Mohamed E. El-Zaria

m-Carborane-Based Chiral NBN Pincer-Metal Complexes: Synthesis, Structure, and Application in Asymmetric Catalysis

We have succeeded in synthesizing m-carborane-based chiral NBN-pincer ligands, 1,7-bis(oxazolinyl)-1,7-dicarba-closo-dodecaborane (Carbox) (7-9). The combination of bis(hydroxyamides) and 3 equiv of diethylaminosulfur trifluoride (DAST) is a key step for cyclization to form oxazoline rings in excellent yields. X-ray crystal structures of these ligands confirmed three donor sites, one central B and two flanking N atoms in fixed positions. The electrophilic halogenation of the Carbox pincer ligands with iodine and a catalytic amount of Lewis acid led to ring-opening of the oxazolines and afforded bis(haloamides) (13 and 14). The air- and moisture-stable Carbox pincer complexes of rhodium(III), nickel(II), and palladium(II) were synthesized by the oxidative addition of RhCl(3)·3H(2)O, Ni(COD)(2), and Pd(CH(3)CN)(4)[BF(4)](2) to the Carbox pincer ligands (7-9), respectively. The catalytic activity of the rhodium(III) complexes (18-20) was examined for the asymmetric conjugate reduction of α,β-unsaturated esters and reductive aldol reaction. Among these catalysts, [(S,S)-Carbox-iPr]Rh(OAc)(2)·H(2)O (18) showed the highest enantioselective catalytic ability for both asymmetric conjugate reduction and reductive aldol reaction.

Boron‐Containing Protoporphyrin IX Derivatives and Their Modification for Boron Neutron Capture Therapy: Synthesis, Characterization, and Comparative In Vitro Toxicity Evaluation

A novel series of boronated porphyrins for potential use in boron neutron capture therapy (BNCT) and photodynamic therapy (PDT) for tumor suppression is described. Protoporphyrin IX {i.e., bis(alpha-methyl-beta-pentylethylether)protoporphyrin IX, and bis(alpha-methyl-beta-dodecanylethylether)protoporphyrin IX} bearing polyhedral borane anions (B(12)H(11)SH(2-), B(12)H(11)NH(3) (-), or B(12)H(11)OH(2-)) were synthesized with reasonable yields. Modification of the protoporphyrin IX structure was achieved by variation of the lengths of the alkyl chains (pentyl and dodecanyl) attached through ether linkages to the former vinyl groups. The goal of this modification was to develop boronated porphyrins with chemical and physical properties that differed from those of protoporphyrin IX. Performance of an MTT assay with each derivative revealed that the synthesized boronated porphyrins showed low cytotoxicities in a variety of cancer cells. Of these compounds, B(12)H(11)NH(2) (2-)-conjugated porphyrin induced a significant increase in the level of boron accumulation and PDT efficacy against HeLa cells.

High Yielding Preparation of Dicarba-closo-dodecaboranes Using a Silver(I) Mediated Dehydrogenative Alkyne-Insertion Reaction

The synthesis of 1,2-dicarba-closo-dodecaboranes (ortho-carboranes) is often low yielding which is a critical issue given the increasing use of boron clusters in material science and medicinal chemistry. To address this barrier, a series of Cu, Ag, and Au salts were screened to identify compounds that would enhance the yields of ortho-caboranes produced when treating alkynes with B10H12(CH3CN)2. Using a variety of functionalized ligands including mono- and polyfunctional internal and terminal alkynes, significant increases in yield were observed when AgNO3 was used in catalytic amounts. AgNO3 appears to prevent unwanted reduction/hydroboration of the alkyne prior to carborane formation, and the process is compatible with aryl, halo, hydroxy, nitrile, carbamate, and carbonyl functionalized alkynes.

Synthesis of protoporphyrin–lipids and biological evaluation of micelles and liposomes

Protoporphyrin IX (PPIX) lipids were synthesized by introducing a long alkyl chain, such as C13, C15, and C17, at each vinyl group on PPIX via hydrobromination. The PPIX lipids exhibited a water-soluble property by forming their micelles in water and the PPIX-lipid micelles showed relatively low cytotoxicity toward HeLa cells (IC50=151.7-379.9μM) without light irradiation. PL-C17 liposomes (post-inserted liposomes) were readily prepared by adding PL-C17 micelle solution to the liposome solution. The IC50 values of PPIX, PL-C17 micelles, and PL-C17 liposomes toward HeLa cells were 0.53, 5.65, and 12.9μM, respectively, after irradiation with a xenon lamp in the 400-800nm range for 2min. PL-C17 liposomes were selectively accumulated in the Golgi apparatus in cells.

New Strategy for Synthesis of Mercaptoundecahydrododecaborate Derivatives via Click Chemistry: Possible Boron Carriers and Visualization in Cells for Neutron Capture Therapy

A new method that utilizes the click cycloaddition reaction to functionalize B(12)H(11)SH(2-) (BSH) with organic molecules was investigated. S,S-Dipropargyl-SB(12)H(11)(-) (1) and S-propargyl-SB(12)H(11)(2-) (4) were prepared from [(CH(3))(4)N](2)B(12)H(11)SH and [(CH(3))(4)N](2)B(12)H(11)S(CH(2))(2)CN (2) with propargyl bromide, respectively. Compound 1 or 4 reacted with various azides with mediation by Cu(II) ascorbate to give the corresponding bis-triazolo BSH derivatives (1-) or monotriazole BSH derivatives (2-), respectively, in excellent yields. The click cycloaddition reaction is very useful not only for the synthesis of various BSH-containing organic compounds for boron neutron capture therapy (BNCT) but also for the visualization of boron clusters in cells. We succeeded in the click cycloaddition reaction of compound 1 with Alexa Fluor 488 azide dye and found that 1 accumulated not in the cytoplasm but in the nuclei of HeLa cells.

Triphenyltin chloride complexes containing bidentate organodiimines as effective antitumor agents

Three triphenyltin chloride complexes, [(Ph3SnCl)2 · (bpy)1.5] (1), [(Ph3SnCl)2.tbpe] (2), and [(Ph3SnCl)2 · bpe] (3), were synthesized by reaction of triphenyltin chloride with 4,4′-bipyridine (bpy), trans-1,2-bis(4-pyridyl)ethylene (tbpe), and 1,2-bis(4-pyridyl)ethane (bpe) in water/acetonitrile. Both 2 and 3 are binuclear; each consists of two Ph3SnCl molecules bridged by the bidentate ligand. Complex 1 consists of two crystallographically independent and chemically different coordination complexes, mononuclear and binuclear in equal proportion. The structures of these complexes were investigated by single-crystal X-ray analysis, elemental analyses, NMR spectroscopy as well as electronic absorption and emission spectroscopy. The three complexes exhibit in vitro antitumor activity against human breast cancer cell line, MCF7.

Synthesis of triazolyl methyl-substituted amino- and oxy-undecahydrododecaborates for potential application in boron neutron capture therapy

A general approach to the synthesis of triazole conjugates containing undecahydro-closo-dodecaborate anions based on Huisgen 1,3-dipolar cycloaddition is presented. Undecahydro-closo-dodecaborate anions bearing terminal alkyne groups were synthesized by the reaction of H3N–B12H11− or HO–B12H112− with alkyne halides in N,N-dimethylformamide using KOH as a base. Variation of reaction time, alkyne halide concentration and steric demands of the alkyne halide resulted in the stepwise introduction of one to three alkyne groups into H3N–B12H11−. Two compounds {(CHCCH2)3N–B12H11− and (CHCCH2)O–B12H112−} were crystallized for single-crystal X-ray diffraction studies. N- and O-alkyne undecahydro-closo-dodecaborate anions reacted with various functionalized azides including lipid, carborane, aryl and hydroxyalkyl groups. The current study provides various synthetic applications not only for BNCT but also for boron cluster materials.

Synthesis of oligo-closo-dodecaborates by Hüisgen click reaction as encapsulated agents for the preparation of high-boron-content liposomes for neutron capture therapy

High-boron-content compounds, 8, 10, and 13, were designed and synthesized as boron agents encapsulated in liposomes by the Huisgen click cycloaddition of closo-dodecaborate-containing azides and alkynes. These compounds have relatively low cytotoxicities and their GI50 values for B16, CT26, and HeLa cells are higher than 0.14 mM, indicating toxicities similar to that of BSH. High-boron-content liposomes were prepared using 13, which has the largest number of boron atoms in a molecule among the synthesized compounds. The final boron concentration in 13-encapsulating liposomes reached 11.0 × 103 ppm with a B/P ratio of 5.1. A significantly high tumor boron accumulation (72.2 ppm) was observed in tumor-bearing mice 36 h after the injection of 13-encapsulating liposomes at a dose of 15 mgB kg−1 body weight with the tumor/blood (T/B) ratio of approximately 14.

The first synthesis of azanonaborane-containing sugars, possible boron carriers for neutron capture therapy

A novel class of boron containing sugars is described. They were synthesized in acceptable yields from readily available starting materials. Reaction of (4-aminobutylamine)-(N-aminobutyl)azanonaborane(11) [H2N(CH2)4H2NB8H11NH(CH2)4NH2] with acetobromo-α-D-glucose or acetobromo-α-D-galactose in acetonitrile followed by hydrolysis with sodium methoxide afforded (4-α-glucopyranosylaminobutylamine)-(N-α-glucopyranosylaminobutyl)azanonaborane(11) or (4-α-galactopyranosylaminobutylamine)-(N-α-galactopyranosylaminobutyl)azanonaborane(11) in 65% and 63% yields, respectively. In a one step process, treatment of a B8N cluster with D-ribose in methanol in the presence of a catalytic amount of glacial acetic acid gave (4-α-ribofuranosylaminobutylamine)-(N-α-ribofuranosylaminobutyl)azanonaborane(11) in 78% yield. The connection of monosaccharide units to the azanonaborane cluster enhances the stability and the water solubility of the resulting compounds, which are considered important factors for boron neutron capture therapy (BNCT) delivery agents. The in vitro toxicity test using B16 melanoma cells showed that azanonaborane clusters containing sugar are not toxic even at boron concentrations of 3 mM, whereas (4-aminobutylamine)-(N-aminobutyl)azanonaborane(11) has an LD50 of about 700 μM. Results obtained from these studies may provide a more definitive answer as to the potential usefulness of these compounds for BNCT.

Preparation and Evaluation of Radiolabeled Antibody Recruiting Small Molecules That Target Prostate-Specific Membrane Antigen for Combined Radiotherapy and Immunotherapy

The feasibility of developing a single agent that can deliver radioactive iodine and also direct cellular immune function by engaging endogenous antibodies as an antibody-recruiting small molecule (ARM) was determined. A library of new prostate-specific membrane antigen (PSMA)-binding ligands that contained antibody-recruiting 2,4-dinitrophenyl (DNP) groups and iodine were synthesized and screened in vitro and in vivo. A lead compound (9b) showed high affinity for PSMA and the ability to bind anti-DNP antibodies. Biodistribution studies of the iodine-125 analogue showed 3% ID/g in LNCaP xenograft tumors at 1 h postinjection with tumor-to-blood and tumor-to-muscle ratios of 10:1 and 44:1, respectively. The radiolabeled analogue was bound and internalized by LNCaP cells, with both functions blocked using a known PSMA inhibitor. A second candidate showed high tumor uptake (>10% ID/g) but had minimal binding to anti-DNP antibodies. The compounds reported represent the first examples of small molecules developed specifically for combination immunotherapy and radiotherapy for prostate cancer.