- DIRECTED CONJUGATION TECHNOLOGIES
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Among other things, the present disclosure provides technologies for site-directed conjugation of various moieties of interest to target agents. In some embodiments, the present disclosure utilizes target binding moieties to provide high conjugation efficiency and selectivity. In some embodiments, provided technologies are useful for preparing antibody conjugates.
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Paragraph 0652; 0653
(2021/05/29)
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- Synthesis and pharmacological evaluation of piperidine (piperazine)-amide substituted derivatives as multi-target antipsychotics
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We report the optimisation of a series of novel amide-piperidine (piperazine) derivatives using the multiple ligand approach with dopamine and serotonin receptors. Of the derivatives, compound 11 exhibited high affinity for the D2, 5-HT1A, and 5-HT2A receptors, but low affinity for the 5-HT2C and histamine H1 receptors and human ether-a-go-go-related gene (hERG) channels. In vivo, compound 11 reduced apomorphine-induced climbing, MK-801-induced hyperactivity and DOI-induced head twitching without observable catalepsy, even at the highest dose tested. In addition, it exhibited suppression in a CAR test. Furthermore, in a novel object recognition task, it displayed procognition properties. Therefore, compound 11 is a promising candidate multi-target antipsychotic.
- Huang, Ling,Gao, Lanchang,Zhang, Xiaohua,Yin, Lei,Hu, Jintao,Song, Ting,Chen, Yin
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- NOVEL AMINOMETHYL-PHENOL DERIVATIVES AS ANTIMALARIAL AGENTS
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The invention relates to novel aminomethyl-phenol derivatives of formula I wherein R1 to R4, X, A and B are as defined for formula I and their use as active ingredients in the preparation of pharmaceutical compositions. The invention
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Page/Page column 37
(2014/05/24)
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- Quinone methides tethered to naphthalene diimides as selective G-quadruplex alkylating agents
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We have developed novel G-quadruplex (G-4) ligand/alkylating hybrid structures, tethering the naphthalene diimide moiety to quaternary ammonium salts of Mannich bases, as quinone-methide precursors, activatable by mild thermal digestion (40°C). The bis-substituted naphthalene diimides were efficiently synthesized, and their reactivity as activatable bis-alkylating agents was investigated in the presence of thiols and amines in aqueous buffered solutions. The electrophilic intermediate, quinonemethide, involved in the alkylation process was trapped, in the presence of ethyl vinyl ether, in a hetero Diels-Alder [4 + 2] cycloaddition reaction, yielding a substituted 2-ethoxychroman. The DNA recognition and alkylation properties of these new derivatives were investigated by gel electrophoresis, circular dichroism, and enzymatic assays. The alkylation process occurred preferentially on the G-4 structure in comparison to other DNA conformations. By dissecting reversible recognition and alkylation events, we found that the reversible process is a prerequisite to DNA alkylation, which in turn reinforces the G-quadruplex structural rearrangement.
- Di Antonio, Marco,Doria, Filippo,Richter, Sara N.,Bertipaglia, Carolina,Mella, Mariella,Sissi, Claudia,Palumbo, Manlio,Freccero, Mauro
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supporting information; experimental part
p. 13132 - 13141
(2009/12/08)
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- New analgesics synthetically derived from the paracetamol metabolite N-(4-hydroxyphenyl)-(5Z,8Z,11Z,14Z)-icosatetra-5,8,11,14-enamide
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N-(4-Hydroxyphenyl)-(5Z,8Z,11Z,14Z)-icosatetra-5,8,11,14-enamide (AM404) is a metabolite of the well-known analgesic paracetamol. AM404 inhibits endocannabinoid cellular uptake, binds weakly to CB1 and CB 2 cannabinoid receptors, and is formed by fatty acid amide hydrolase (FAAH) in vivo. We prepared three derivatives of this new (endo)cannabinoid using bioisosteric replacement (1), homology (2), and derivatization (3) of the 4-aminophenol moiety in AM404 and tested them against CB1, CB 2, and FAAH. We found affinities toward both cannabinoid receptors equal to or greater than that of AM404. Shortening the acyl chain from C 20 to C2 led to three new paracetamol analogues: N-(1H-indazol-5-yl)acetamide (5), N-(4-hydroxybenzyl)acetamide (6), and N-(4-hydroxy-3-methoxyphenyl)acetamide (7). Again, 5, 6, and 7 were tested against CB1, CB2, and FAAH without significant activity. However, 5 and 7 behaved like inhibitors of cyclooxygenases in whole blood assays. Finally, 5 (50 mg/kg) and 6 (275 mg/kg) displayed analgesic activities comparable to paracetamol (200 mg/kg) in the mouse formalin test.
- Sinning, Christian,Watzer, Bernhard,Coste, Ovidiu,Nüsing, Rolf M.,Ott, Ingo,Ligresti, Alessia,Di Marzo, Vincenzo,Imming, Peter
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experimental part
p. 7800 - 7805
(2009/12/07)
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- (P2O5/SiO2): a useful heterogeneous alternative for the Ritter reaction
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Tertiary alcohols as well as primary and secondary benzylic alcohols react efficiently with nitriles to give the corresponding amides in good to excellent yields in the presence of P2O5/SiO2 (60% w/w).
- Tamaddon, Fatemeh,Khoobi, Mehdi,Keshavarz, Elham
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p. 3643 - 3646
(2008/02/03)
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- Colorimetric and fluorescence sensing of anions using thiourea based coumarin receptors
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Thiourea-containing coumarins 1, 2 have been designed and synthesized via reaction of 6-aminomethylcoumarin and the corresponding isothiocyanates. Their anion-binding ability has been examined using UV-vis, fluorescence and 1H NMR. The anion recognition takes place through charge neutral thiourea receptor sites with concomitant fluorescence quenching of the coumarin moiety with 1 showing a strong binding to C6H5COO- over F- with a distinct change in color.
- Ghosh, Kumaresh,Adhikari, Suman
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p. 8165 - 8169
(2007/10/03)
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- Anti-Helicobacter pylori agents. 4. 2-(Substituted guanidino)-4-phenylthiazoles and some structurally rigid derivatives
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In order to find a new class of anti-Helicobacter pylori (H. pylori) agents, a series of 4-[(3-acetamido)phenyl]-2-(substituted guanidino)thiazoles and some structurally rigid analoges were synthesized and evaluated for antimicrobial activity against H. pylori. Among the compounds obtained, high anti-H. pyrori activities were observed in benzyl derivative 34 (MIC = 0.025 μg/mL) and phenethyl derivatives 35 and 36 (MIC = 0.037 μg/mL and 0.017 μg/mL). Though alkyl derivatives generally showed lower activity, the 2-methoxyethyl derivative 28 preserved significant activity (MIC = 0.32 μg/mL) and also exhibited more potent gastric antisecretory activity than ranitidine. Structural restriction by bridging between the thiazole and the phenyl rings with an alkyl chain did not improve the activity in this series.
- Katsura,Tomishi,Inoue,Sakane,Matsumoto,Morinaga,Ishikawa,Takasugi
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p. 3315 - 3321
(2007/10/03)
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- AROMATIC HYDROXYLATION OF BENZYLAMIDES BY POTASSIUM SUPEROXIDE
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N-benzylamides react with potassium superoxide in benzene in presence of 18-crown-6 ether to give ortho and para hydroxylated products.A mechanism is proposed for this reaction, involving the nucleophilic attack of superoxide anion to amide carbonyl and hydrogen abstraction from benzyle methylene by the substrate-superoxide adduct.
- Galliani, Guido,Rindone, Bruno
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p. 2313 - 2318
(2007/10/02)
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