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1.
J Med Chem ; 59(6): 2660-73, 2016 Mar 24.
Article in English | MEDLINE | ID: mdl-26894427

ABSTRACT

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.


Subject(s)
Antigens, Neoplasm/drug effects , Prostate-Specific Antigen/immunology , Prostatic Neoplasms/therapy , Radioimmunotherapy/methods , Radiopharmaceuticals/chemical synthesis , Radiopharmaceuticals/pharmacology , Animals , Cell Line, Tumor , Dinitrophenols/chemical synthesis , Dinitrophenols/pharmacology , Female , Humans , Ligands , Male , Mice , Mice, Nude , Prostatic Neoplasms/metabolism , Radiopharmaceuticals/pharmacokinetics , Small Molecule Libraries , Tissue Distribution , Xenograft Model Antitumor Assays
2.
Eur J Med Chem ; 93: 574-83, 2015 Mar 26.
Article in English | MEDLINE | ID: mdl-25748122

ABSTRACT

A series of mercaptoundecahydrododecaborate (B12H11SH(2-), BSH) bearing mono- and dicarboxyalkyl derivatives was prepared, characterized, and their reactivity towards amidation and esterification in DMF was evaluated. Symmetrical alkylation of BSH was achieved by treatment with primary haloalkyl carboxylic acids in aqueous acetonitrile to produce S,S-bis(carboxyalkyl)sulfonium-undecahydro-closo-dodecaborate tetramethylammonium salts. Unsymmetrically substituted sulfonium salts were obtained through a similar treatment of cyanoethylthioether-undecahydro-closo-dodecaborate tetramethylammonium salt with haloalkyl carboxylic acid. Selective removal of the remaining cyanoethyl group upon treatment with tetramethylammonium hydroxide yielded S-carboxyalkyl-thioether-undecahydro-closo-dodecaborate ditetramethylammonium salts. N,N'-dicyclohexylcarbodiimide (DCC) activated amidation of S,S-bis(carboxyalkyl)sulfonium-undecahydro-closo-dodecaborate or S-carboxyalkyl-thioether-undecahydro-closo-dodecaborate tetramethylammonium salts with propargylamine provided the opportunity to install terminal acetylene groups for further conjugation. These compounds acted as powerful building blocks for the synthesis of a broad range of 1,4-disubstituted 1,2,3-triazole products in high yields, utilizing the Cu(I)-mediated click cycloaddition reaction. The synthesis of BSH-lipid with a two-tailed moiety was also achieved, by esterification of S,S-bis(carboxyethyl)sulfoniumundecahydro-closo-dodecaborate(1-) tetramethylammonium salt with 1,2-O-distearoyl-sn-3-glycerol, which may prove useful in the liposomal boron delivery system. The bio-compatibility of the azide-alkyne click reaction was then utilized by performing this reaction in cell culture. The distribution of BSH in HeLa cells could be visualized by treating the cells first with a BSH-alkyne compound and then with Alexa Fluor 488(®) azide dye. The BSH-dye conjugate, which did not wash out, revealed the distribution of boron in the HeLa cells. Cytotoxicity assays of these BSH derivatives revealed that the synthesized BSH-conjugated triazoles possessed low cytotoxicity in HeLa cancer cells. Of these compounds, BSH conjugated triazole 15 induced a significant increase in the level of boron accumulation in HeLa cells.


Subject(s)
Borohydrides/chemical synthesis , Borohydrides/pharmacology , Boron Neutron Capture Therapy , Molecular Imaging , Sulfhydryl Compounds/chemical synthesis , Sulfhydryl Compounds/pharmacology , Alkylation , Amides/chemistry , Biological Transport/drug effects , Borohydrides/chemistry , Boron/metabolism , Chemistry Techniques, Synthetic , Click Chemistry , Esterification , HeLa Cells , Humans , Intracellular Space/drug effects , Intracellular Space/metabolism , Sulfhydryl Compounds/chemistry , Triazoles/chemistry
3.
Chem Commun (Camb) ; 50(82): 12325-8, 2014 Oct 21.
Article in English | MEDLINE | ID: mdl-25182569

ABSTRACT

closo-Dodecaborate-encapsulating liposomes were developed as boron delivery vehicles for neutron capture therapy. The use of spermidinium as a counter cation of closo-dodecaborates was essential not only for the preparation of high boron content liposome solutions but also for efficient boron delivery to tumors.


Subject(s)
Antineoplastic Agents/administration & dosage , Boron Compounds/administration & dosage , Animals , Antineoplastic Agents/chemistry , Boron/administration & dosage , Boron Compounds/chemistry , Boron Neutron Capture Therapy , Cell Line, Tumor , Cell Survival/drug effects , Female , Liposomes , Mice, Inbred BALB C , Neoplasms/pathology , Neoplasms/therapy , Tumor Burden/drug effects
4.
Bioorg Med Chem ; 22(17): 4745-51, 2014 Sep 01.
Article in English | MEDLINE | ID: mdl-25066052

ABSTRACT

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.


Subject(s)
Antineoplastic Agents/pharmacology , Lipids/pharmacology , Liposomes/pharmacology , Micelles , Protoporphyrins/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , HeLa Cells , Humans , Lipids/chemistry , Liposomes/chemistry , Molecular Structure , Protoporphyrins/chemistry , Reactive Oxygen Species/analysis , Reactive Oxygen Species/metabolism , Structure-Activity Relationship
5.
Angew Chem Int Ed Engl ; 53(20): 5156-60, 2014 May 12.
Article in English | MEDLINE | ID: mdl-24700630

ABSTRACT

Methods used to prepare functionalized carboranes generally require heating to high temperatures, and thus limits the range of derivatives which can be prepared directly from alkynes. We show here that by using a homogeneous silver(I) catalyst it is now possible to prepare carboranes in good to excellent yield at temperatures below 40 °C, including at room temperature. The process is general and provides an important new synthetic strategy for the preparation of functionalized boron clusters.


Subject(s)
Boron Compounds/chemical synthesis , Silver/chemistry , Boron Compounds/chemistry , Catalysis , Proton Magnetic Resonance Spectroscopy
6.
Dalton Trans ; 43(13): 4950-61, 2014 Apr 07.
Article in English | MEDLINE | ID: mdl-24481236

ABSTRACT

A series of C-hydroxy carborane derivatives of (S)-2-(3-((S)-5-amino-1-carboxypentyl)ureido)-pentanedioic acid were prepared as a new class of boron rich inhibitors of prostate specific membrane antigen (PSMA), which is overexpressed on prostate cancer tumours and metastases. Closo-, nido- and iodo-carborane conjugates were prepared and screened in vitro where the water soluble iodinated cluster had the highest affinity with an IC50 value (73.2 nM) that was comparable to a known PSMA inhibitor 2-(phosphonomethyl)-pentanedioic acid (PMPA, 63.9 nM). The radiolabeled analogue was prepared using (123)I and the biodistribution determined in a prostate cancer model derived from a PSMA positive cell line (LNCaP) at 1, 2, 4, 6 and 24 h post injection (n = 4 per time point). The results showed good initial tumour uptake of 4.17% at 1 h, which remained at that level only decreasing somewhat at 6 h (3.59%). At the latter time point tumour-to-blood and tumour-to-muscle ratios peaked at 3.47 at 25.52 respectively. There was significant off-target binding particularly in the liver and gall bladder and a surprising amount of deiodination in vivo. Notwithstanding, this work demonstrates that carboranes can be used to prepare potent ligands for PSMA creating the opportunity to develop a new class of BNCT agents for prostate cancer.


Subject(s)
Boron Compounds , Glutamate Carboxypeptidase II/antagonists & inhibitors , Animals , Antigens, Surface/metabolism , Boron Compounds/blood , Boron Compounds/chemical synthesis , Boron Compounds/pharmacokinetics , Boron Compounds/pharmacology , Cell Line, Tumor , Gallbladder/metabolism , Glutamate Carboxypeptidase II/metabolism , Humans , Intestinal Mucosa/metabolism , Liver/metabolism , Male , Mice , Mice, Nude , Prostatic Neoplasms/metabolism , Tissue Distribution
7.
Inorg Chem ; 52(15): 8743-9, 2013 Aug 05.
Article in English | MEDLINE | ID: mdl-23829543

ABSTRACT

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.

8.
Chemistry ; 18(35): 11071-8, 2012 Aug 27.
Article in English | MEDLINE | ID: mdl-22807279

ABSTRACT

The synthesis, radiolabelling and biodistribution of iodinated C-hydroxy-nido-carborane ligands is described. Microwave heating by using NaF in aqueous ethanol was used to prepare {sodium [7-hydroxy-7,8-dicarba-nido-undecaborate], nido-carboranol} and {sodium [7-hydroxy-7,8-dicarba-nido-undecaborate-8-carboxylic acid], nido-salborin} in 97 and 90 % yield, respectively. Radioiodination of these nido-carboranes was completed by using both (125)I and (123)I, and the products were obtained in high radiochemical purity (>99 %) and yield (72 to 87 %). The structures of the radiolabelled products were validated through comparison to authentic standards. Biodistribution studies in BALB/c mice showed low accumulation of the labelled compounds in the liver and intestines, which are sites where labelled carboranes typically localise. The labelled cluster bearing hydroxy and carboxylic acid groups on the two carbon vertices demonstrated preferential clearance through the kidneys and low thyroid uptake. This compound had substantially reduced non-specific binding than the deshydroxy analogue making it an attractive bifunctional ligand for preparing targeted molecular imaging and therapy agents.


Subject(s)
Boranes/chemical synthesis , Boranes/pharmacokinetics , Carboxylic Acids/chemistry , Iodine Radioisotopes/chemistry , Radiopharmaceuticals/chemical synthesis , Radiopharmaceuticals/pharmacokinetics , Animals , Diagnostic Imaging , Female , Intestines/diagnostic imaging , Isotope Labeling , Kidney/diagnostic imaging , Ligands , Liver/diagnostic imaging , Mice , Mice, Inbred BALB C , Molecular Structure , Radionuclide Imaging , Thyroid Gland/diagnostic imaging , Tissue Distribution
9.
Inorg Chem ; 50(9): 4149-61, 2011 May 02.
Article in English | MEDLINE | ID: mdl-21438543

ABSTRACT

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,ß-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.

10.
Chemistry ; 16(5): 1543-52, 2010 Feb 01.
Article in English | MEDLINE | ID: mdl-20020518

ABSTRACT

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.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/toxicity , Boron Neutron Capture Therapy/methods , Brain Neoplasms/radiotherapy , Protoporphyrins/chemical synthesis , Protoporphyrins/toxicity , Animals , Antineoplastic Agents/therapeutic use , Cell Line, Tumor , Humans , Magnetic Resonance Spectroscopy , Molecular Structure , Photochemotherapy , Protoporphyrins/therapeutic use , Rats , Spectrophotometry, Infrared
11.
Inorg Chem ; 48(24): 11896-902, 2009 Dec 21.
Article in English | MEDLINE | ID: mdl-19928788

ABSTRACT

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.


Subject(s)
Borohydrides/chemical synthesis , Boron/chemistry , Cell Nucleus/chemistry , Neutron Capture Therapy , Sulfhydryl Compounds/chemical synthesis , Ascorbic Acid/chemistry , Azides/chemistry , Borohydrides/chemistry , Cell Nucleus/metabolism , Copper/chemistry , HeLa Cells , Humans , Molecular Structure , Stereoisomerism , Sulfhydryl Compounds/chemistry
12.
Eur J Med Chem ; 43(2): 357-63, 2008 Feb.
Article in English | MEDLINE | ID: mdl-17524526

ABSTRACT

A new simple and fast spectroscopic method was presented as a new marker for heroin use. Novel azo-morphine derivatives with spectroscopic absorption peaks ranging from 330-470 nm, were synthesized by the coupling of morphine (M) and 6-acetyl morphine (6-AM) with freshly prepared diazonium salt of aniline hydrochloride at 0 degrees C. However, no reaction was observed with codeine under the same reaction conditions. Separation of azo dyes was performed by TLC using tetrahydrofuran and dichloromethane in the ratio 1:1. The chemical structure of the products was established by their microanalysis, NMR, IR, UV-vis, and mass spectroscopies. Electronic absorption and excitation spectra of the dyes were measured in solvents of different polarities. The dyes exhibited positive solvatochromism, i.e., a bathochromic band shift as the solvent polarity is increased. Also, the fluorescence quantum yield was sensitive to the polarity and the pH of the medium. The UV-vis spectroscopy of spiked compounds in human urine samples was also reported. The drugs (M, 6-AM and mixture of both) were coupled with freshly prepared diazonium salt even at very low concentration of the drugs 10(-9)M.


Subject(s)
Azo Compounds/chemical synthesis , Morphine Derivatives/chemical synthesis , Substance Abuse Detection/methods , Azo Compounds/chemistry , Chromatography, Thin Layer , Humans , Illicit Drugs/urine , Morphine Derivatives/chemistry , Sensitivity and Specificity , Spectrum Analysis
13.
Article in English | MEDLINE | ID: mdl-17493866

ABSTRACT

Charge transfer complexes (CTC) of 5,10,15,20-tetraphenylporphyrin (TPP), 5,10,15,20-tetra(4-tolyl)porphyrin (TTP), 5,10,15,20-tetra(4-methoxyphenyl)porphyrin (TMP), Zn-5,10,15,20-tetraphenylporphyrin (Zn-TPP), and Zn-5,10,15,20-tetra(4-tolyl)porphyrin (Zn-TTP) with tetracyanoethylene (TCNE) have been studied at various temperatures in CH(2)Cl(2) and CCl(4). The data are discussed in terms of equilibrium constant (K(CT)), molar extinction coefficient (epsilon(CT)), thermodynamic standard reaction quantities (DeltaG degrees , DeltaH degrees and DeltaS degrees ), oscillator strength (f), and transition dipole moment (mu). The spectrum obtained for TPP/TCNE, TTP/TCNE, and TMP/TCNE systems shows two main absorption bands at 475 and 690nm, which are not due to the absorption of any of the reactants. These bands are characteristic of an intermolecular charge transfer involving the overlap of the lowest unoccupied molecular orbital (LUMO) of the acceptor with the highest occupied molecular orbital (HOMO) of the donor. The results reveal that the interaction between the donors and acceptor is due to pi-pi(*) transitions by the formation of radical ion pairs. The stoichiometry of the complexes was found to be 1:1 ratio by the Job and straight line methods between donors and acceptor with the maximum absorption bands at wavelengths of 475 and 690nm. The observed data show salvation effects on the spectral and thermodynamics properties of CTC. The ionization potential of the donors and the dissociation energy of the CTC were also determined and are found to be constant.


Subject(s)
Electrons , Ethylenes/chemistry , Nitriles/chemistry , Porphyrins/chemistry , Electric Conductivity , Kinetics , Solutions , Spectrophotometry , Temperature , Thermodynamics
14.
Chemistry ; 12(31): 8084-9, 2006 Oct 25.
Article in English | MEDLINE | ID: mdl-16865752

ABSTRACT

A number of azanonaboranes containing imidazole derivatives have been synthesized by a ligand-exchange reaction. The exo-NH(2)R group of the azanonaborane of the type [(RH(2)N)B(8)H(11)NHR] can be exchanged by one hetero-nitrogen atom of the imidazole ring. In the case of histamine, the exchange takes place on the aliphatic amino group, the hetero-nitrogen atom of the imidazole ring or both of them. The products were confirmed by NMR, IR spectroscopy, elemental analysis, and mass spectrometry. The electron-withdrawing effect of the nitro group in 2-nitroimidazole is the main hindrance to achieve the exchange reaction. In vitro experiments were performed with B16 melanoma cells. A comparison of the biological properties of the products in which the B(8)N cluster is connected to the hetero-nitrogen atom of imidazole ring or the aliphatic NH(2) group showed that incorporation of B(8)N cluster unit into primary amino group increases the compound's toxicity. In contrast, this specificity for cytotoxicity effect was not observed in the case of histamine containing two B(8)N clusters which was relatively nontoxic and did not inhibit colony formation up to concentrations of 2 mM.


Subject(s)
Aza Compounds/chemistry , Boranes/toxicity , Boron/therapeutic use , Imidazoles/chemistry , Neoplasms/radiotherapy , Neutrons/therapeutic use , Animals , Boranes/chemical synthesis , Boranes/chemistry , Boron/chemistry , Melanoma, Experimental/radiotherapy , Radiotherapy , Tumor Cells, Cultured
15.
J Med Chem ; 45(26): 5817-9, 2002 Dec 19.
Article in English | MEDLINE | ID: mdl-12477367

ABSTRACT

New boron-containing polyamine have been synthesized: (aminoalkylamine)-N-(aminoalkyl)azanonaborane(11) derivatives [H(2)N(CH(2))(n)H(2)NB(8)H(11)NH(CH(2))(n)NH(2)], where n = 4-6 and 12, and [H(2)N(CH(2))(3)H(2)NB(8)H(11)NH(CH(2))(4)NH(2)]. (4-Aminobutylamine)-N-(4-aminobutyl)azanonaborane and (3-aminopropylamine)-N-(4-aminobutyl)azanonaborane were less toxic in vitro (LD(50) of approximately 700 and approximately 1100 microM, respectively) than spermine, while (4-aminobutylamine)-N-isopropylazanonaborane with its hydrophobic isopropyl group and those with n = 5, 6, and 12 were already toxic under similar conditions (LD(50) << 500 microM). These compounds may be useful as delivery agents for boron neutron capture therapy.


Subject(s)
Boranes/chemical synthesis , Polyamines/chemical synthesis , Animals , Boranes/chemistry , Boranes/toxicity , Boron Neutron Capture Therapy , CHO Cells , Cell Survival/drug effects , Cricetinae , Lethal Dose 50 , Polyamines/chemistry , Polyamines/toxicity , Solubility , Structure-Activity Relationship
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