Search

Immortal copolymerization of lactide (LA) and 2-methyl-2-benzyloxycarbonyl-1,3-trimethylene carbonate (MBC) affords random, tapered, and diblock microstructured poly(lactide-co-carbonate)s. Subsequ...

Hydroboration of pyridine derivatives at room temperature with earth-abundant and biocompatible magnesium catalysts ligated by phosphinimino amides is developed. Fine turnover frequency (TOF) and distinguished 1,2-regioselectivity have been achieved. The exclusive chemoselective carbonyl hydroboration happens with competitive TOF. A HBpin assisted mechanism is deduced by the reaction rate law, activation parameters, and kinetic isotope effect (KIE) in combination with DFT calculations. To our knowledge, this is the first example of pyridine 1,2-dearomatization by Mg-based catalysts.

d-Lactate dehydrogenase (d-LDH) catalyzes the reversible reaction pyruvate + NADH + H+ ↔ lactate + NAD+, which is a principal step in the production of d-lactate in lactic acid bacteria. In this study, we identified and characterized the major d-LDH (d-LDH1) from three d-LDHs in Leuconostoc mesenteroides, which has been extensively used in food processing. A molecular simulation study of d-LDH1 showed that the conformation changes during substrate binding. During catalysis, Tyr101 and Arg235 bind the substrates by hydrogen bonds and His296 acts as a general acid/base for proton transfer. These residues are also highly conserved and have coevolved. Point mutations proved that the substrate binding sites and catalytic site are crucial for enzyme activity. Network and phylogenetic analyses indicated that d-LDH1 and the homologues are widely distributed but are most abundant in bacteria and fungi. This study expands the understanding of the functions, catalytic mechanism, and evolution of d-LDH.

The controlled ring-opening polymerizations of enantiopure (L-LA or D-LA) or racemic lactide (rac-LA) with achiral functionalized cyclic carbonates (TMCR) have been performed by using the aminobisphenolate yttrium and lutetium alkyl complexes or an organo-base catalyst DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), in combination with various alcohols as chain transfer agents. When using the highly heteroselective precatalyst 1Y, the copolymerization of rac-LA and TMCR afforded tapered copolymer poly(rac-LA-t-TMCR), while the copolymerization of enantiopure L-LA or D-LA, respectively, with TMCR gave pseudo-random product poly(L-LA-r-TMCR). When the low heteroselective rare-earth metal precatalysts or organic DBU were applied, the difference in the monomer distributions for the above two systems disappeared gradually. On the contrary, the monomer sequence distribution was not influenced by the types of chain transfer agents and TMCR. The kinetics study revealed that the competitive reaction ratios were rL-LA = ...

The stoichiometric reactions of phosphinimino-amino (PIA)-supported magnesium hydride complex 1, [L1MgH]2 (L1 = (2,6-iPr2-C6H3)NC(Me)CHP(Cy2)N(2,6-Me2-C6H3)), with pyridine N-oxide and 2-phenylpyridine N-oxide afforded 2,4-pentadiene-1-oximate complex 2 and 5-phenyl-2,4-pentadiene-1-oximate complex 3, respectively. The reaction of 1 with 2-methylpyridine N-oxide showed a unique regioselectivity to produce 2,4-hexadiene-1-oximate 4a in toluene and 3,5-hexadiene-2-oximate 4b in THF, respectively. Treatment of β-diketiminato (BDI)-supported magnesium hydride complex 5, [L2MgH]2 (L2 = (2,6-iPr2-C6H3)NC(Me)CHC(Me)N(2,6-iPr2-C6H3)), with quinoline N-oxide gave 1,2-dihydroquinoline type product 6, while treatment of complex 5 with 2-methylpyridine N-oxide either in toluene or THF afforded 1-methyl-2,4-pentadiene-1-oximate complex 7 as the only product. All these complexes were fully characterized by NMR spectroscopy and X-ray diffraction analyses, and mechanism researches were conducted to understand the ring-op...

A highly efficient strategy for synthesizing the first biocompatible polyesters with AIE characteristics has been established via immortal ring-opening polymerizations of cyclic esters bearing nonluminophores. In the process, the large excess hydroxyl-modified AIE active compound, acting as the chain transfer agent, attaches to the active rare-earth metal catalyst via the rapid-reversible exchange reaction to initiate the polymerization. Thus, more polyester chains appear to grow from one active metal species, and the AIE fragments are incorporated into the polymer chains at specific sites, in situ. The resultant polyesters have linear, block, or star-shaped microstructures mimicking those of the modified AIE compounds. The polymerization solutions can be directly fabricated to large-area thin solid films. The obtained PLA, for instance, emits fluorescence in water/THF mixtures owing to aggregation, the intensity of which is 2850-fold stronger than that in THF solution. This strategy avoids complicated pr...

Hyaluronan-grafted liposomes (HA-liposomes) preferentially target CD44-overexpressing tumor cells in vitro via receptor-mediated endocytosis. We investigated the pharmacokinetics and biodistribution of HA-liposomes with various sizes of HA (MW 5-8, 50-60, and 175-350 kDa) in mice. Incorporation of negatively charged HA on the liposome surface compromised its blood circulation time, which led to decreased tumor accumulation in CD44+ human breast cancer MDA-MB-231 xenografts compared to PEGylated liposomes (PEG-5000). Clearance of HA-liposomes was HA polymer length-dependent; high MW (175-350 kDa, highest ligand binding affinity) HA-liposomes displayed faster clearance compared to low MW (5-8, 50-60 kDa) HA-liposomes or PEGylated liposomes. Surface HA ligand density can also affect clearance of HA-liposomes. Thus, HA is not an effective stealth coating material. When dual coating of PEG and HA was used, the PEG-HA-liposomes displayed similar blood circulation time and tumor accumulation to that of the PEGylated liposomes; however, the PEG-HA-liposomes displayed better cellular internalization capability in vivo. Tumor histology showed that PEG-HA-liposomes had a more direct association with CD44+ cancer cells, while PEGylated liposomes located predominantly in the tumor periphery, with less association with CD44+ cells. Flow cytometry analysis of ex vivo tumor cells showed that PEG-HA-liposomes had significantly higher tumor cell internalization compared to PEGylated liposomes. This study demonstrates that a long blood circulation time is critical for active tumor targeting. Furthermore, the use of the tumor-targeting ligand HA does not increase total tumor accumulation of actively targeted liposomes in solid tumors; however, it can enhance intracellular delivery.

A series of oxophosphine (3,5-Me2Pz)2CHP(R)2O (Pz = pyrazole; R = tBu (HL1), Cy (HL2)) and iminophosphine (3,5-Me2Pz)2CHP(R)2NAr (R = Cy, Ar = Ph (HL3); R = Ph, Ar = Ph (HL4), Ar = 2,6-Me2-phenyl (HL5)) heteroscorpionate ligands were synthesized. Abstraction of the methide proton of these ligands by rare-earth-metal tris(alkyl)s, Ln(CH2SiMe3)3(THF)2, afforded the corresponding zwitterionic bis(alkyl) complexes L1–5Ln(CH2SiMe3)2(THF) (L1, Ln = Y (1a), Lu (1b); L2, Ln = Y (2a), Lu (2b); L3, Ln = Y (3a), Lu (3b); L4, Ln = Y (4a), Lu (4b); L5, Ln = Y (5a), Lu (5b), while metathesis reaction of the lithium salts of LiL3 and LiL4 with YCl3(THF)2 or YBr3(THF)2 followed by treatment with LiCH2SiMe3 and KN(SiHMe2)2, respectively, afforded the first heteroscorpionate yttrium mixed halogen/alkyl or amido complexes L3–4Y(Cl)(CH2SiMe3)(THF) (L3 (6a), L4 (7a)), L3–4Y(Cl)(N(SiHMe2)2)(THF) (L3 (8a), L4 (9a)), L4Y(Br)(CH2SiMe3)(THF) (10a), and L4Y(Br)(N(SiHMe2)2)(THF) (11a). The structures of these complexes were well-def...

A simple, inexpensive, and convenient catalyst system consisting of supporting ligand-free MgnBu2 in combination with an alcohol, isopropanol (iPrOH), benzyl methanol (PhCH2OH), diphenylmethanol (Ph2CHOH), or triphenylmethanol (Ph3COH), generates a convenient catalyst system to promote the polymerization of l-LA. In particular, the binary system MgnBu2/Ph2CHOH demonstrates an unprecedentedly high activity in the presence of a large excess amount of Ph2CHOH with the [OH]0/[Mg]0 ratio varying from 2 to 500, producing up to 500 polylactide (PLA) chains per Mg center and thus showing a typical nature of immortal polymerization. The molecular weights of the obtained PLAs with a broad range of monomer-to-metal ratios ([l-LA]0/[Mg]0 = 200–5000) are rather accurately controlled by the Ph2CHOH loading, relative to [Mg]0, while the molecular weight distributions remain nearly constant with polydispersity index (PDI) = 1.08–1.18. Moreover, the active polymerization intermediate has been isolated from the stoichiomet...

The N,O-bidentate pyridyl functionalized alkoxy ligands 2-(6-methyl-2-pyridinyl)-1,1-dimethyl-1-ethanol (L-1-H) and 2-(6-methyl-2-pyridinyl)-1,1-diphenyl-1-ethanol (L-2-H) have been prepared by treatment of acetone and benzophenone with monolithiated 2,6-lutidine. Deprotonolysis of the ligands L-1-H and L-2-H with 1 equiv of (MgBu2)-Bu-n and ZnEt2 in toluene by releasing butane and ethane, respectively, gave the corresponding dimeric metal-monoalkyl complexes [(LMgBu)-Mg-1-Bu-n](2) (1), [(LMgBu)-Mg-2-Bu-n](2) (2), [(LZnEt)-Zn-1](2) (3), and [(LZnEt)-Zn-2](2) (4). Complexes 1-4 were characterized by H-1 and C-13 NMR spectroscopy analysis, and the molecular structures of 1, 3, and 4 were further confirmed by X-ray diffraction analysis. The investigation of the catalytic behavior of these complexes toward epsilon-caprolactone (epsilon-CL) and L-lactide (L-LA) polymerizations showed that the Mg-based complexes gave higher activity than those attached to zinc metal, probably owing to the greater ionic character of the magnesium metal. Remarkably, the magnesium complex 2 exhibited a striking "immortal" nature in the presence of primary alcohols where up to 500 PCL chains grew from each Mg active center when benzyl alcohol was employed, while, in particular, in the presence of triethanolamine, complex 2 also displayed an immortal mode for the polymerization of L-LA.

Highly pathogenic influenza viruses have become a global threat to humans. It is important to select an effective therapeutic option suitable for the subtypes in an epidemic or pandemic. To increase the options, the development of novel antiviral agents acting on targets different from those of the currently approved drugs is required. In this study, we performed molecular dynamics simulations on a spike protein on the viral envelop, hemagglutinin, for the wild-type and three kinds of mutants using a model system consisting of a trimeric hemagglutinin complex, viral lipid membrane, solvation waters, and ions. A natural product, stachyflin, which shows a high level of antiviral activity specific to some subtypes of influenza viruses, was examined on binding to the wild-type hemagglutinin by docking simulation. The compound potency of stachyflin is, however, easily lost due to resistant mutations. From a comparison of simulation results between the wild-type and the resistant mutants, the reason for the drug resistance of hemagglutinin was clarified. Next, 8 compounds were selected from a chemical database by in silico screening, considering the findings from the simulations. Inhibitory activities to suppress the proliferation of influenza virus were measured by cell-based antiviral assays, and two chemical scaffolds were found to be potent for an inhibitor. More than 30 derivatives bearing either of these two chemical scaffolds were synthesized, and cell culture assays were carried out to evaluate the compound potency. Several derivatives displayed a high compound potency, and 50% effective concentrations of two synthesized compounds were below 1 μM.

Benzyl isothiocyanate (BITC), a compound found in cruciferous vegetables, is an effective chemopreventive agent. The objective of this study was to develop nanoemulsion formulations for the oral delivery of BITC. Optimized oil-in-water BITC nanoemulsions were prepared by a spontaneous self-nanoemulsification method and a homogenization-sonication method. Both nanoemulsions entrapped high amounts of BITC (15-17 mg/mL), with low polydispersity and good colloidal stability. The BITC nanoemulsions showed enhanced solubility and dissolution compared to pure BITC. These formulations markedly increased the apical to basolateral transport of BITC in Caco-2 cell monolayers. The apparent permeability values were 3.6 × 10(-6) cm/s for pure BITC and (1.1-1.3) × 10(-5) cm/s for BITC nanoemulsions. The nanoemulsions were easily taken up by human cancer cells A549 and SKOV-3 and inhibited tumor growth in vitro. This work shows for the first time that BITC can be formulated into nanoemulsions and may show promise in enhancing absorption and bioavailability.

Triethanolamine (TEA) reacted with 3 equiv of yttrium alkyl complex 1 bearing O,N,N,O-tetradentate Salan ligand to give a trinuclear yttrium alkoxide counterpart 2 via metathesis reaction. Complex 2 initiated the ring-opening polymerization of rac-lactide in a livingness mode under mild conditions. Remarkably, 2 was so tolerant of the protic TEA that under various TEA-to-yttrium molar ratios ranging from 1:3 up to 81:1, the polymerization performed smoothly, suggesting an immortal characteristic. The resultant polylactides had variable molecular weights (Mn = 1.36 × 104to 32.54 × 104) but narrow molecular weight distributions (PDI = 1.02−1.09), and, especially, pure heterotactic (Pr = 0.99), hydroxyl-functionalized and star-shaped architecture, which were fully characterized by NMR spectroscopy and MALDI−TOF mass spectrum analyses and confirmed further by calculating the contraction factor value g′ (g′ = 0.96) via Mark−Houwink equations. Detailed investigation of the “immortal” polymerization gave a uniqu...

Treatment of anilido-phosphinimine-ligated yttrium mono(alkyl) complex 1a, LY(CH2Si(CH3)(3))(THF) (L = o-(2,6-(C6H3Pr2)-Pr-i)NC6H4P(C6H4)(C6H5)N(2,4,6-C6H2Me3)), with 2 equiv of phenylsilane in DME afforded methoxy-bridged complex 2, [LY(mu-OCH3)](2), via the corresponding hydrido intermediate. When excess isoprene was added to the mixture of la and phenylsilane, a eta(3)-isopentene product, 3, LY(CH2C(CH3)=CHCH3)(THF), was isolated. A lutetium chloride, LLuCl(DME) (4), was generated through the reaction of lutetium mono(alkyl) complex 1b, LLu(CH2Si(CH3)(3))(THF), with [Ph3C]-[B(C6F5)(4)]center dot LiCl accompanied by the formation of [Li(DME)(3)](+)[B(C6F5)(4)](-). Metathesis reaction of 1b with excess AlMe3 at room temperature gave a methyl-terminated counterpart, 5, LLu(CH3)(THF)(2). In all these reactions, the Ln-C-phenyl bonds of complexes 1 remained untouched.

A series of new rare-earth metal bis(alkyl) complexes [L1−3Ln(CH2SiMe3)2(THF)n] (L1 = MeC4H2SCH2NC6H4(Ph)2P═NC6H2Me3-2,4,6: Ln = Sc, n = 1 (1a); Ln = Lu, n = 1 (1b); L2 = MeC4H2SCH2NC6H4(Ph)2P═NC6H3Et2-2,6: Ln = Sc, n = 1 (2a); Ln = Lu, n = 1 (2b); Ln = Y, n = 1 (2c); L3 = MeC4H2SCH2NC6H4(Ph)2P═NC6H3iPr2-2,6: Ln = Sc, n = 0 (3a)) and L4Sc(CH2SiMe3)2(THF) (4a) (L4 = C6H5CH2NC6H4(Ph)2P═NC6H3Et2-2,6) have been prepared by reaction of rare-earth metal tris(alkyl)s with the corresponding HL1−4 ligands via alkane elimination. Complexes 1a, 1b, 2a−2c, and 4a are monomeric with a coordinating THF molecule. Each metal ion is coordinated by a NPN ligand, two trans-located alkyl groups, and a THF molecule, forming a distorted trigonal-bipyramidal geometry. Complex 3a is THF-free, adopting a distorted tetrahedron geometry. In combination with AlR3 and borate, these complexes have shown medium activity and good trans-1,4 selectivity for the polymerization of butadiene. The resultant polymer has moderate molecular weig...

The ligand binding/unbinding process is critical to our understanding of the pharmacology of both the nicotinic acetylcholine receptor (nAChR) and the acetylcholine binding protein (AChBP). Steered molecular dynamics simulations were performed to learn about the unbinding process of the full agonist nicotine. Three different pulling models were designed to investigate the possible binding/unbinding pathways: radial and tangent models, and also a mixed model. Of the three, the tangent pulling model finally failed to dissociate nicotine from the ligand binding pocket. The efficiency of the pulling force profiles was superior, and the opening of the C-loop was smaller in the mixed pulling model than that in the radial model. The most favorable pathway for the cholinergic agonist nicotine to enter or leave the binding pocket is through the principal binding side, following a curvilinear track. Noticeably, it has been seen that the unbinding of the nicotine is concomitant with a global rotation of the protein-ligand complex which could be caused by the interactions of the ligand with protein at the tangent direction.

Alkane elimination reactions of amino-amino-bis(phenols) H2L1-4, Salan H2L5, and methoxy-beta-diimines HL6,7 with lanthanide tris(alkyl) s, Ln(CH2SiMe3)(3)(THF)(2) (Ln = Y, Lu), respectively, afforded a series of lanthanide alkyl complexes 1-8 with the release of tetramethylsilane. Complexes 1-6 are THF-solvated mono( alkyl) s stabilized by O, N, N, O-tetradentate ligands. Complexes 1-3 and 5 adopt twisted octahedral geometry, whereas 4 contains a tetragonal bipyramidal core. Bearing a monoanionic moiety L-6 (L-7), complex 7 ( 8) is a THF-free bis(alkyl). In complex 7, the O, N, N-tridentate ligand combined with two alkyl species forms a tetrahedral coordination core. Complexes 1, 2, and 3 displayed modest activity but high stereoselectivity for the polymerization of rac-lactide to give heterotactic polylactide with the racemic enchainment of monomer units P-r ranging from 0.95 to 0.99, the highest value reached to date. Complex 5 exhibited almost the same level of activity albeit with relatively low selectivity. In contrast, dramatic decreases in activity and stereoselectivity were found for complex 4. The Salan yttrium alkyl complex 6 was active but nonselective. Bis(alkyl) complexes 7 and 8 were more active than 1-3 toward polymerization of rac-LA, however, to afford atactic polylactides due to di-active sites. The ligand framework, especially the "bridge" between the two nitrogen atoms, played a significant role in governing the selectivity of the corresponding complexes via changing the geometry of the metal center.

A sensitive and selective capillary liquid chromatography nanoelectrospray isotope dilution mass spectrometric method was developed to identify and quantify the endogenous cyclic DNA adducts derived from trans-4-hydroxy-2-nonenal with 2'-deoxyguanosine (HNE-dG) in human brain tissues. Authentic and 13C and 15N stable isotope-labeled HNE-dG were synthesized to serve as standards. The in vitro HNE-modified calf-thymus DNA as well as the DNA samples isolated from human brain tissues of normal and Alzheimer's disease subjects were enzymatically digested to nucleosides in vitro with the presence of internal standard (HNE-dG-13C10, 15N5). The enzymatic digests were cleaned up by solid phase extraction. Only 1-2 microg of DNA digests was loaded on a laboratory-constructed reversed phase capillary chromatography column, and the HNE-dG adducts were separated from intact nucleosides and quantified by a high capacity ion trap mass spectrometer in the MS/MS mode. This method was able to quantify an adduct level of approximately 40 lesions/10(9) normal DNA nucleosides. The detected level of HNE-dG adducts in hippocampus/parahippocampal gyrus and inferior parietal regions of postmortem brains from AD subjects were 556 +/- 379 and 238 +/- 72 adducts per 10(9) normal nucleosides, respectively. These results were consistent with the 32P postlabeling results, which detected 400-600 adducts per 10(9) normal nucleotides in the hippocampus.

We describe a versatile prodrug strategy for loading the liposomal lumen with water-insoluble camptothecins. The procedure involves conversion of an active camptothecin analogue to a 20-OR omega-aminoalkanoanic ester prodrug in which R = CO[CH(2)](n)()NH(2) and n = 1-3. The basic amino group of the prodrug serves three roles. First, at pH ranges of 3-5, the amine enhances aqueous solubility. Second, it enhances responsiveness to a transmembrane ammonium sulfate gradient across the liposomal bilayer, thereby facilitating active loading of the agent into the liposomal aqueous core. Third, at a physiological pH of 7 or above (the pH to be encountered following drug release at the tumor site), the nucleophilicity of the amine manifests itself and cyclization to the C-21 carbonyl carbon occurs. This cyclization triggers a rapid and convenient nonenzymatic decomposition process that releases active camptothecin. Accordingly, this novel liposomal approach offers a potential system for tumor-targeting prodrugs of many water-insoluble camptothecins, including the highly lipophilic and clinically attractive analogues SN-38, 9-nitrocamptothecin and DB-67. The rate of formation of the active agent at the tumor site can be controlled through the selection of n (the length of the alkyl spacer group).