Polymerization of a Photocleavable Monomer Using Visible Light

The polymerization of the photocleavable monomer, o‐nitrobenzyl methacrylate (NBMA), is investigated using photoinduced electron/energy transfer reversible addition‐fragmentation chain transfer polymerization. The polymerizations under visible red (λ _max = 635 nm, 0.7 mW cm⁻²) and yellow (λ _max = 560 nm, 9.7 mW cm⁻²) light are performed and demonstrate rational evidence of a controlled/living radical polymerization process. Well‐defined poly(o‐nitrobenzyl methacrylate) (PNBMA) homopolymers with good control over the molecular weight and polymer dispersity are successfully synthesized by varying the irradiation time and/or targeted degree of polymerization. Chain extension of a poly(oligo(ethylene glycol) methyl ether methacrylate) macro‐chain transfer agent with NBMA is carried out to fabricate photocleavable amphiphilic block copolymers (BCP). Finally, these self‐assembled BCP rapidly dissemble under UV light suggesting the photoresponsive character of NBMA is not altered during the polymerization under yellow or red light. Such photoresponsive polymers can be potentially used for the remote‐controlled delivery of therapeutic compounds.

     

A Novel Molecule: 1-(2,6 Dichlorobenzyl)-4-(2-(2-4-hydroxybenzylidene)hydrazinyl)pyridinium Chloride and its Interaction with DNA

Herein, a novel pyridine derivative, 1-(2,6 dichlorobenzyl)-4-(2-(2-4-hydroxybenzylidene)hydrazinyl)-pyridinium chloride (DHPC), was synthesized as a candidate drug molecule. Interaction of DHPC with DNA was used to explore its effect on DNA via Differential Pulse Voltammetry, Cyclic Voltammetry, and Electrochemical Impedance Spectroscopy. We demonstrated that oxidation signal of guanine bases of DNA decreased significantly while that of DHPC increased after its interaction with one another. Our candidate drug molecule exhibits LOD and LOQ, e.g., 1.5 μg/mL and 4.9 μg/mL, respectively. Toxicity effect value for DHPC (S%) was calculated as %31, demonstrating the candidate drug molecule's toxic effect on DNA.     

Ozonic acid and its ionic salts: ab initio probing of the O(4)(2)(-) dianion

The pyramidal O(4)(2)(-) dianion is valence isoelectronic to the well-known ClO(3)(-) and SO(3)(2)(-) anions, and yet it has not been observed. The synthesis of any molecule containing such a dianion would represent a major breakthrough in making molecules containing more than three covalently bound oxygen atoms. We found that the parent H(2)O(4) ozonic acid is unstable in the form of the valence isoelectronic sulfurous acid H(2)SO(3). Our quantum chemical probing of the Li(2)O(4) ionic salt molecule is inconclusive. However, we found that the specially designed FLi(3)O(4) gas phase molecule is a true metastable species and could be considered as the first molecule containing the O(4)(2)(-) dianion. Our theoretical prediction of the first compound containing the tetraatomic covalently bound O(4)(2)(-) dianion opens the possibility to even more oxygen rich compounds, which will have a great potential as high density oxygen storage.     

Influence of blood proteins on biomedical analysis. XII. Effects of glycation on gliclazide (oral hypoglycemic drug)-binding with serum albumin in diabetics.

The sera of diabetic patients showed an inverse correlation (r = -0.67, n = 57) between free gliclazide (oral hypoglycemic drug) level and the fructosamine value. The binding capacity of the primary binding site for gliclazide in the albumin molecule was increased from 4.5 x 10(-4) to 8.0 x 10(-4) M-1 by glycation of albumin, but not that of the secondary binding site (1.2 x 10(-4) M-1). This suggests that the glycation of albumin increases its total binding capacity for gliclazide, resulting in a low free gliclazide level. Therefore, a low hypoglycemic activity of the drug is observed when it is administered to diabetic patients with hyperglycemia.     

Structure and properties of bis{[2-(4-<Emphasis Type="Italic">tert</Emphasis>-butyl)phen]ethyl}phosphine sulfide

Previously unknown bis[2-(4-tert-butyl)phen]ethylphosphine sulfide is obtained with a high yield from 4-tert-butyl styrene, red phosphorus, and elemental sulfur. Using single crystal XRD, multinuclear NMR, IR, and UV spectroscopy, it is found that the phosphorus atom is four-coordinated in the bis[2-(4-tert-butyl)phen]ethylphosphine sulfide molecule (regardless of the phase state of the compound: crystal, solution). By the example of phosphorylation of bis[2-(4-tert-butyl)phen]ethylphosphine sulfide acetylene in the KOH-DMSO system it is shown that the reaction proceeds by double addition with the participation of phosphorus-centered nucleophiles.     

Synthesis of Cyclosporine and Analogues: Structural Requirements for Immunosuppressive Activity

Cyclosporine is a new immunosuppressive drug which was first marketed in 1983 under the trade name Sandimmune®. This compound, an innovation in selective immune modulation, was isolated from a fungal culture and characterized as a cyclic undecapeptide containing a novel amino acid together with several N-methylated amino acids. The new amino acid (4R)-4-[(E)-2-butenyl]-4,N-dimethyl-L -threonine (MeBmt) was the only unknown amino acid of cyclosporine and there had previously been no means for its isolation. For this reason and because it seemed possible that MeBmt could play a significant role in determining the pharmacological activity of cyclosporine, its synthesis in enantiomerically pure form was undertaken. The next step was the development of a total synthesis of cycloporine, which appeared attractive, not only for its intrinsic worth, but also as an important tool for investigating the relationships between structure and immunosuppressive activity. Essential for the immunosuppression are the amino acids MeBmt, Abu, Sar, and MeVal in the positions 1, 2, 3 and 11, but probably also still larger parts of the molecule. Such information could be valuable for finding new chemical leads or drugs with a new activity profile.     

Oxidizing Reactions of Azines. 7. Imination of 4-Aryl-1,2,3,6-tetrahydropyridines by Arylamines in the Presence of Potassium Permanganate. Molecular Structure of 1-Methyl-2-(4-nitrophenylimino)-4-phenyl-1,2,5,6-tetrahydropyridine

On treating 4-aryl substituted 1-methyl-1,2,3,6-tetrahydropyridines with potassium permanganate in the presence of arylamines a previously unknown intermolecular oxidative imination reaction occurs leading to the formation of 2-(arylimino)-1,2,5,6-tetrahydropyridines. The molecular structure of 1-methyl-2-(4-nitrophenylimino)-4-phenyl-1,2,5,6-tetrahydropyridine was studied by X-ray analysis and it was shown that the hydropyridine ring of the molecule has a sofa conformation and its amidine fragment is in the E-configuration.     

Nanosized mixed aggregates of alkylated <Emphasis Type="Italic">p</Emphasis>-sulfonatocalix[<Emphasis Type="Italic">n</Emphasis>]arenes and cetyltrimethylammonium bromide: self-organization and catalytic activity

Self-organization and catalytic activity of supramolecular systems based on a series of O-alkylated p-sulfonatocalix[n]arenes (SCA: n = 4, 6, 8; R = Bu, Oct, Dod (Oct is octyl, Dod is dodecyl)) and cetyltrimethylammonium bromide (CTAB) were studied by dynamic light scattering, tensimetry, and spectrophotometry. In aqueous solutions containing SCA (10^-6-10^-4 mol L^-1) and CTAB (10^-2-10^-12 mol L^-1), mixed associates and SCA—CTAB micelles are formed in a wide concentration range. Their sizes (100–300 nm), properties, and reactivity depend mainly on the structure and concentration of the starting components, as well as on the nature of their associates in solutions. A relationship between the nonlinear concentration dependences of the sizes of SCA—CTAB micelles (SCA: n = 4, 6, 8; R = Dod) and their catalytic activity in the hydrolysis of _O-ethyl _O-(4-nitrophenyl) chloromethylphosphonate was established. The study of the physiological effect on plant cells in solutions of SCA (n = 6; R = Dod), CTAB, and their mixtures showed that SCA and CTAB exerted opposite effects on the energy exchange in the wheat root cells, while a mixed solution of these substances (1: 1) has almost no effect on the physiological state of the roots, which is due to the formation of stable CTAB—SCA aggregates that protect the biosystem from the action of the starting components.     

The basicity of unsaturated hydrocarbons as probed by hydrogen-bond-acceptor ability: bifurcated N-H+ ...pi hydrogen bonding

The competitive substitution of the anion (A(-)) in contact ion pairs of the type [Oct3NH+]B(C6F5)4 (-) by unsaturated hydrocarbons (L) in accordance with the equilibrium Oct3NH+...A(-) + nL right arrow over left arrow [Oct3NH+...Ln]A(-) has been studied in CCl4. On the basis of equilibrium constants, K, and shifts of nuNH to low frequency, it has been established that complexed Oct3NH...+Ln cations with n=1 and 2 are formed and have unidentate and bifurcated N--H+...pi hydrogen bonds, respectively. Bifurcated hydrogen bonds to unsaturated hydrocarbons have not been observed previously. The unsaturated hydrocarbons studied include benzene and methylbenzenes, fused-ring aromatics, alkenes, conjugated dienes, and alkynes. From the magnitude of the redshifts in the N--H stretching frequencies, Delta nuNH, a new scale for ranking the pi basicity of unsaturated hydrocarbons is proposed: fused-ring aromatics相似文献   

Identification of platelet activating factor by tandem mass spectrometry

Platelet activating factor, a phospholipid (1-O-alkyl-2-O-acetyl-sn-glycerophosphocholine), is a potent mediator of inflammation and acute hypersensitivity reactions. Chemical ionization mass spectra provide useful information for confirmation of structure. However at low levels the confirmation of structure in biological samples is difficult because the chemical noise level is too great. Collisionally activated decomposition daughter spectra of the protonated molecule and major fragment ions of authentic standards were recorded and are discussed. Selected tandem mass spectral scans provided the improvement in signal-to-noise to allow positive confirmation of structure at nanogram levels in partially purified extracts from a biological source, the epidermal cell secretions of the saltwater catfish Arius thalassinus.     

不同催化剂作用下聚乳酸/聚碳酸亚丙酯的酯交换反应

选用辛酸亚锡[Sn(Oct)₂]和钛酸四丁酯(TBT)作为聚乳酸(PLA)/聚碳酸亚丙酯(PPC)的酯交换反应催化剂, 研究了溶液条件下单一催化剂及复合催化剂对PLA/PPC酯交换反应的催化作用. 通过对反应产物的分子结构、 热力学及流变学行为进行分析, 结果发现, 无论在单一催化剂还是复合催化剂作用下, PLA与PPC分子间均发生了酯交换反应, 同时伴随着断链反应. 其中, 当Sn(Oct)₂作为单一催化剂或Sn(Oct)₂/TBT作为复合催化剂时, 样品更倾向发生断链反应而非显著的酯交换反应. 进一步分析纯样品在催化剂Sn(Oct)₂或TBT作用下的反应情况, 结果发现, PPC在反应最初阶段以高分子量的分子链断链为主, 且会发生明显的解拉链降解, 从而导致PLA/PPC在等质量比时酯交换反应程度不高, 这为今后更好地研究PLA/PPC酯交换反应提供了思路.     

New solvates of the drug naltrexone: protonation,conformation and interplay of synthons

Naltrexone [systematic name: (4R,4aS,7aR,12bS)‐3‐cyclopropylmethyl‐4a,9‐dihydroxy‐2,4,5,6,7a,13‐hexahydro‐1H‐4,12‐methanobenzofuro[3,2‐e]isoquinolin‐7‐one] is an important morphine‐related drug used for combating alcoholism and opioid dependence. Of the eight crystal forms of naltrexone known thus far, only one exists in the neutral form and it crystallizes as a monohydrate. We have isolated the naltrexone free base as two new solvate forms, i.e. the ethyl acetate 0.33‐solvate, C₂₀H₂₃NO₄·0.33C₄H₈O₂, (I), and the diethyl ether hemisolvate, C₂₀H₂₃NO₄·0.5C₄H₁₀O, (II). While just one solvent molecule is present in the asymmetric unit of each solvate, there are three drug molecules (Z′ = 3) in ethyl acetate solvate (I) and two (Z′ = 2) in diethyl ether solvate (II). In (I), one of the three crystallographically independent drug molecules is present with its cyclopropyl group disordered over two sets of positions, as is the whole diethyl ether solvent molecule in (II). In all known forms, including the title forms, the naltrexone molecule exhibits the same conformation of the fused rings. The only conformational variability of naltrexone is in the cyclopropylmethyl group. Two conformations can be found around the bond connecting this group to the N‐heterocycle, which is directly related to drug protonation. We have calculated, at the B3LYP/6‐31G** level of theory, the minimum energy conformations of protonated and neutral naltrexone molecules for a chosen torsion angle about this bond. The lowest energy conformers depend on the protonation state and are in agreement with those found in the solid state. Within the cyclopropylmethyl group, the bond joining the methylene C atom to the cyclopropyl fragment also evidences conformational variability. In the literature, there are two well defined conformations around this bond. A third cyclopropyl conformation around this second bond is observed in the title solvates. Concerning the supramolecular features of the previously reported crystal structures, only one classical hydrogen bond between naltrexone molecules and one C(8) homosynthon is known, pointing to the robustness of this synthon and the difficulty in disrupting it. New R₂²(7) and C₂²(10) homosynthons are found in both (I) and (II), suggesting that their occurrence derives from crystallization of the neutral drug from nonpolar solvents.     

Synthesis of tetraoctylammonium-protected gold nanoparticles with improved stability

This paper shows that an introduction of thiosulfate anions in place of bromide anions greatly improves both chemical and thermal stability of tetraoctylammonium-protected gold nanoparticles. Tetraoctylammonium thiosulfate [(Oct)4N+-O3SS]-protected gold nanoparticles are synthesized by the reduction of (Oct)4N+-AuCl4 to Au(I)-SSO3-, followed by the addition of sodium borohydride. The presence of thiosulfate anions instead of bromide anions on the surface of gold nanoparticles results in a significant dampening of the surface plasmon band of gold at 526 nm due to the strong interaction between thiosulfate and the gold nanoparticle surface. Cyanide decomposition and heating treatment studies suggest that (Oct)4N+-O3SS-protected nanoparticles have much higher overall stability compared to (Oct)4N+-Br-protected gold nanoparticles.     

Delayed Doublet Emission in a Cerium(III) Complex

Doublet emission from open-shell molecules has demonstrated its research and application value in recent years. However, understandings of the photoluminescence mechanism of open-shell molecules are far less than that of closed-shell molecules, leading to challenges in molecular design of efficient doublet emission systems. Here we report a cerium(III) 4-(9H-carbozol-9-yl)phenyl-tris(pyrazolyl)borate complex Ce(CzPhTp)₃ with a new luminescence mechanism of delayed doublet emission, which also represents the first example with metal-centered delayed photoluminescence. The energy gap between the doublet and triplet excited states of Ce(CzPhTp)₃ is reduced by the management of the inner and outer coordination spheres, thereby promoting efficient energy transfer between the two excited states and activating the delayed emission. The photoluminescence mechanism discovered may provide a new way for the design of efficient doublet emission and bring insights into rational molecular design and energy level regulation in open-shell molecules.     

Identification of a Novel Delta Opioid Receptor Agonist Chemotype with Potential Negative Allosteric Modulator Capabilities

The δ-opioid receptor (δOR) holds great potential as a therapeutic target. Yet, clinical drug development, which has focused on δOR agonists that mimic the potent and selective tool compound SNC80 have largely failed. It has increasingly become apparent that the SNC80 scaffold carries with it potent and efficacious β-arrestin recruitment. Here, we screened a relatively small (5120 molecules) physical drug library to identify δOR agonists that underrecruit β-arrestin, as it has been suggested that compounds that efficaciously recruit β-arrestin are proconvulsant. The screen identified a hit compound and further characterization using cellular binding and signaling assays revealed that this molecule (R995045, compound 1) exhibited ten-fold selectivity over µ- and κ-opioid receptors. Compound 1 represents a novel chemotype at the δOR. A subsequent characterization of fourteen analogs of compound 1, however did not identify a more potent δOR agonist. Computational modeling and in vitro characterization of compound 1 in the presence of the endogenous agonist leu-enkephalin suggest compound 1 may also bind allosterically and negatively modulate the potency of Leu-enkephalin to inhibit cAMP, acting as a ‘NAM-agonist’ in this assay. The potential physiological utility of such a class of compounds will need to be assessed in future in vivo assays.     

The antitumour drug 7‐ethyl‐10‐hydroxycamptothecin monohydrate and its solid‐state hydrolysis mechanism on heating

7‐Ethyl‐10‐hydroxycamptothecin [systematic name: (4S)‐4,11‐diethyl‐4,9‐dihydroxy‐1H‐pyrano[3′,4′:6,7]indolizino[1,2‐b]quinoline‐3,14(4H,12H)‐dione, SN‐38] is an antitumour drug which exerts activity through the inhibition of topoisomerase I. The crystal structure of SN‐38 as the monohydrate, C₂₂H₂₀N₂O₅·H₂O, reveals that it is a monoclinic crystal, with one SN‐38 molecule and one water molecule in the asymmetric unit. When the crystal is heated to 473 K, approximately 30% of SN‐38 is hydrolyzed at its lactone ring, resulting in the formation of the inactive carboxylate form. The molecular arrangement around the water molecule and the lactone ring of SN‐38 in the crystal structure suggests that SN‐38 is hydrolyzed by the water molecule at (x, y, z) nucleophilically attacking the carbonyl C atom of the lactone ring at (x − 1, y, z − 1). Hydrogen bonding around the water molecules and the lactone ring appears to promote this hydrolysis reaction: two carbonyl O atoms, which are hydrogen bonded as hydrogen‐bond acceptors to the water molecule at (x, y, z), might enhance the nucleophilicity of this water molecule, while the water molecule at (−x, y + , −z), which is hydrogen bonded as a hydrogen‐bond donor to the carbonyl O atom at (x − 1, y, z − 1), might enhance the electrophilicity of the carbonyl C atom.     

Crystal structures and biological activity of 1,1,4‐triphenyl‐substituted 1,3‐enyne compounds

1,3‐Enyne structural motifs are versatile building blocks in organic synthesis and occur widely in various natural products with many of them being highly active as cytotoxic macrolides and antitumour antibiotics. This article presents the crystal structure of three 1,1,4‐triphenyl‐substituted 1,3‐enynes, viz. 4‐(2‐methylphenyl)‐1,1‐diphenylbut‐1‐en‐3‐yne, C₂₃H₁₈ ( 1 ), 4‐(2‐methoxyphenyl)‐1,1‐diphenylbut‐1‐en‐3‐yne, C₂₃H₁₈O ( 2 ), and 4‐(4‐nitrophenyl)‐1,1‐diphenylbut‐1‐en‐3‐yne, C₂₂H₁₅NO₂ ( 3 ). The benzene ring at position 4 of the but‐1‐en‐3‐yne group bears a weakly activating methyl group in compound 1 , a moderately activating methoxy group in 2 and a strongly deactivating nitro group in 3 . The crystal structures of 1 and 3 both have monoclinic symmetry, while that of 2 is orthorhombic, and all of them have one molecule in the asymmetric unit. All three compounds were investigated for their antibacterial and antifungal activities. Interestingly, enyne 2 is the only compound tested that inhibited the growth of Aspergillus niger.     

Quantification of sofosbuvir in human serum by liquid chromatography with negative ionization mass spectrometry using the parent peak and its source‐induced fragment: Application to a bioequivalence study

In the mass spectrometry of sofosbuvir, a new orally administered antihepatitis C drug, a weak peak is detected at the m/z value of the parent ion (m/z 530) as a result of in‐source dissociation and current methods to its quantification, is based on monitoring of the parent peak using ultra high‐performance liquid chromatography with tandem mass spectrometry. With these methods serum concentration of the drug is quantifiable only up to 4–5 h postdose. However, the fragmentation of the molecule generates a more stable ion at m/z 287 (base peak) with a signal intensity of about tenfold compared to the parent ion. Our study was aimed to improve sensitivity of analysis by acquisition of the m/z value of the daughter ion from which it originated instead of the parent molecule. This novelty allows us to measure serum concentrations of the drug for a longer time postdose and provides more opportunity for pharmacokinetic studies of sofosbuvir. Our method was linear over the concentration range of 2–2560 ng/mL of sofosbuvir in human serum with a limit of quantification of 2 ng/mL compared to 10 ng/mL reported previously. The coefficient variation values of both inter and intraday analysis were less than 13.8%, and the percentage error was less than 6.3.     

Phototriggered release of photolabile drugs via two-photon absorption-induced cleavage of polymer-bound dicoumarin

7-(tert-Butyldimethylsiloxy)-7′-(methacryloxy)dicoumarin (TBS-Cum-D -MA) is introduced as a versatile polymerizable and photocleavable linker system for drug attachment to acrylic polymers. Following the copolymerization of the TBS-Cum-D -MA with monomeric methylmethacrylate, a model drug chlorambucil was attached in a simple reaction. Phototriggered drug release via single- and two-photon absorption induced cycloreversion of the cyclobutane of the dicoumarin part was investigated. The bound drug chlorambucil is sensitive to UV light being required for single-photon induced cleavage of the dicoumarin linker and decomposes upon UV exposure. However, under the conditions of two-photon absorption induced drug release, no photodegradation of chlorambucil was observed. As the only effective two-photon absorber in the molecule is the cyclobutane structure, even high energies of visible light do not cause any degradation of the drug. This suggests that two-photon-triggered drug release may be successfully accomplished even with UV light sensitive drugs. The concept introduced here may be a powerful strategy in polymer design for photocontrolled drug delivery devices. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 45: 2443–2452, 2007