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1.  Synthesis and properties of a series of carboranyl-BODIPYs 
Journal of organometallic chemistry  2015;798(Pt 1):209-213.
A series of four BODIPYs containing one or two ortho- or para-carborane clusters were synthesized using palladium(0)-catalyzed Suzuki cross-coupling or nucleophilic substitution reactions, at the 2,6- or the 8-positions of halogenated boron dipyrromethenes (BODIPYs). The spectroscopic, structural (including one X-ray) and in vitro BBB permeability of the BODIPYs using hCMEC/D3 brain endothelial cells were investigated.
Graphical Abstract
Two synthetic routes to four BODIPYs containing one or two ortho- or para-carborane clusters, are described. The most promising compound for application as boron delivery agent for BNCT is 8-(ortho-carboranyl-1-thio)-1,3,5,7-tetramethyl-BODIPY, due to its higher permeability across hCMEC/D3 cell monolayers.
doi:10.1016/j.jorganchem.2015.05.009
PMCID: PMC4681003  PMID: 26688595
BODIPY; carborane; BNCT; fluorescence; BBB model
2.  Synthesis and spectroscopic properties of β,β′-dibenzo-3,5,8-triaryl-BODIPYs† 
A series of β,β′-bicyclo-3,5-diaryl-BODIPYs were synthesized from the corresponding β,β′-bicyclo-3,5-diiodo-BODIPYs (1a,b) via Pd(0)-mediated Suzuki cross-coupling reactions in 82–92% yields. Subsequent aromatization with DDQ afforded the corresponding β,β′-dibenzo-aryl-BODIPYs, which showed red-shifted absorptions and emissions in the near-IR range. The dibenzo-appended BODIPYs showed characteristic 1H-, 13C-, 11B- and 19F-NMR shifts, and nearly planar conformations by X-ray crystallography.
doi:10.1039/C5NJ03324A
PMCID: PMC5047295  PMID: 27708532
3.  Antileukemic α-pyrone derivatives from the endophytic fungus Alternaria phragmospora 
Tetrahedron letters  2014;55(24):3478-3481.
Four new (1–4) and two known (5 and 6) α-pyrone derivatives have been isolated from Alternaria phragmospora, an endophytic fungus from Vinca rosea, leaves. The isolated compounds were chemically identified to be 5-butyl-4-methoxy-6-methyl-2H-pyran-2-one (1), 5-butyl-6-(hydroxymethyl)-4-methoxy-2H-pyran-2-one (2), 5-(1-hydroxybutyl)-4-methoxy-6-methyl-2H-pyran-2-one (3), 4-methoxy-6-methyl-5-(3-oxobutyl)-2H-pyran-2-one (4), 5-(2-hydroxyethyl)-4-methoxy-6-methyl-2H-pyran-2-one (5), and 5-[(2E)-but-2-en-1-yl]-4-methoxy-6-methyl-2H-pyran-2-one (6). Compounds 2 and 4 showed moderate antileukemic activities against HL60 cells with IC50 values of 2.2 and 0.9 μM and against K562 cells with IC50 values of 4.5 and 1.5 μM, respectively.
doi:10.1016/j.tetlet.2014.04.085
PMCID: PMC5047437  PMID: 27708462
Antileukemic; α-Pyrone derivatives; Alternaria phragmospora; Endophytic fungi
4.  Crystallographic and NMR studies of antiinfective tricyclic guanidine alkaloids from the sponge Monanchora unguifera 
Bioorganic & medicinal chemistry  2004;12(24):6461-6464.
Three tricyclic guanidine alkaloids, including 1,8a;8b,3a-didehydro-8β-hydroxyptilocaulin (1), 1,8a;8b,3a-didehydro-8α-hydroxyptilocaulin (2) and mirabilin B (3), were identified from the marine sponge Monanchora unguifera. 1,8a;8b,3a-Didehydro-8α-hydroxyptilocaulin (2) is a new stereoisomer of 1, the structure of which was elucidated by spectroscopic analysis, comparison of its spectral data with those of 1, and confirmed by X-ray analysis. Compounds 1 and 2 co-crystallized in an unusual perfect order and packed around an approximate inversion center. A mixture of 1 and 2 is active against the malaria parasite Plasmodium falciparum with an IC50 value of 3.8 μg/mL while mirabilin B (3) exhibited antifungal activity against Cryptococcus neoformans with an IC50 value of 7.0 μg/mL and antiprotozoal activity against Leishmania donovani with an IC50 value of 17 μg/mL.
doi:10.1016/j.bmc.2004.09.026
PMCID: PMC4969008  PMID: 15556763
Tricyclic guanidine alkaloids; Monanchora unguifera; Sponge; X-ray crystallography; Antimalarial; Antifungal
5.  Chemical and Biological Investigation of the Fungus Pulveroboletus ravenelii 
Journal of natural products  2003;66(1):103-107.
Two new compounds, pulveraven A (1) and pulveraven B (2), as well as vulpinic acid (3) and its previously unreported polymorph were isolated from the fruiting body of Pulveroboletus ravenelii. The structures were determined using a combination of NMR, MS, IR, optical rotation, molecular modeling, and X-ray analysis. The isolates were evaluated for antimicrobial activity as well as their potential to inhibit cyclooxygenase (COX) activity and carcinogen-induced preneoplastic lesion formation with mouse mammary organ culture (MMOC).
doi:10.1021/np0203990
PMCID: PMC4969011  PMID: 12542354
6.  Synthesis and Regioselective Functionalization of Perhalogenated BODIPYs 
Organic & biomolecular chemistry  2016;14(26):6184-6188.
Three perhalogenated BODIPYs (1b–3b), bearing chloro and bromo groups at all carbon positions, were synthesized and characterized. The reactivity of BODIPY 3b was investigated under Stille cross-coupling reactions, and single crystal X-ray analysis was used to confirm the regioselectivity of the reactions. Further substitution at the boron atom produced nona-functionalized BODIPYs 7a,b, which show 676 and 739 nm emissions with 91 and 100 nm Stokes shifts, respectively.
doi:10.1039/c6ob00935b
PMCID: PMC4927422  PMID: 27251595
7.  Crystal structure of di­aqua­bis­(7-di­ethyl­amino-3-formyl-2-oxo-2H-chromen-4-olato-κ2 O 3,O 4)zinc(II) dimethyl sulfoxide disolvate 
A near-perfect octa­hedral zinc(II) complex coordinated to two coumarin fluoro­phores.
The structure of the title coordination complex, [Zn(C14H14NO4)2(H2O)2]·2C2H6OS, shows that the ZnII cation adopts an octa­hedral geometry and lies on an inversion center. Two organic ligands occupy the equatorial positions of the coordination sphere, forming a chelate ring motif via the O atom on the formyl group and another O atom of the carbonyl group (a pseudo-β-diketone motif). Two water mol­ecules occupy the remaining coordination sites of the ZnII cation in the axial positions. The water mol­ecules are each hydrogen bonded to a single dimethyl sulfoxide mol­ecule that has been entrapped in the crystal lattice.
doi:10.1107/S2056989016009853
PMCID: PMC4992932  PMID: 27555957
crystal structure; zinc complex; coumarin ligands; hydrogen bonding; DMSO solvate
8.  Synthesis and in Vitro Studies of a Series of Carborane-Containing Boron Dipyrromethenes (BODIPYs) 
Journal of medicinal chemistry  2016;59(5):2109-2117.
A series of seven BODIPYs functionalized with ortho-carborane groups at the 8(meso) or 3/5(α) position were synthesized and characterized by NMR, HRMS, HPLC, and in the cases of 2b and 5b, by X-ray analysis. The BODIPYs exhibited low dark toxicity and phototoxicity toward human glioma T98G cells, and their cellular uptake varied significantly, with 5b accumulating the most and 7 the least. All BODIPYs localized mainly within the cell ER. The BODIPYs showed higher permeabilities than lucifer yellow across human hCMEC/D3 brain endothelial cell monolayers as the BBB model. Among this series, 1b showed the highest BBB permeability (Pe = 16.4 × 10−5 cm/s), probably as a result of its lower MW (366 Da) and favorable hydrophobicity (log P = 1.5). The combination of low cytotoxicity, amphiphilicity, high boron content, high cellular uptake, and moderate BBB permeability renders these compounds promising boron delivery agents for the BNCT of brain tumors.
Graphical Abstract
doi:10.1021/acs.jmedchem.5b01783
PMCID: PMC4893941  PMID: 26849474
9.  Chlorin e6 131:152-Anhydride: A Key Intermediate in Conjugation Reactions of Chlorin e6** 
European journal of organic chemistry  2015;2015(17):3661-3665.
Since the patent for the photodynamic therapy agent Talaporfin (mono-L-aspartylchlorin e6) was issued in 1987, confusion has existed regarding which of the three carboxylic acid groups in the chlorophyll degradation product, chlorin e6 (1), is modified in standard amino acid type conjugations (using DCC or EDC and an organic base) with amino acids and other biomolecules. Here it is shown that the site of conjugation is the central 152-carboxylic acid, such reactions proceeding in numerous examples via a 131,152-anhydride for which a high resolution X-ray structure is reported. Conjugation with eight oxygen and nitrogen nucleophiles, in every case, afforded the 152-conjugate, reinforcing the earlier conclusion that Talaporfin is the 152-aspartyl conjugate of chlorin e6 and suggesting that reports of 173-conjugation of chlorin e6 using stoichiometric peptide coupling procedures should be subjected to further scrutiny.
doi:10.1002/ejoc.201500478
PMCID: PMC4525479  PMID: 26257578
Talaporfin; chlorin e6; anhydride; amino acid conjugation; LS-11
10.  Stepwise Polychlorination of 8-Chloro-BODIPY and Regioselective Functionalization of 2,3,5,6,8-Pentachloro-BODIPY 
The Journal of organic chemistry  2015;80(16):8377-8383.
An effective, stepwise methodology for polychlorination of BODIPY using trichloroisocyanuric acid (TCCA) in acetic acid was developed. In this way, selectively substituted di-, tri-, tetra-, and pentachloro-BODIPYs 2–5 were prepared. The pentachloro-BODIPY is shown to undergo regioselective Pd(0)-catalyzed Stille and Suzuki coupling reactions, first at the 8-position followed by the 3,5- and then the 2,6-positions; nucleophilic substitution reactions occur first at the 8-followed by the 3,5-positions, while the 2,6 are unreactive.
doi:10.1021/acs.joc.5b01147
PMCID: PMC4881425  PMID: 26186141
11.  Synthesis of 3,8-Dichloro-6-ethyl-1,2,5,7-tetramethyl–BODIPY from an Asymmetric Dipyrroketone and Reactivity Studies at the 3,5,8-Positions** 
The asymmetric BODIPY 1a (BODIPY=4,4-difluoro-4-bora-3a,4a-diaza-s-indacene), containing two chloro substituents at the 3,8-positions and a reactive 5-methyl group, was synthesized from the asymmetric dipyrroketone 3, which was readily obtained from available pyrrole 2a. The reactivity of 3,8-dichloro-6-ethyl-1,2,5,7-tetramethyl-BODIPY 1a was investigated by using four types of reactions. This versatile BODIPY undergoes regioselective Pd0-catalyzed Stille coupling reactions and/or regioselective nucleophilic addition/elimination reactions, first at the 8-chloro and then at the 3-chloro group, using a variety of organostannanes and N-, O-, and S-centered nucleophiles. On the other hand, the more reactive 5-methyl group undergoes regioselective Knoevenagel condensation with an aryl aldehyde to produce a monostyryl-BODIPY, and oxidation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) gives the corresponding 5-formyl-BODIPY. Investigation of the reactivity of asymmetric BODIPY 1a led to the preparation of a variety of functionalized BODIPYs with λmax of absorption and emission in the ranges 487–587 and 521–617 nm, respectively. The longest absorbing/emitting compound was the monostyryl-BODIPY 16, and the largest Stokes shift (49 nm) and fluorescence quantum yield (0.94) were measured for 5-thienyl-8-phenoxy-BODIPY 15. The structural properties (including 16 X-ray structures) of the new series of BODIPYs were investigated.
doi:10.1002/chem.201406550
PMCID: PMC4382426  PMID: 25761150
addition/elimination; BODIPY; fluorescence; Pd0-catalyzed coupling; oxidation; substitution
12.  Synthesis, Spectroscopic, and in vitro Investigations of 2,6-Diiodo-BODIPYs with PDT and Bioimaging Applications 
A series of five mono-styryl and their corresponding symmetric di-styryl-2,6-diiodo-BODIPYs containing indolyl, pyrrolyl, thienyl or tri(ethylene glycol)phenyl groups were synthesized using Knoevenagel condensations. The yields for the condensation reactions were improved up to 40% using microwave irradiation (90 °C for 1 h at 400 W) due to lower decomposition of BODIPYs upon prolonged heating. The spectroscopic, structural (including the X-ray of a di-styryl-2,6-diiodo-BODOPY) and in vitro properties of the BODIPYs were investigated. The extension of π-conjugation through the 3,5-dimethyls of the known phototoxic 2,6-diiodo-BODIPY 1 produced bathochromic shifts in the absorption and emission spectra, in the order of 59–125 nm for the mono-styryl- and 126–220 nm for the di-styryl-BODIPYs in DMSO. The largest red-shifts were observed for the indolyl-containing BODIPYs while the largest fluorescence quantum yields were observed for the tri(ethyleneglycol)phenylstyryl-BODIPYs. Among this series, only the mono-styryl-BODIPYs were phototoxic (IC50 = 2–15 µM at 1.5 J/cm2), and were observed to localize preferentially in the cell ER and mitochondria. On the other hand, the di-styryl-BODIPYs were found to have low or no phototoxicity (IC50 > 100 µM at 1.5 J/cm2). Among this series of compounds BODIPY 2a shows the most promise for application as photosensitizer in PDT.
doi:10.1016/j.jphotobiol.2015.02.006
PMCID: PMC4369175  PMID: 25771382
BODIPY; PDT; fluorescence; cytotoxicity; cellular uptake
13.  Experimental and Theoretical Studies on Halide Binding with a p-Xylyl-Based Azamacrocycle 
A p-xylyl-based macrocycle L has been synthesized and its binding properties with halides have been investigated by 1H NMR titrations, single crystal X-ray diffraction analysis, and density functional theory (DFT) calculations. As investigated by 1H NMR titrations, the ligand preferentially binds a halide in a 1:2 binding mode, with the association constants (in log K2) of 2.82, 2.70, 2.28, and 2.20 for fluoride, chloride, bromide, and iodide, respectively. The overall binding trend was found to be in the order of fluoride > chloride > bromide > iodide, reflecting that the binding strength correlates with the relative basicity and size of the respective halide. Crystallographic studies indicate that the ligand forms 1:2 complexes with chloride, bromide and iodide. In the chloride complex, the ligand is hexaprotonated and each chloride is held via three NH···Cl– bonds. The ligand is tetraprotonated for the other complexes, where each halide is H-bonded to two secondary ammonium NH+ groups via NH···X– bonds. The results of DFT calculations performed on [H6L]6+ at M062x/6-311G (d,p) level in both gas and solvent phases, suggest that the ligand binds halides with the binding energy in the order of F– > Cl– > Br– > I–, supporting the experimental data obtained from 1H NMR studies. Results from DFT calculations further indicate that a 1:2 binding is energetically more favorable than a 1:1 binding of the ligand.
doi:10.1021/jp511040p
PMCID: PMC4298355  PMID: 25517862
14.  Functionalization of 3,5,8-Trichlorinated BODIPY Dyes 
The Journal of organic chemistry  2014;79(21):10342-10352.
Catalytic hydrogenation of dibenzyl 5-dipyrroketone-2,9-dicarboxylates followed by decarboxylative iodination affords a 2,9-diiododipyrroketone which gives a 2,5,9-trichlorodipyrromethene hydrochloride after nucleophilic addition/elimination, with adventitious chloride to replace the two iodide groups. Treatment with BF3·Et2O gives a 3,5,8-trichloro-BODIPY that readily undergoes regioselective Stille coupling at the 8-position, or homo/mixed couplings at the 3,8- or 3,5- and 8-positions. Stepwise and controlled replacement of the 3,5- and 8-chlorine atoms using Stille reagents results in formation of a completely unsymmetrical trisubstituted BODIPY. Several examples of unsymmetrical BODIPYs were synthesized and characterized using this methodology. Structure features of new BODIPYs are discussed within the context of 14 new X-ray structures, and photophysical parameters of all new BODIPY compounds are reported and discussed.
doi:10.1021/jo501969z
PMCID: PMC4227577  PMID: 25268574
15.  Functionalization of 3,5,8-Trichlorinated BODIPY Dyes 
The Journal of Organic Chemistry  2014;79(21):10342-10352.
Catalytic hydrogenation of dibenzyl 5-dipyrroketone-2,9-dicarboxylates followed by decarboxylative iodination affords a 2,9-diiododipyrroketone which gives a 2,5,9-trichlorodipyrromethene hydrochloride after nucleophilic addition/elimination, with adventitious chloride to replace the two iodide groups. Treatment with BF3·Et2O gives a 3,5,8-trichloro-BODIPY that readily undergoes regioselective Stille coupling at the 8-position, or homo/mixed couplings at the 3,8- or 3,5- and 8-positions. Stepwise and controlled replacement of the 3,5- and 8-chlorine atoms using Stille reagents results in formation of a completely unsymmetrical trisubstituted BODIPY. Several examples of unsymmetrical BODIPYs were synthesized and characterized using this methodology. Structure features of new BODIPYs are discussed within the context of 14 new X-ray structures, and photophysical parameters of all new BODIPY compounds are reported and discussed.
doi:10.1021/jo501969z
PMCID: PMC4227577  PMID: 25268574
16.  A co-crystal of nona­hydrated disodium(II) with mixed anions from m-chloro­benzoic acid and furosemide 
In view of its potential for developing useful pharamaceutical formulations of furosemide, a widely-used loop diuretic, the crystal structure of the furosemide anion with m-chloro­benzoate has been investigated. In these co-crystals, the monoanions of furosemide and m-chloro­benzoate are balanced by two independent Na+ ions, both of which are hexa­coordinated by three monodentate water mol­ecules, two double-water bridge mol­ecules and one single-water bridge mol­ecules, thus yielding centrosymmetric Na2(OH2)8 units linked by single water bridges to form chains in the [10] direction.
In the title compound, [Na2(H2O)9](C7H4ClO2)(C12H10ClN2O5S) {systematic name: catena-poly[[[triaquasodium(I)]-di-μ-aqua-[triaquasodium(I)]-μ-aqua] 3-chlorobenzoate 4-chloro-2-[(furan-2-ylmethyl)amino]-5-sulfamoylbenzoate]}, both the original m-chloro­benzoic acid and furosemide exist with deprotonated carboxyl­ates, and the sodium cations and water mol­ecules exist in chains with stoichiometry [Na2(OH2)9]2+ that propagate in the [-110] direction. Each of the two independent Na+ ions is coordinated by three monodentate water mol­ecules, two double-water bridges, and one single-water bridge. There is considerable cross-linking between the [Na2(OH2)9]2+ chains and to furosemide sulfonamide and carboxyl­ate by inter­molecular O—H⋯O hydrogen bonds. All hydrogen-bond donors participate in a complex two-dimensional array parallel to the ab plane. The furosemide NH group donates an intra­molecular hydrogen bond to the carboxyl­ate group, and the furosemide NH2 group donates an intra­molecular hydrogen bond to the Cl atom and an inter­molecular one to the m-chloro­benzoate O atom. The plethora of hydrogen-bond donors on the cation/water chain leads to many large rings, up to graph set R 4 4(24), involving two chains and two furosemide anions. The chloro­benzoate is involved in only one R 2 2(8) ring, with two water mol­ecules cis-coordinated to Na. The furan O atom is not hydrogen bonded.
doi:10.1107/S2056989015017430
PMCID: PMC4647361  PMID: 26594422
crystal structure; loop diuretics; co-crystals; pharmaceutical formulations; hydrogen bonding
17.  Orally Bioavailable 6-Chloro-7-methoxy-4(1H)-quinolones Efficacious against Multiple Stages of Plasmodium 
Journal of Medicinal Chemistry  2014;57(21):8860-8879.
The continued proliferation of malaria throughout temperate and tropical regions of the world has promoted a push for more efficacious treatments to combat the disease. Unfortunately, more recent remedies such as artemisinin combination therapies have been rendered less effective due to developing parasite resistance, and new drugs are required that target the parasite in the liver to support the disease elimination efforts. Research was initiated to revisit antimalarials developed in the 1940s and 1960s that were deemed unsuitable for use as therapeutic agents as a result of poor understanding of both physicochemical properties and parasitology. Structure–activity and structure–property relationship studies were conducted to generate a set of compounds with the general 6-chloro-7-methoxy-2-methyl-4(1H)-quinolone scaffold which were substituted at the 3-position with a variety of phenyl moieties possessing various properties. Extensive physicochemical evaluation of the quinolone series was carried out to downselect the most promising 4(1H)-quinolones, 7, 62, 66, and 67, which possessed low-nanomolar EC50 values against W2 and TM90-C2B as well as improved microsomal stability. Additionally, in vivo Thompson test results using Plasmodium berghei in mice showed that these 4(1H)-quinolones were efficacious for the reduction of parasitemia at >99% after 6 days.
doi:10.1021/jm500942v
PMCID: PMC4234439  PMID: 25148516
18.  Crystal structure of [N,N′-bis­(4-methyl­phen­yl)-1,2-di­phenyl­ethane-1,2-di­imine-κ2 N,N′]di­chlorido­palladium(II) methanol monosolvate 
The title compound, [PdCl2(C28H24N2)]·CH3OH, was pre­pared from the reaction of PdCl2(DMSO)2 (DMSO is di­methyl sulfoxide) and N,N′-bis­(4-methyl­phen­yl)-1,2-di­phenyl­ethane-1,2-di­imine in methanol. The chelating di­imine core of the title compound deviates slightly from planarity, with an N—C—C—N torsion angle of 5.3 (3)°. Delocalization in the di­imine core is indicated by N—C and C—C bonds that are, respectively, longer and shorter than those found in related nonchelating di­imines. The distorted square-planar coordination environment around the PdII atom is manifested as bond angles that are smaller and larger than 90°, and palladacycle torsion angles of −173.22 (16) and 167.06 (16)°. These deviations are attributed to the small bite angle of 79.13 (8)° of the di­imine chelate. The crystal packing exhibits weak inter­molecular hydrogen-bonding inter­actions involving aromatic H atoms, Cl atoms and inter­calated methanol solvent mol­ecules, defining layers parallel to (010).
doi:10.1107/S2056989015014851
PMCID: PMC4555432  PMID: 26396867
crystal structure; palladium(II) di­chlorido di­imine complex; polymerization catalyst
19.  Synthesis and in Vitro Evaluation of BBB Permeability, Tumor Cell Uptake, and Cytotoxicity of a Series of Carboranylporphyrin Conjugates 
Journal of Medicinal Chemistry  2014;57(15):6718-6728.
A series of tri[(p-carboranylmethylthio)tetrafluorophenyl]porphyrin conjugates of linear and branched polyamines, glucose, arginine, tri(ethylene glycol), and Tyr-d-Arg-Phe-β-Ala (YRFA) peptide were synthesized. These conjugates were investigated for their BBB permeability in human hCMEC/D3 brain endothelial cells, and their cytotoxicity and uptake were assessed using human glioma T98G cells. For comparison purposes, a symmetric tetra[(p-carboranylmethylthio)tetrafluorophenyl]porphyrin was also synthesized, and its crystal structure was obtained. All porphyrin conjugates show low dark cytotoxicity (IC50 > 400 μM) and low phototoxicity (IC50 > 100 μM at 1.5 J/cm2) toward T98G cells. All conjugates were efficiently taken up by T98G cells, particularly the cationic polyamine and arginine conjugates, and were localized in multiple cellular organelles, including mitochondria and lysosomes. All compounds showed relatively low in vitro BBB permeability compared with that of lucifer yellow because of their higher molecular weight, hydrophobicity, and tendency for aggregation in solution. Within this series, the branched polyamine and YRFA conjugates showed the highest permeability coefficient, whereas the glucose conjugate showed the lowest permeability coefficient.
doi:10.1021/jm500786c
PMCID: PMC4136688  PMID: 25029034
20.  A New Series of Complexes Possessing Rare “Tertiary” Sulfonamide Nitrogen-to-Metal Bonds of Normal Length: fac-[Re(CO)3(N(SO2R)dien)]PF6 Complexes with Hydrophilic Sulfonamide Ligands 
Inorganic chemistry  2014;53(2):1144-1155.
Tertiary sulfonamide nitrogen-to-metal bonds of normal length are very rare. We recently discovered such a bond in one class of fac-[Re(CO)3(N(SO2R)(CH2Z)2)]n complexes (Z = 2-pyridyl) with N(SO2R)dpa ligands derived from di-(2-picolyl)amine (N(H)dpa). fac-[M(CO)3(N(SO2R)(CH2Z)2)]n agents (M = 186/188Re, 99mTc) could find use as radiopharmaceutical bioconjugates when R is a targeting moiety. However, the planar, electron-withdrawing 2-pyridyl groups of N(SO2R)dpa destabilize the ligand to base and create relatively rigid chelate rings, raising the possibility that the rare M– N(sulfonamide) bond is an artifact of a restricted geometry. Also, the hydrophobic 2-pyridyl groups could cause undesirable accumulation in the liver, limiting future use in radiopharmaceuticals. Our goal is to identify a robust, hydrophilic, and flexible N(CH2Z)2 chelate framework. New C2-symmetric ligands, N(SO2R)(CH2Z)2 with (Z = CH2NH2; R = Me, dmb, or tol), were prepared by treating N(H)dien(Boc)2, a protected diethylenetriamine (N(H)dien) derivative, with methanesulfonyl chloride (MeSO2Cl), 3,5-dimethylbenzenesulfonyl chloride (dmbSO2Cl), and 4-methylbenzenesulfonyl chloride (tolSO2Cl). Treatment of fac-[Re(CO)3(H2O)3]+ with these ligands, designated as N(SO2R)dien, afforded new fac-[Re(CO)3(N(SO2R)dien)]PF6 complexes. Comparing the fac-[Re(CO)3(N(SO2Me)dien)]PF6 and fac-[Re(CO)3(N(SO2Me)dpa)]PF6 complexes, we find that the ReI–N(sulfonamide) bonds are normal in length and statistically identical and that the methyl 13C NMR signal has an unusually upfield shift compared to that in the free ligand. We attribute this unusual upfield shift to the fact that the sulfonamide N undergoes an sp2-to-sp3 rehybridization upon coordination to ReI in both complexes. Thus, the sulfonamide N of N(SO2R)dien ligands is a good donor, even though the chelate rings are conformationally flexible. Addition of the strongly basic and potentially monodentate ligand, 4-dimethylaminopyridine, did not affect the fac-[Re(CO)3(N(SO2tol)dien)]PF6 complex, even after several weeks. This complex is also stable to heat in aqueous solution. These results indicate that N(SO2R)dien ligands form fac-[Re(CO)3(N(SO2R)dien)]PF6 complexes sufficiently robust to be utilized for radiopharmaceutical development.
doi:10.1021/ic4026987
PMCID: PMC4465231  PMID: 24400928
21.  Formation of a Metal-to-Nitrogen Bond of Normal Length by a Neutral Sufonamide Group within a Tridentate Ligand. A New Approach to Radiopharmaceutical Bioconjugation 
Inorganic chemistry  2013;52(5):2412-2421.
We demonstrate that a tertiary sulfonamide group, N(SO2R)R′2, can re-hybridize to form a M–N bond of normal length even when the group is in a linear tridentate ligand, such as in the new tridentate N(SO2R)dpa ligands derived from di-(2-picolyl)amine (N(H)dpa). N(SO2R)dpa ligands were used to prepare fac-[Re(CO)3(N(SO2R)dpa)](PF6 or BF4) complexes. Structural characterization of the new complexes established that the tertiary sulfonamide nitrogen atom binds to Re with concomitant sp2-to-sp3 re-hybridization, facilitating facial coordination. The new fac-[Re(CO)3(N(SO2R)dpa)]X structures provide the only examples for any metal with the sulfonamide as part of a noncyclic linear tridentate ligand and with a normal metal-to-nitrogen(tertiary sulfonamide) bond length. Rare previous examples of such normal M–N bonds have been found only in more constrained situations, such as with tripodal tetradentate ligands. Our long-term objectives for the new tridentate N(SO2R)dpa ligands are to develop the fundamental chemistry relevant to the eventual use of the fac-[MI(CO)3]+ core (M = 99mTc, 186/188Re) in imaging and therapy. The sulfonamide group uniquely contributes to two of our goals: expanding ways to conjugate the fac-[MI(CO)3]+ core to biological molecules and also developing new symmetrical tridentate ligands that can coordinate facially to this core. Tests of our conjugation method, conducted by linking the fac-[ReI(CO)3]+ core to a new tetraarylporphyrin (T(N(SO2C6H4)dpa)P) as well as to a dansyl (5-(dimethylamino)naphthalene-1-sulfonyl) group, demonstrate that large molecular fragments can be tethered via a coordinated tertiary sulfonamide linkage to this core.
doi:10.1021/ic302180t
PMCID: PMC4465213  PMID: 23421481
22.  Discovery and Structure–Activity Relationship of Novel 2,3-Dihydrobenzofuran-7-carboxamide and 2,3-Dihydrobenzofuran-3(2H)-one-7-carboxamide Derivatives as Poly(ADP-ribose)polymerase-1 Inhibitors 
Journal of Medicinal Chemistry  2014;57(13):5579-5601.
Novel substituted 2,3-dihydrobenzofuran-7-carboxamide (DHBF-7-carboxamide) and 2,3-dihydrobenzofuran-3(2H)-one-7-carboxamide (DHBF-3-one-7-carboxamide) derivatives were synthesized and evaluated as inhibitors of poly(ADP-ribose)polymerase-1 (PARP-1). A structure-based design strategy resulted in lead compound 3 (DHBF-7-carboxamide; IC50 = 9.45 μM). To facilitate synthetically feasible derivatives, an alternative core was designed, DHBF-3-one-7-carboxamide (36, IC50 = 16.2 μM). The electrophilic 2-position of this scaffold was accessible for extended modifications. Substituted benzylidene derivatives at the 2-position were found to be the most potent, with 3′,4′-dihydroxybenzylidene 58 (IC50 = 0.531 μM) showing a 30-fold improvement in potency. Various heterocycles attached at the 4′-hydroxyl/4′-amino of the benzylidene moiety resulted in significant improvement in inhibition of PARP-1 activity (e.g., compounds 66–68, 70, 72, and 73; IC50 values from 0.718 to 0.079 μM). Compound 66 showed selective cytotoxicity in BRCA2-deficient DT40 cells. Crystal structures of three inhibitors (compounds (−)-13c, 59, and 65) bound to a multidomain PARP-1 structure were obtained, providing insights into further development of these inhibitors.
doi:10.1021/jm5002502
PMCID: PMC4094269  PMID: 24922587
23.  Synthesis and Transformations of 5-Chloro-2,2′-Dipyrrins and Their Boron Complexes, 8-Chloro-BODIPYs** 
Symmetric dipyrrylketones 1a,b were synthesized in two steps from the corresponding α-free pyrroles, by reaction with thiophosgene followed by oxidative hydrolysis under basic conditions. The dipyrrylketones produced the corresponding 5-chloro-dipyrrinium salts or 5-ethoxy-dipyrrins on reaction with phosgene or Meerwein’s salt, respectively. Boron complexation of the dipyrrins afforded the corresponding 8-functionalized BODIPYs (borondipyrromethenes) in high yields. The 5-chloro-dipyrrinium salts reacted with methoxide or ethoxide ions to produce monopyrrole esters, presumably via a 5,5-dialkoxy-dipyrromethane intermediate. In contrast, 8-chloro-BODIPYs underwent a variety of nucleophilic substitutions of the chloro group in the presence of alkoxide ions, Grignard reagents, and thiols. In the presence of excess alkoxide or Grignard reagent, at room temperature or above, substitution at the boron center also occurred. The 8-chloro-BODIPY was a particularly useful reagent for the preparation of 8-aryl-, 8-alkyl-, and 8-vinyl-substituted BODIPYs in very high yields, using Pd0-catalyzed Stille cross-coupling reactions. The X-ray structures of eleven BODIPYs and two pyrroles are presented, and the spectroscopic properties of the synthesized BODIPYs are discussed.
doi:10.1002/chem.201304310
PMCID: PMC4012389  PMID: 24616111
bodipy; dipyrrin; dipyrrylketone; fluorescence
24.  Phenyl Derivative of Iron 5,10,15-Tritolylcorrole 
Inorganic Chemistry  2014;53(8):4215-4227.
The phenyl–iron complex of 5,10,15-tritolylcorrole was prepared by reaction of the starting chloro–iron complex with phenylmagnesium bromide in dichloromethane. The organometallic complex was fully characterized by a combination of spectroscopic methods, X-ray crystallography, and density functional theory (DFT) calculations. All of these techniques support the description of the electronic structure of this phenyl–iron derivative as a low-spin iron(IV) coordinated to a closed-shell corrolate trianion and to a phenyl monoanion. Complete assignments of the 1H and 13C NMR spectra of the phenyl–iron derivative and the starting chloro–iron complex were performed on the basis of the NMR spectra of the regioselectively β-substituted bromo derivatives and the DFT calculations.
The preparation of complex 1 fills a gap in the series of triarylcorrole iron derivatives. The spectroscopic and theoretical characterization of this complex indicates that it can be described as an Fe(IV) derivative, with a nonoxidized corrole species, acting as a trianionic ligand. However also in this case significant spin density is present on the corrole ring, as predicted by DFT calculations and confirmed by the 1H NMR isotropic shifts.
doi:10.1021/ic5003572
PMCID: PMC4002138  PMID: 24697623
25.  Colourimetric and fluorescent detection of oxalate in water by a new macrocycle-based dinuclear nickel complex: a remarkable red shift of the fluorescence band† 
A new macrocycle-based dinuclear nickel chemosensor selectively binds oxalate anions both in solution and the solid state, displaying a remarkable red shift of the fluorescence band with a visible colour change in water at physiological pH in the presence of an external dye.
doi:10.1039/c3dt53467g
PMCID: PMC3976989  PMID: 24419223

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