(10)-10-Me 2e isomer is also isolated in a low yield. The isomers are separated by HPLC, and are identified and characterised by NMR spectroscopy and by single-crystal X-ray diffraction analyses of 2c and 2d. The formation of the products implies an unexpected cluster rearrangement, which is discussed in terms of dsd and vertex-flip reaction pathways. Two additional isomers, 9-(SMe(2))-nido-7,8-C(2)B(9)H(10)-5-Me 2f and 9-(SMe(2))-nido-7,8-C(2)B(9)H(10)-6-Me 2g occur when [nido-7,8-C(2)B(9)H(11)-5-Me](-) 1b is used as the starting substrate, in a reaction in which no cluster rerarrangement is observed. The corresponding bromide, [nido-7,8-C(2)B(9)H(11)-5-Br](-) 1c, behaves similarly, forming only 9-(SMe(2))-nido-7,8-C(2)B(9)H(10)-5-Br 2h and 9-(SMe(2))-nido-7,8-C(2)B(9)H(10)-6-Br 2i.

The [2,5,12-C3B8H15]- anion, the first representative of the eleven-vertex hypho family of tricarbaboranes.

In one synthetic step from the readily available 9-Me(2)SCH(2)-nido-7,8-C(2)B(9)H(11) (compound 1), the first representative of the eleven-vertex hypho family of tricarbaboranes, [2,5,12-C(3)B(8)H(15)][X] (X=[NMe4]+ or [PPh4]+) (compound 2), has been isolated in 32% yield and structurally characterised by single-crystal X-ray diffraction, multi-nuclear NMR spectroscopy, mass spectrometry, and computational methods. Both [NMe4]+ or [PPh4]+ salts of anion 2 were found to undergo degradative conversion to the [hypho-6,7-C(2)B(6)H(13)]- anion (anion 3) in alkaline medium. The [PPh4]+ salt of anion 2 converted quantitatively to the [6-CH3-arachno-5,10-C(2)B(8)H(12)]- anion (anion 4) if passed through a silica column or to the neutral 5-CH3-arachno-6,9-C(2)B(8)H(13) (compound 5) on treatment of its [NMe4]+ salt with dilute HCl. Moreover, the reaction of compound 2 with [RhCl2(C(5)Me(5))]2 afforded the eleven-vertex ruthenadicarbaborane [1-C(5)Me(5)-4-CH(3)-closo-1,2,3-RhC(2)B(8)H(9)] (compound 8). All these reactions resulted in an extrusion of one of the cluster carbon atoms into an exoskeletal position.

Nucleoside-metallacarborane conjugates for base-specific metal labeling of DNA.

A general approach to the synthesis of nucleoside conjugates between derivatives of thymidine (T), 2'-O-deoxycytidine (dC), 2'-O-deoxyadenosine (dA), and 2'-O-deoxyguanosine (dG), and metallacarborane complexes is described. Metallacarborane-nucleoside derivatives are prepared by reaction of the dioxane-metallacarborane adduct with a base-activated 3',5'-protected nucleoside. In the case of T and dG a mixture of regioisomers, which is easily separable by chromatographic methods, is obtained, thus yielding a series of modifications containing metallacarborane groups at the 2-O, 3-N, 4-O and 1-N, 2-N, 6-O locations, respectively; dC and dA are alkylated at the exo-amino function. The proposed methodology provides a route for the synthesis and study of nucleic acids modified with metallacarboranes at designated locations and a versatile approach to the incorporation of metals into DNA.

New route to 1-thia-closo-dodecaborane(11), closo-1-SB11H11, and its halogenation reactions. The effect of the halogen on the dipole moments and the NMR spectra and the importance of spin-orbit coupling for the 11B chemical shifts.

Reaction between nido-B10H14 (1) and elemental sulfur in CHCl3 in the presence of Et3N at room temperature, followed by treatment with Et3N.BH3 at 170-190 degrees C, resulted in the isolation of closo-1-SB11H11 (2) in 50% yield. Selected electrophilic halogenation reactions of compound led to the isolation of a series of monohalogenated derivatives of general constitution 12-X-closo-1-SB11H10 (12-X-, where X = Cl, Br, and I). The structures of 12-Cl- and 12-I- were determined by an X-ray diffraction analysis and the structures of all compounds were geometry optimised at the RMP2(fc)/6-31G* level. The constitution of all compounds is consistent with the results of mass spectrometry and multinuclear (1H and 11B) spectroscopy complemented by two-dimensional [11B-11B]-COSY and 1H{11B(selective)} NMR measurements. Experimental 11B chemical shifts generally show acceptable agreement with theoretical values calculated by GIAO methods, but spin-orbit coupling must be included for nuclei bearing heavy-atom substituents such as Br or I. The dipole moments determined for the B12-X bonds show similarities to those of aliphatic C-X bonds and confirm unambiguously the B12 --> S dipole moment orientation in the SB11 cage.

From nonpeptide toward noncarbon protease inhibitors: metallacarboranes as specific and potent inhibitors of HIV protease.

HIV protease (PR) represents a prime target for rational drug design, and protease inhibitors (PI) are powerful antiviral drugs. Most of the current PIs are pseudopeptide compounds with limited bioavailability and stability, and their use is compromised by high costs, side effects, and development of resistant strains. In our search for novel PI structures, we have identified a group of inorganic compounds, icosahedral metallacarboranes, as candidates for a novel class of nonpeptidic PIs. Here, we report the potent, specific, and selective competitive inhibition of HIV PR by substituted metallacarboranes. The most active compound, sodium hydrogen butylimino bis-8,8-[5-(3-oxa-pentoxy)-3-cobalt bis(1,2-dicarbollide)]di-ate, exhibited a K(i) value of 2.2 nM and a submicromolar EC(50) in antiviral tests, showed no toxicity in tissue culture, weakly inhibited human cathepsin D and pepsin, and was inactive against trypsin, papain, and amylase. The structure of the parent cobalt bis(1,2-dicarbollide) in complex with HIV PR was determined at 2.15 A resolution by protein crystallography and represents the first carborane-protein complex structure determined. It shows the following mode of PR inhibition: two molecules of the parent compound bind to the hydrophobic pockets in the flap-proximal region of the S3 and S3' subsites of PR. We suggest, therefore, that these compounds block flap closure in addition to filling the corresponding binding pockets as conventional PIs. This type of binding and inhibition, chemical and biological stability, low toxicity, and the possibility to introduce various modifications make boron clusters attractive pharmacophores for potent and specific enzyme inhibition.

Carboranethiol-modified gold surfaces. A study and comparison of modified cluster and flat surfaces.

Four different carboranethiol derivatives were used to modify the surfaces of gold nanoparticles and flat gold films. The novel materials engendered from these modifications are extraordinarily stable species with surfaces that support self-assembled monolayers of 1-(HS)-1,2-C2B10H11, 1,2-(HS)2-1,2-C2B10H10, 1,12-(HS)2-1,12-C2B10H10, and 9,12-(HS)2-1,2-C2B10H10, respectively. Surprisingly, characterization of these materials revealed that a number of molecules of the carboranethiol derivatives are incorporated inside the nanoparticles. This structural feature was studied using a number of techniques, including X-ray photoelectron spectroscopy (XPS), UV-vis, and IR spectroscopies. Thermal desorption experiments show that carborane molecules detach and leave the nanoparticle surface mostly as 1,2-C2B10H10 isotopic clusters, leaving sulfur atoms bound to the gold surface. The surfaces of both the gold nanoparticles and the flat gold films are densely packed with carboranethiolate units. One carborane cluster molecule occupies an area of six to seven surface gold atoms of the nanoparticle and eight surface gold atoms of the flat film. XPS data showed that molecules of 1,12-(HS)2-1,12-C2B10H10 bind to the flat gold surface with only half of the thiol groups due to the steric demands of the icosahedral carborane skeleton. Electrochemical measurements indicate complete coverage of the modified gold surfaces with the carboranethiol molecules.

Towards new boron carriers for boron neutron capture therapy: metallacarboranes and their nucleoside conjugates.

Thymidine conjugates containing metallacarborane, {8-[5-(N(3)-thymidine)-3-oxa-pentoxy]-3-cobalt bis(1,2-dicarbollide)}- (5) and {8-[5-(O(4)-thymidine)-3-oxa-pentoxy]-3-cobalt bis(1,2-dicarbollide)}- (6) ions and several simple [3-cobalt bis(1,2-dicarbollide)]- ion (1) derivatives have been studied as potential boron carriers for BNCT. Compound 6 and some nonnucleoside derivatives of 1 were not toxic above 100 microM. The partition coefficient for both metallacarborane bearing thymidine conjugates 5 and 6 was more than 500 times higher than that of unmodified nucleoside. The cellular uptake studies showed accumulation of compounds 6 in V79 Chinese hamster cells but not of compound 5. The low toxicity of conjugate type of 6 together with its high partition coefficient suggest that judicially designed derivatives of metallacarboranes can be considered as potential boron carriers for BNCT.

Dicarbaheteroborane Chemistry. Representatives of Two Eleven-Vertex Dicarbaazaundecaborane Families: nido-10,7,8-NC(2)B(8)H(11), Its N-Substituted Derivatives, and arachno-1,8,11-NC(2)B(8)H(13).

Treatment of an acidified solution of the [nido-7,8-C(2)B(9)H(12)](-) anion (1(-)) with NaNO(2) at 0 degrees C in the presence of benzene resulted in the formation of two eleven-vertex azadicarbaboranes, nido-10,7,8-NC(2)B(8)H(11) (2) and arachno-1,8,11-NC(2)B(8)H(13)( )()(3), isolated in yields of 15 and 35%, respectively, together with a small amount (0.9%) of 5-Ph-nido-7,8,10-C(2)NB(8)H(10) (5-Ph-2). Compound 3 was converted in 68% yield into 2 by reaction with PS (PS = "proton sponge"; 1,8-(dimethylamino)naphthalene and acetone. Deprotonation of 2 at the N(10)H vertex gave the [nido-10,7,8-NC(2)B(8)H(10)](-) anion (2(-)), which was easily alkylated with Me(2)SO(4) or PhCH(2)Br to produce the N-alkylated derivatives of 2, 10-R-nido-10,7,8-NC(2)B(8)H(10), where R = Me (10-Me-2, 86%) and PhCH(2) (10-PhCH(2)-2, 69%). The geometries of the parent dicarbazaboranes 2 and 3 were optimized at the MP2(fc)/6-31G level, and the structures of all compounds were thence confirmed by the excellent agreement between experimental data and IGLO/NMR calculations of the (11)B chemical shifts for the parent compounds at the DZ//6-31G, DZ//MP2/6-31G, and II'//MP2/6-31G levels.