- Synthetic Studies on Tautomycin Synthesis of 2,3-Disubstituted Maleic Anhydride Segment
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The 2,3-disubstituted maleic anhydride segment of tautomycin has been synthesized in optically active form.Oxidation of 3,4-disubstituted furan employing singlet oxygen completes the construction of the maleic anhydride moiety.Esterification of the maleic anhydride segment without protecting anhydride moiety resulted in the successful coupling reaction with fragment derived from tautomycin.
- Naganawa, Atsushi,Ichikawa, Yoshiyasu,Isobe, Minoru
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- Acidic pH-responsive siRNA conjugate for reversible carrier stability and accelerated endosomal escape with reduced IFNα-associated immune response
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An siRNA conjugate is based on an acid-labile maleic acid amide linkage for programmed transfer of siRNA from the endosome to the cytosol and siRNA release in the cell interior. The procedure relies on reversible stability in response to endosomal acidic
- Takemoto, Hiroyasu,Miyata, Kanjiro,Hattori, Shota,Ishii, Takehiko,Suma, Tomoya,Uchida, Satoshi,Nishiyama, Nobuhiro,Kataoka, Kazunori
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- A medusa-like β-cyclodextrin with 1-methyl-2-(2'-carboxyethyl) maleic anhydrides, a potential carrier for pH-sensitive drug delivery
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We developed a new pH-sensitive drug delivery carrier based on β-cyclodextrin (β-CD) and 1-methyl-2-(2'-carboxyethyl) maleic anhydrides (MCM). The primary hydroxyl groups of β-CD were successfully attached to MCM residues to produce a medusa-like β-CD-MCM. The MCM residue was conjugated with cephradine (CP) with high efficiency (>90%). More importantly, β-CD-MCM-CP responded to the small pH drop from 7.4 to 5.5 and released greater than 80% of the drugs within 0.5h at pH 5.5. In addition, the inclusion complex between β-CD-MCM-CP and the adamantane derivative was formed by simple mixing to show the possibility of introducing multi-functionality. Based on these results, β-CD-MCM can target weakly acidic tissues or organelles, such as tumours, inflammatory tissues, abscesses or endosomes, and be easily modified with various functional moieties, such as ligands for cell binding or penetration, enabling more efficient and specific drug delivery.
- Kang, Sunyoung,Park, Euddeum,Kim, Youngeun,Lee, Seonju,Kwon, Jiwoong,Cho, Hyungdo,Lee, Yan
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- REVERSING THE UNDESIRABLE pH-PROFILE OF DOXORUBICIN VIA ACTIVATION OF A DISUBSTITUTED MALEAMIC ACID PRODRUG AT TUMOR ACIDITY
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A pre-prodrug, comprising a drug, e.g., doxorubicin, which has off-target toxicity (e.g., cardiotoxicity) with respect to its antineoplastic activity, and an amine functionality of the drug incorporated into a disubstituted maleimide (DMI). The pre-prodrug may be linked to a targeting or de-targeting agent or a polar modulator, e.g., charged ligand, amino acid, peptide, etc., to increase therapeutic index. The pre-prodrug is hydrolyzed to the prodrug, having a disubstituted maleamic acid (DMA). A polar modulator such as glutamic acid prevents cellular uptake of the prodrug, but not the doxorubicin drug released from the prodrug after dissociation. The prodrug is pH sensitive, and below pH 7.0, tends to cleave to form free drug and cyclized maleic anhydride. Tumor environments tend to be more acidic, e.g., pH 6.8, than cardiac tissue, e.g., pH 7.4, and therefore the heart is spared while the drug is selectively released within a tumor.
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Paragraph 0165; 0267-0269; 0274-0277; 0352; 0354-0356
(2021/05/07)
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- Nano clustering enzyme with hypoxia activation prodrug and preparation method and application of enzyme
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The invention provides a nano clustering enzyme with a hypoxia activation prodrug. The nano clustering enzyme has capacity of targeted tumor hunger and hypoxia activation and is a mode for cancer treatment through cooperation of a chemotherapy and metabolic treatment. An adopted cross-linking agent material polyethylene glycol-b-poly(2-hydroxyethyl methacrylate)segmented copolymer modified by 2-carboxyethyl cellulose-3-methyl maleic anhydride has the acidity response characteristic and can have specificity in tumor targeting breaking. The nano clustering enzyme takes a bovine serum albumin-hypoxia activation drug as a shell, the bovine serum albumin has good biocompatibility and stability so that the nano clustering enzyme can stably exist in the blood, the blood circulation time is prolonged, and the tumor gathering effect is improved. Through the shell, advanced exposure of the enzyme in a core can be avoided, and the toxicity to the normal tissue is lowered. The nano clustering enzyme has good stability and dispersity and is beneficial to biological application.
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Paragraph 0095-0097
(2019/08/20)
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- Reversing the undesirable pH-profile of doxorubicin: Via activation of a di-substituted maleamic acid prodrug at tumor acidity
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The acid-labile behavior of di-substituted maleamic acid (DMA) and its equilibrium with di-substituted maleimide (DMI) are exploited to build an ultra acid-sensitive, small molecule prodrug that can be activated by tumor extracellular pH (pHe) in the range of 6.5-6.9. Such a DMA prodrug reversed the unfavorable pH-profile of doxorubicin (Dox), which may improve its therapeutic window.
- Zhang, Anqi,Yao, Lan,An, Ming
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supporting information
p. 12826 - 12829
(2017/12/06)
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- Galactose cluster-pharmacokinetic modulator targeting moiety for siRNA
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The present invention is directed compositions for targeted delivery of RNA interference (RNAi) polynucleotides to cell in vivo. The pharmacokinetic modulator improve in vivo targeting compared to the targeting ligand alone. Targeting ligand-pharmacokinet
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Page/Page column 35; 36
(2016/02/29)
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- COMPOSITIONS FOR TARGETED DELIVERY OF SIRNA
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The present invention is directed compositions for targeted delivery of RNA interference (RNAi) polynucleotides to hepatocytes in vivo. Targeted RNAi polynucleotides are administered together with co-targeted delivery polymers. Delivery polymers provide m
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Paragraph 0133
(2016/03/05)
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- A pH responsive cyclodextrin derivative, a preparation method therof and a pH responsive conjugate of the cyclodextrin derivative and a drug
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The present invention relates to a pH-responsive cyclodextrin derivative, a preparation method thereof, and a pH-responsive conjugate of the pH-responsive cyclodextrin derivative and a drug, and more specifically, to a cyclodextrin derivative having a novel structure, a preparation method thereof, and a pH-responsive conjugate of the pH-responsive cyclodextrin derivative and a drug. The cyclodextrin derivative has a novel structure formed by a covalent bond between a maleic anhydride derivative and a cyclodextrin or a cyclodextrin derivative, in which a residue of the maleic anhydride derivative bonds to a primary hydroxyl group of cyclodextrin or a terminal functional group, such as NH_2, N_3, or amino acid, of a cyclodextrin derivative to produce a pH-responsive cyclodextrin derivative.(AA) Cyclodextrin(BB) Maleic acid derivative(CC) Amine group (-NH_2)-containing drugCOPYRIGHT KIPO 2016
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Paragraph 0126; 0129-0131; 0135-0137
(2016/12/01)
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- Comparison of pH-sensitive degradability of maleic acid amide derivatives
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We synthesized five maleic acid amide derivatives (maleic, citraconic, cis-aconitic, 2-(2′-carboxyethyl) maleic, 1-methyl-2-(2′- carboxyethyl) maleic acid amide), and compared their degradability for the future development of pH-sensitive biomaterials with tailored kinetics of the release of drugs, the change of charge density, and the degradation of scaffolds. The degradation kinetics was highly dependent upon the substituents on the cis-double bond. Among the maleic acid amide derivatives, 2-(2′-carboxyethyl) maleic acid amide with one carboxyethyl and one hydrogen substituent showed appropriate degradability at weakly acidic pH, and the additional carboxyl group can be used as a pH-sensitive linker.
- Kang, Sunyoung,Kim, Youngeun,Song, Youngjun,Choi, Jin Uk,Park, Euddeum,Choi, Wonmin,Park, Jeongseon,Lee, Yan
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supporting information
p. 2364 - 2367
(2014/05/20)
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- GALACTOSE CLUSTER-PHARMACOKINETIC MODULATOR TARGETING MOIETY FOR siRNA
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The present invention is directed compositions for targeted delivery of RNA interference (RNAi) polynucleotides to cell in vivo. The pharmacokinetic modulator improve in vivo targeting compared to the targeting ligand alone. Targeting ligand-pharmacokinetic modulator targeting moiety targeted RNAi polynucleotides can be administered in vivo alone or together with co-targeted delivery polymers.
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- Compositions for Targeted Delivery of siRNA
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The present invention is directed compositions for targeted delivery of RNA interference (RNAi) polynucleotides to hepatocytes in vivo. Targeted RNAi polynucleotides are administered together with co-targeted delivery polymers. Delivery polymers provide m
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- Enzymatic synthesis of a 6-sialyl lactose analogue using a pH-responsive water-soluble polymer support
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The Letter describes a strategy for the enzymatic synthesis of glycans based on a pH-responsive water-soluble polymer. In neutral condition, the polymer is water-soluble and convenient for in-solution enzymatic synthesis, whereas in acidic condition (pH lower than 4.0), the polymer disconnects with the product and becomes insoluble, which can be easily removed. A 6-Sialyl lactose analogue was synthesized as a model reaction using this approach.
- Wang, Wenjun,Li, Lei,Jin, Chen,Niu, Yujie,Li, Sen,Ma, Ji,Li, Linfeng,Liu, Yu,Cai, Li,Zhao, Wei,Wang, Peng George
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p. 5041 - 5044
(2011/10/09)
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- Compounds with anti-cancer activity
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Novel substituted azole diones are provided that kill cells, suppress cell proliferation, suppress cell growth, abrogate the cell cycle G2 checkpoint and/or cause adaptation to G2 cell cycle arrest. Methods of making and using the invention compounds are provided. The invention provides substituted azole diones to treat cell proliferation disorders. The invention includes the use of substituted azole diones to selectively kill or suppress cancer cells without additional anti-cancer treatment. The invention includes the use of cell cycle G2-checkpoint-abrogating substituted azole diones to selectively sensitize cancer cells to DNA damaging reagents, treatments and/or other types of anti-cancer reagents.
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Page/Page column 72
(2008/12/08)
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- Polyconjugates for In Vivo Delivery of Polynucleotides
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The present invention is directed to compounds, compositions, and methods useful for delivering polynucleotides or other cell-impermeable molecules to mammalian cells. Described are polyconjugates systems that incorporate targeting, anti-opsonization, anti-aggregation, and transfection activities into small biocompatible in vivo delivery vehicles. The use of multiple reversible linkages connecting component parts provides for physiologically responsive activity modulation.
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Page/Page column 18
(2008/12/06)
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- Polyampholytes for delivering polyions to a cell
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An polyampholyte is utilized in a condensed polynucleotide complex for purposes of nucleic acid delivery to a cell. The complex can be formed with an appropriate amount of positive and/or negative charge such that the resulting complex can be delivered to the extravascular space and may be further delivered to a cell.
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- Endosomolytic polymers
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We describe pH-sensitive endosomolytic polymers, delivery particles containing pH-sensitive endosomolytic polymers. The described particles are capable of delivering polynucleotides to cells from the peripheral circulation with subsequent release from endosomes. The endosomolytic polymers are inactive outside the cell but disrupt membranes upon exposure to an acidified endosomal compartment.
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- Delivery of siRNA to cells using polyampholytes
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A polyampholyte is utilized in a complex with siRNA for purposes of siRNA delivery to a cell. The complex can be formed with an appropriate amount of positive and/or negative charge such that the resulting complex can be delivered a cell in vivo or in vitro.
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- Reversible attachment of a membrane active polymer to a polynucleotide
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Described is a process for delivering a biologically active compound to a cell by reversibly linking the compound to a membrane active polymer. In particular, polymer-polynucleotide conjugates are described. Methods for reversibly modifying the polymers to decrease cellular toxicity and improve efficacy are provided.
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- Novel methods for the delivery of polynucleotides to cells
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Process are described for the delivery of a polynucleotide to a cell. The process comprises forming a salt stable complex between the polynucleotide and a cationic surfactant. Ternary complexes are also made by associating an amphipathic compound with the binary complex. The resultant complexes are suitable for delivery of the polynucleotide to cells in vitro and in vivo.
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- A facile synthesis of a (±)-2,3-disubstituted maleic anhydride segment of tautomycin
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A convenient method for construction of a (±)-2,3-disubstituted maleic anhydride segment of antibiotic tautomycin is reported. The key steps involved in the synthesis are chemoselective condensation of diethyl malonate with 2-(bromomethyl)-3-methylmaleic anhydride (3) and regioselective NBS-bromination of the maleic anhydride derivative 7.
- Deshpande,Natu,Argade
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p. 702 - 704
(2007/10/03)
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