- A minimally-masked inactive prodrug of panobinostat that is bioorthogonally activated by gold chemistry
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The recent incorporation of Au chemistry in the bioorthogonal toolbox has opened up new opportunities to deliver biologically independent reactions in living environments. Herein we report that the O-propargylation of the hydroxamate group of the potent HDAC inhibitor panobinostat leads to a vast reduction of its anticancer properties (>500-fold). We also show that this novel prodrug is converted back into panobinostat in the presence of Au catalysts in vitro and in cell culture.
- Rubio-Ruiz, Belén,Pérez-López, Ana M.,Sebastián, Víctor,Unciti-Broceta, Asier
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- With biological activity mixed oxygen benzene oxygen N- the oxygen radical is thick carboxylic acid amide compound and its preparation method
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The present invention discloses a N-oxyl fused heterocycle oxy phenoxy carboxylic acid amide compound having biological activity, and a preparation method thereof, wherein the compound is represented by a formula (I), A is selected from the following groups, R is C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 halogenated alkenyl, C3-C6 halogenated alkynyl, C3-C6 cycloalkyl methyl and C3-C6 halogenated cycloalkyl alkyl methyl, R1 is H, C1-C3 alkyl, and C1-C3 halogenated alkyl, and R2 is H, halogen, C1-C3 alkyl, and C1-C3 halogenated alkyl. The compound represented by the formula (I) has broad-spectrum biological activity of weed removing or insect killing and bacterial killing, wherein some compounds have high weed removing activity and can achieve a good prevention and control effect at a use amount of 3.75-75 g effective component/hectare.
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Paragraph 0071; 0072; 0074
(2016/10/08)
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- One-pot: N -glycosylation remodeling of IgG with non-natural sialylglycopeptides enables glycosite-specific and dual-payload antibody-drug conjugates
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Chemoenzymatic transglycosylation catalyzed by endo-S mutants is a powerful tool for in vitro glycoengineering of therapeutic antibodies. In this paper, we report a one-pot chemoenzymatic synthesis of glycoengineered Herceptin using an egg-yolk sialylglycopeptide (SGP) substrate. Combining this one-pot strategy with novel non-natural SGP derivatives carrying azido or alkyne tags, glycosite-specific conjugation was enabled for the development of new antibody-drug conjugates (ADCs). The site-specific ADCs and semi-site-specific dual-drug ADCs were successfully achieved and characterized with SDS-PAGE, intact antibody or ADC mass spectrometry analysis, and PNGase-F digestion analysis. Cancer cell cytotoxicity assay revealed that small-molecule drug release of these ADCs relied on the cleavable Val-Cit linker fragment embedded in the structure. These results represent a new approach for glycosite-specific and dual-drug ADC design and rapid synthesis, and also provide the structural requirement for their biologic activities.
- Tang, Feng,Yang, Yang,Tang, Yubo,Tang, Shuai,Yang, Liyun,Sun, Bingyang,Jiang, Bofeng,Dong, Jinhua,Liu, Hong,Huang, Min,Geng, Mei-Yu,Huang, Wei
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supporting information
p. 9501 - 9518
(2016/10/22)
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- TETRAZOLINONE COMPOUND AND APPLICATIONS THEREOF
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Disclosed is a tetrazolinone compound having a high pest control effect and represented by the formula (1): wherein R1, R2, R3, and R11 each represent a halogen atom, a C1-C6 alkyl group, or the like; R4 and R5 each represent a hydrogen atom, a halogen atom, a C1-C3 alkyl group, or the like; R6 represents a C1-C3 alkyl group which may have a halogen atom(s) or the like; R7, R8, and R9 each represent a hydrogen atom, a halogen atom, or the like; R10 represents a C1-C3 alkyl group or the like; R12 represents a C1-C6 alkyl group, a C3-C6 cycloalkyl group, or the like, and R13 represents a C1-C6 alkyl group, a C2-C6 alkenyl group, or the like.
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Paragraph 0879; 0908
(2015/11/24)
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- METHODS FOR POST-FABRICATION FUNCTIONALIZATION OF POLY(ESTER UREAS)
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Amino acid-based poly(ester urea)s (PEU) are emerging as a class of polymers that have shown promise in regenerative medicine applications. Embodiments of the invention relate to the synthesis of PEUs carrying pendent "clickable" groups on modified tyrosine amino acids. The pendent species include alkyne, azide, alkene, tyrosine-phenol, and ketone groups. PEUs with Mw exceeding 100k Da were obtained via interfacial polycondensation methods and the concentration of pendent groups was varied by copolymerization. The incorporation of derivatizable functionalities is demonstrated using 1H NMR and UV-Vis spectroscopy methods. Electrospinning was used to fabricate PEU nanofibers with a diameters ranging from 350 nm to 500 nm. The nanofiber matricies possess mechanical strengths suitable for tissue engineering (Young's modulus: 30045 MPa; tensile stress: 8.51.2 MPa). A series of bioactive peptides and fluorescent molecules were conjugated to the surface of the nanofibers following electrospinning using bio-orthogonal reactions in aqueous media.
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Paragraph 00234
(2015/04/15)
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- NOVEL ORALLY BIOAVAILABLE BREATHING CONTROL MODULATING COMPOUNDS, AND METHODS OF USING SAME
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The present invention includes compositions that are useful in the prevention and/or treatment of breathing control diseases or disorders in a subject in need thereof. The present invention also includes a method of preventing and/or treating a respiratory disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition of the invention. The present invention further includes a method of preventing destabilization or stabilizing breathing rhythm in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition of the invention.
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Page/Page column 204-205
(2014/06/11)
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- Synthesis and antiviral evaluation of 4′-(1,2,3-triazol-1-yl) thymidines
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Non-obligate chain terminating nucleosides with a linear substituent (azido or ethynyl group) at the 4′ position represent an important class of compounds in antiviral discovery, particularly against hepatitis C virus (HCV) and human immunodeficiency virus (HIV). We have previously shown that 3′-azidothymidine (AZT)-derived 1,2,3-triazoles can be potent inhibitors of HIV-1. To gauge the medicinal chemistry impact of functionalizing the 4′-linear substituent and possibly generate novel antiviral nucleoside scaffolds, we have explored azide-alkyne cycloaddition reactions with 4′-azidothymidine (ADRT). The Ru-mediated reaction failed and the Cu-catalyzed variant generated 1,2,3-triazoles (9a-y) with only modest yields and efficiencies, indicating a substantial steric barrier around the 4′-azido group. Antiviral screening identified a few triazole analogues moderately active against HIV-1 (18-62% inhibition at 10 μM) and/or influenza A virus (15-50% inhibition at 10 μM), and none active against West Nile virus (WNV) or HCV. These results suggest that the linear 4′ azido group of ADRT may be essential for target binding and that its chemical manipulation could largely compromise antiviral potency. This journal is the Partner Organisations 2014.
- Vernekar, Sanjeev Kumar V.,Qiu, Li,Zacharias, Jeana,Geraghty, Robert J.,Wang, Zhengqiang
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supporting information
p. 603 - 608
(2014/05/06)
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- NOVEL VASCULAR LEAKAGEAGE INHIBITOR
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The present disclosure relates to a novel vascular leakage inhibitor. The novel vascular leakage inhibitor of the present invention inhibits the apoptosis of vascular endothelial cells, inhibits the formation of actin stress fibers induced by VEGF, and enhances the cortical actin ring structure, thereby inhibiting vascular leakage. Accordingly, the vascular leakage inhibitor of the present invention can prevent or treat various diseases caused by vascular leakage. Since the vascular leakage inhibitor of the present invention is synthesized from commercially available or easily synthesizable pregnenolones, it has remarkably superior feasibility of commercial synthesis.
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Paragraph 0093
(2015/01/07)
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- Pyridone-conjugated monobactam antibiotics with gram-negative activity
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Herein we describe the structure-aided design and synthesis of a series of pyridone-conjugated monobactam analogues with in vitro antibacterial activity against clinically relevant Gram-negative species including Pseudomonas aeruginosa, Klebsiella pneumoniae, and Escherichia coli. Rat pharmacokinetic studies with compound 17 demonstrate low clearance and low plasma protein binding. In addition, evidence is provided for a number of analogues suggesting that the siderophore receptors PiuA and PirA play a role in drug uptake in P. aeruginosa strain PAO1.
- Brown, Matthew F.,Mitton-Fry, Mark J.,Arcari, Joel T.,Barham, Rose,Casavant, Jeffrey,Gerstenberger, Brian S.,Han, Seungil,Hardink, Joel R.,Harris, Thomas M.,Hoang, Thuy,Huband, Michael D.,Lall, Manjinder S.,Lemmon, M. Megan,Li, Chao,Lin, Jian,McCurdy, Sandra P.,McElroy, Eric,McPherson, Craig,Marr, Eric S.,Mueller, John P.,Mullins, Lisa,Nikitenko, Antonia A.,Noe, Mark C.,Penzien, Joseph,Plummer, Mark S.,Schuff, Brandon P.,Shanmugasundaram, Veerabahu,Starr, Jeremy T.,Sun, Jianmin,Tomaras, Andrew,Young, Jennifer A.,Zaniewski, Richard P.
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supporting information
p. 5541 - 5552
(2013/07/26)
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- A general method for fluorescent labeling of the N-termini of lanthipeptides and its application to visualize their cellular localization
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Labeling of natural products with biophysical probes has greatly contributed to investigations of their modes of action and has provided tools for visualization of their targets. A general challenge is the availability of a suitable functional group for chemoselective modification. We demonstrate here that an N-terminal ketone is readily introduced into various lanthipeptides by the generation of a cryptic N-terminal dehydro amino acid by the cognate biosynthetic enzymes. Spontaneous hydrolysis of the N-terminal enamines results in α-ketoamides that site-specifically react with an aminooxy-derivatized alkyne or fluorophore. The methodology was successfully applied to prochlorosins 1.7 and 2.8, as well as the lantibiotics lacticin 481, haloduracin α, and haloduracin β. The fluorescently modified lantibiotics were added to bacteria, and their cellular localization was visualized by confocal fluorescence microscopy. Lacticin 481 and haloduracin α localized predominantly at sites of new and old cell division as well as in punctate patterns along the long axis of rod-shaped bacilli, similar to the localization of lipid II. On the other hand, haloduracin β was localized nonspecifically in the absence of haloduracin α, but formed specific patterns when coadministered with haloduracin α. Using two-color labeling, colocalization of both components of the two-component lantibiotic haloduracin was demonstrated. These data with living cells supports a model in which the α component recognizes lipid II and then recruits the β-component.
- Bindman, Noah A.,Van Der Donk, Wilfred A.
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supporting information
p. 10362 - 10371
(2013/08/23)
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- Synthesis and pharmacological characterization of O-alkynyloximes of tropinone and N-methylpiperidinone as muscarinic agonists
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A number of O-alkynyloximes of tropinone and N-methyl-4-piperidinone have been synthesized and evaluated for muscarinic activity. The affinities of these oximes were tested in homogenates of cerebral cortex, heart, and submandibulary glands from rats using [3H]pirenzepine and [3H]-N- methylscopolamine as radioligands. The oximes bind to the cortical muscarinic receptors with pK(i) values varying from 3 to 7. Higher binding affinities were observed for the O-alkynyl tropinone oximes than the corresponding piperidinone analogues. Binding to the muscarinic sites in the heart and submandibulary glands was also observed but with lower affinities. Good M1 subtype selectivity (10-fold or greater) was observed with some oximes (26a, 28a, 32a) at the cortical sites. These oximes also attenuated scopolamine- induced impairment of the water mask task in mice. Functional assays for M3 activity on the rat aorta showed that all oximes possessed M3 agonist action but M2 agonist activity was not observed at the endothelium-denuded rabbit aorta. Analysis of the quantitative structure-activity relationship (QSAR) indicated that the Connolly surface area is an important determinant of activity, accounting for 70% of the variation in cortical binding affinity among the oximes.
- Xu, Rong,Sim, Meng-Kwoon,Go, Mei-Lin
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p. 3220 - 3231
(2007/10/03)
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- Improved synthesis of N-alkoxyphthalimides
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Synthetically useful N-alkoxyphthalimide derivatives can be conveniently prepared in high yields from the reactions of N-hydroxyphthalimide with alkyl halides by using DBU in DMF.
- Kim,Kim,Ryu
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p. 1427 - 1432
(2007/10/02)
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- Nematicidal salicylaldehyde derivatives
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A method is described for the control of nematodes in agricultural crops which comprises applying to the situs of infestation of a nematicidal composition containing as active ingredient a compound of the formula STR1 wherein Q is hydroxy, carbamoyloxy, or acyloxy, R is alkyl, alkenyl, alkynyl, X is halogen or methyl, n is 1 or 2. Preparation of active ingredient compounds is described, and nematicidal utility of compositions is exemplified.
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