- New pyrido[3,4-g]quinazoline derivatives as CLK1 and DYRK1A inhibitors: synthesis, biological evaluation and binding mode analysis
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Cdc2-like kinase 1 (CLK1) and dual specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) are involved in the regulation of alternative pre-mRNA splicing. Dysregulation of this process has been linked to cancer progression and neurodegenerative diseases, making CLK1 and DYRK1A important therapeutic targets. Here we describe the synthesis of new pyrido[3,4-g]quinazoline derivatives and the evaluation of the inhibitory potencies of these compounds toward CDK5, CK1, GSK3, CLK1 and DYRK1A. Introduction of aminoalkylamino groups at the 2-position resulted in several compounds with low nanomolar affinity and selective inhibition of CLK1 and/or DYRK1A. Their evaluation on several immortalized or cancerous cell lines showed varying degree of cell viability reduction. Co-crystal structures of CLK1 with two of the most potent compounds revealed two alternative binding modes of the pyrido[3,4-g]quinazoline scaffold that can be exploited for future inhibitor design.
- Tazarki, Helmi,Zeinyeh, Wael,Esvan, Yannick J.,Knapp, Stefan,Chatterjee, Deep,Schr?der, Martin,Joerger, Andreas C.,Khiari, Jameleddine,Josselin, Béatrice,Baratte, Blandine,Bach, Stéphane,Ruchaud, Sandrine,Anizon, Fabrice,Giraud, Francis,Moreau, Pascale
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p. 304 - 317
(2019/02/07)
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- Continuous-Flow Hydrogenation and Reductive Deuteration of Nitriles: a Simple Access to α,α-Dideutero Amines
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A simple and efficient continuous flow methodology has been developed for hydrogenation and reductive deuteration of nitriles to yield primary amines and also valuable α,α-dideutero analogues. Raney nickel proved to be a useful catalyst for the transformation of a wide range of nitriles under reasonably mild conditions with excellent deuterium incorporation (>90 %) and quantitative conversion. Among known model compounds, three new deuterated primary amines were prepared. The large-scale synthesis of deuterated tryptamine was also carried out to deliver 1.1 g product under flow conditions.
- Mészáros, Rebeka,Peng, Bai-Jing,?tv?s, Sándor B.,Yang, Shyh-Chyun,Fül?p, Ferenc
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p. 1508 - 1511
(2019/11/03)
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- Structure-activity relationship study of hypoxia-activated prodrugs for proteoglycan-targeted chemotherapy in chondrosarcoma
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Due to an abundant chondrogenic, poorly vascularized and particularly hypoxic extracellular matrix, chondrosarcoma, a malignant cartilaginous tumour, is chemo- and radio-resistant. Surgical resection with wide margins remains the mainstay of treatment. To address the lack of therapy, our strategy aims to increase anticancer drugs targeting and delivery in the tumour, by leveraging specific chondrosarcoma hallmarks: an extensive cartilaginous extracellular matrix, namely the high negative fixed charge density and severe chronic hypoxia. A dual targeted therapy for chondrosarcoma was investigated by conjugation of a hypoxia-activated prodrug (HAP) to quaternary ammonium (QA) functions which exhibit a high affinity for polyanionic sites of proteoglycans (PGs), the major components of the chondrosarcoma extracellular matrix. Based on preclinical results, an imidazole prodrug, ICF05016, was identified and provided the basis for a lead optimization study. A series of 27 QA-phosphoramide mustard conjugates, differing by the type of QA function and the length of the alkyl linker, was yielded by a common multi-step sequence involving phosphorylation of a key 2-nitroimidazole alcohol. Then, a screening was realized by surface plasmon resonance technology to assess biomolecular interactions between QA derivatives and aggrecan, the most abundant PG in chondrosarcoma. Results revealed that affinity depends more on the type of QA function, than on the linker length. Moreover, the presence of a benzyl group enhanced affinity to aggrecan. Twelve compounds were shortlisted and evaluated for antiproliferative activity (i.e., growth inhibiting concentration 50), under normoxic and hypoxic conditions using the human extraskeletal myeloid chondrosarcoma cell line (HEMC-SS). For all prodrugs, hypoxic selectivity was maintained and even increased, compared with the lead. From this study, compound 31f emerged as the most effective PG-targeted HAPs with a dissociation constant of 2.10 μM in the SPR experiment, a hypoxia cytotoxicity ratio of 24 and an efficient reductive cleavage under chemical and enzymatic conditions.
- Ghedira, Donia,Voissière, Aurélien,Peyrode, Caroline,Kraiem, Jamil,Gerard, Yvain,Maubert, Elise,Vivier, Magali,Miot-Noirault, Elisabeth,Chezal, Jean-Michel,Farhat, Farhat,Weber, Valérie
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- STAT3-Hif1α signal pathway inhibitor and its application in anti-tumor
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The invention discloses an STAT3-Hif1 alpha signal pathway inhibitor and application in tumor resistance thereof. The structural general formula of the compound is shown as formula I, wherein R1 and R2 are one of amino, alkyl amino of C1-6, aryl of C5-7, heterocyclic aryl of C5-10, and arylamino of C6-10. Specifically, the heterocyclic aryl is one of pyrrolyl, imidazolyl, furyl, thienyl, pyridyl, benzothiophene, benzofuran, indolyl, benzimidazolyl and benzothiazolyl, n is 2 or 3, and X is an oxygen atom. The STAT3-Hif1 alpha signal pathway inhibitor provided by the invention overcomes the problems of current p-STAT3/Hif1 alpha signal pathway inhibitors in the aspects of inhibition efficiency, broad-spectrum, toxicity and the like. The STAT3-Hif1 alpha signal pathway inhibitor provided by the invention can be preferably used as an anticancer drug molecule and for development of related treatment methods. The anticancer drug molecule prepared according to the invention can show the superior performance of high efficiency, low toxicity, simultaneous action on multiple target points, and wide scope of application. (Formula I).
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Paragraph 0060-0063
(2017/03/28)
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- Synthesis and antitumor activity of 5-bromo-7-azaindolin-2-one derivatives containing a 2,4-dimethyl-1H-pyrrole-3-carboxamide moiety
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We report herein the design and synthesis of a series of novel 5-bromo-7-azaindolin-2-one derivatives containing a 2,4-dimethyl-1H-pyrrole-3-carboxamide moiety. These newly synthesized derivatives were evaluated for in vitro activity against selected cancer cell lines by MTT assay. Results revealed that some compounds exhibit broad-spectrum antitumor potency, and the most active compound 23p (IC50: 2.357-3.012 μM) was found more potent than Sunitinib (IC50: 31.594-49.036 μM) against HepG2, A549 and Skov-3, respectively.
- Zhang, Jun,Shen, Weiyi,Li, Xiaoning,Chai, Yun,Li, Senjun,Lv, Kai,Guo, Huiyuan,Liu, Mingliang
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- CINNAMIC ACID AMIDE DERIVATIVE
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The present invention provides a cinnamic acid amide derivative having an excellent analgesic action. The cinnamic acid amide derivative of the present invention is a compound showing excellent analgesic actions to not only a nociceptive pain model animal but also a neuropathic pain model animal, which is very useful as an agent for treating various pain diseases showing acute or chronic pains or neuropathic pains.
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Paragraph 0075; 0108
(2015/11/24)
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- Incorporation of basic side chains into cryptolepine scaffold: Structure-antimalarial activity relationships and mechanistic studies
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The synthesis of cryptolepine derivatives containing basic side-chains at the C-11 position and their evaluations for antiplasmodial and cytotoxicity properties are reported. Propyl, butyl, and cycloalkyl diamine side chains significantly increased activity against chloroquine-resistant Plasmodium falciparum strains while reducing cytotoxicity when compared with the parent compound. Localization studies inside parasite blood stages by fluorescence microscopy showed that these derivatives accumulate inside the nucleus, indicating that the incorporation of a basic side chain is not sufficient enough to promote selective accumulation in the acidic digestive vacuole of the parasite. Most of the compounds within this series showed the ability to bind to a double-stranded DNA duplex as well to monomeric hematin, suggesting that these are possible targets associated with the observed antimalarial activity. Overall, these novel cryptolepine analogues with substantially improved antiplasmodial activity and selectivity index provide a promising starting point for development of potent and highly selective agents against drug-resistant malaria parasites.
- Lavrado, Jo?o,Cabal, Ghislain G.,Prudêncio, Miguel,Mota, Maria M.,Gut, Jiri,Rosenthal, Philip J.,Díaz, Cecília,Guedes, Rita C.,Dos Santos, Daniel J. V. A.,Bichenkov?, Elena,Dougla?, Kenneth T.,Moreira, Rui,Paulo, Alexandra
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p. 734 - 750
(2011/04/15)
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- Solution-phase parallel synthesis of novel membrane-targeted antibiotics
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The increase in the incidence of antibiotic-resistant infections is a major concern to healthcare workers and requires the development of novel antibacterial agents. Recently, we described a series of benzophenonecontaining antibiotics which displayed activity against antibiotic-resistant bacteria. We have shown that these agents function by disrupting the bacterial membrane. To further explore these compounds, a practical and efficient solution-phase parallel synthesis method was developed which allowed us to prepare combinatorial libraries of these agents. Using this method, we prepared 218 compounds in 58 reactions. All of the compounds were characterized by HPLC and MALDI-TOF mass spectrometry. Analysis of this library for antibacterial activity identified six compounds which displayed MTC values of 2.0 mg/T. against Staphylococcus aureus. Examination of the structure-function relationships of these agents revealed that cationic groups were required and that cyclic, aliphatic amines were crucial for activity. Using the information generated here, we speculate on how the various structural features of the molecule are necessary for the interaction with the bacterial membrane.
- Vooturi, Sunil K.,Firestine, Steven M.
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experimental part
p. 151 - 160
(2010/10/19)
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- USE OF (R) AND (S)-2-ARYL-PROPIONIC ACID DERIVATIVES AS ANTISEPTIC AGENTS
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The present invention relates to the use of amides of (R) and (S)-2-aryl- propionic acids as antiseptic agents. The present invention also provides a pharmaceutical preparation including compounds of formula (I), having antiseptic properties for the treatment of gastrointestinal, muco-epidermal and epidermal infections. The present invention is related to pharmaceutical compositions containing an antiseptic agent carried in a suitable vehicle to provide mouthwashes, tablets, solutions, gels, creams and others. The formulations are applied topically to sites of gastrointestinal, muco-epidermal or epidermal infections. Compounds of present invention can be useful in the treatment of nausea, vomiting, bloating, diarrhea, constipation and oropharyngeal, esophageal, vaginal, rectal, nasal and other mucosal infections.
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Page/Page column 6
(2008/12/07)
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- Cryptolepine analogues containing basic aminoalkyl side-chains at C-11: Synthesis, antiplasmodial activity, and cytotoxicity
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A series of cryptolepine derivatives has been synthesized through the incorporation of short basic side-chains in the C-11 position of the 10H-indolo[3,2-b]quinoline scaffold. Their antiplasmodial activity was evaluated in vitro against the chloroquine resistant Plasmodium falciparum W2 strain, showing IC50 values between 22 and 184 nM, while their cytotoxicity was assessed using HUVEC cells, revealing three compounds with a selectivity ratio higher than 10. The most selective of these derivatives, 4d, with a selectivity ratio of 46, was also the least cytotoxic of the series.
- Lavrado, Joao,Paulo, Alexandra,Gut, Jiri,Rosenthal, Philip J.,Moreira, Rui
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p. 1378 - 1381
(2008/12/21)
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- Fluorescent non-imidazole histamine H3 receptor ligands with nanomolar affinities
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ω-Piperidinoalkanamine derivatives with fluorescent moieties (2-cyanoisoindol-1-yl, 7-nitrobenzofurazan-4-yl) have been synthesized starting from piperidine in three steps. The compounds display moderate to good histamine hH3 receptor affinities with Ki values ranging from 178 to 11 nM. The new compounds may act as tools for identification and understanding of the binding site on the histamine H3 receptor.
- Amon, Michael,Ligneau, Xavier,Schwartz, Jean-Charles,Stark, Holger
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p. 1938 - 1940
(2007/10/03)
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- THIENOPYRIDINONE COMPOUNDS AND METHODS OF TREATMENT
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The invention relates to 5-HT receptor agonists and partial agonists. Novel thienopyridinone compounds represented by Formula I, and synthesis and uses thereof for treating diseases mediated directly or indirectly by 5-HT receptors, are disclosed. Such conditions include Alzheimer's disease, cognition disorders, irritable bowel syndrome, nausea, emesis, vomiting, prokinesia, gastroesophageal reflux disease, nonulcer dyspepsia, depression, anxiety, urinary incontinence, migraine, arrhythmia, atrial fibrillation, ischemic stroke, gastritis, gastric emptying disorders, feeding disorders, gastrointestinal disorders, constipation, erectile dysfunction, and respiratory depression. Methods of preparation and novel intermediates and pharmaceutical salts thereof are also included.
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Page/Page column 16
(2008/06/13)
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- Search for histamine H3 receptor ligands with combined inhibitory potency at histamine N-methyltransferase: ω- piperidinoalkanamine derivatives
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In an effort to design new hybrid compounds with dual properties, i.e. binding affinity at histamine H3 receptors and inhibitory potency at the catabolic enzyme histamine Nτ-methyltransferase (HMT), a novel series of 1-substituted piperidine derivatives was synthesized. This alicyclic heterocycle is structurally linked via aminoalkyl spacers of variable lengths to additional aromatic carbo- or heterocycles. These new hybrid drugs were pharmacologically evaluated regarding their binding affinities at recombinant human H3 receptors, stably expressed in CHO cells, and in a functional assay for their inhibitory potencies at rat kidney HMT. All compounds investigated proved to be H3 receptor ligands with binding affinities in the micro- to nanomolar concentration range despite significant differences in the type of the aromatic moiety introduced. The most potent compound in this series was the quinoline derivative 20 (Ki = 5.6 nM). Likewise, all new ligands studied showed impressive HMT inhibitory activities. Here, compounds 5, 10, 14, and 18-20 exhibited submicromolar potencies (IC50 = 0.061 -0.56 μM). The aminomethylated quinoline 19 showed almost the same, well balanced nanomolar activities on both targets. In this study, new hybrid compounds with a dual mode biological action were developed. These pharmacological agents are valuable leads for further development and candidates for treatment of histamine-dependent disorders.
- Grassmann, Sven,Apelt, Joachim,Ligneau, Xavier,Pertz, Heinz H.,Arrang, Jean-Michel,Ganellin, C. Robin,Schwartz, Jean-Charles,Schunack, Walter,Stark, Holger
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p. 533 - 545
(2007/10/03)
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- Phenyl derivatives
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Novel compounds of the formula I in which W, X, Y, T, R1 and R2 are as defined in Patent claim 1, are inhibitors of coagulation factor Xa and can be employed for the prophylaxis and/or therapy of thromboembolic disorders.
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- Development of a new class of nonimidazole histamine H3 receptor ligands with combined inhibitory histamine N-methyltransferase activity
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In search of novel ways to enhance histaminergic neurotransmission in the central nervous system, a new class of nonimidazole histamine H3 receptor ligands were developed that simultaneously possess strong inhibitory activity on the main histamine metabolizing enzyme, histamine N-methyltransferase (HMT). The novel compounds contain an aminoquinoline moiety, which is an important structural feature for HMT inhibitory activity, connected by different spacers to a piperidino group (for H3 receptor antagonism). Variation of the spacer structure provides two different series of compounds. One series, having only an alkylene spacer between the basic centers, led to highly potent HMT inhibitors with moderate to high affinity at human histamine H3 receptors. The second series possesses a p-phenoxypropyl spacer, which may be extended by another alkylene chain. This latter series also showed strong inhibitory activity on HMT, and in most cases, the H3 receptor affinity even surpassed that of the first series. One of the most potent compounds with this dual mode of action is 4-(4-(3-piperidinopropoxy)phenylamino)quinoline (34) (hH3, Ki = 0.09 nM; HMT, IC50 = 51 nM). This class of compounds showed high antagonist potency and good H3 receptor selectivity in functional assays in guinea pig on H1, H2, and H3 receptors. Because of low or missing in vivo activity of two selected compounds, the proof of concept of these valuable pharmacological tools for the supposed superior overall enhancing effect on histaminergic neurotransmission failed to appear hitherto.
- Apelt, Joachim,Ligneau, Xavier,Pertz, Heinz H.,Arrang, Jean-Michel,Ganellin, C. Robin,Schwartz, Jean-Charles,Schunack, Walter,Stark, Holger
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p. 1128 - 1141
(2007/10/03)
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- N-SUBSTITUTED-N'-SUBSTITUTED UREA DERIVATIVE AND USE THEREOF AS TNF-γ(a) PRODUCTION INHIBITOR
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N-Substituted-N'-substituted urea derivatives represented by the following formula, analogs thereof or pharmaceutically acceptable salts thereof are herein provided. These compounds show a TNF- α production inhibitory activity.
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- Haliclorensin, a novel diamino alkaloid from the marine sponge Haliclona tulearensis
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Haliclorensin (1), a novel diamino alkaloid possessing an azacyclodecane ring, has been isolated from the sponge Haliclona tulearensis. Its structure was elucidated on the basis of spectroscopic data, as well as by comparison with γ-amino azacycloalkanes.
- Koren-Goldshlager,Kashman,Schleyer
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p. 282 - 284
(2007/10/03)
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- Method of treating chloroquine-resistant malaria with aminoquinoline derivatives
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Novel aminoquinoline derivatives of the general formula STR1 are described. Also described are methods for the treatment of malaria pathogens, particularly chloroquine-resistance malaria pathogens with compounds of formula I or the pharmaceutically acceptable salts and hydrolyzable esters thereof.
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- Design, synthesis and biological evaluation of 1,3-diaminopropanes: A new class of polyamine analogs as leishmanicidal agents
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Analogs of 1,3-diaminopropane as inhibitors for the growth of Leishmania donovani have been synthesized and evaluated for their antileishmanial activity. Of the many active compounds, 1-(3-N,N-bis methoxycarbonyl guanidino)propyl-4- methylpiperidine piperazine (4e,f) exhibited significant in vivo inhibitory efficacy against L. donovani by oral and intraperitoneal route of administration.
- Kumar, Versha Vinay,Singh, Sudhir K.,Sharma,Bhaduri,Gupta, Suman,Zaidi, Alima,Tiwari, Suman,Katiyar
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p. 675 - 680
(2007/10/03)
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- Pancreatic imaging agents
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A novel group of radiolabelled diamines are provided, effective for pancreatic imaging and represented by the formula STR1 wherein n is 1 to 10; R1 and R2 are the same or different and are hydrogen, hydroxyl or lower alkyl having 1 to 6 carbon atoms; R3 is lower alkyl having 1 to 6 carbon atoms; and N' is a nitrogen atom forming part of a 4- to 8-membered heterocyclic ring containing one or two hetero atoms, one of which is said nitrogen, said heterocyclic ring being unsubstituted or substituted with one or more lower alkyl groups and pharmaceutically acceptable acid addition salts thereof.
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- NUCLEOPHILIC CLEAVAGE AND FORMATION OF SATURATED HETEROCYCLES. XII. REACTIVITY OF SMALL HETEROCYCLES TOWARD AMINOLYSIS AND HYDROLYSIS
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The cleavage of four-membered saturated heterocycles proceeds via a more product-like transition state than that of three-membered rings.General acid catalysis is characteristic of oxygen heterocycles, but in the case of nitrogen heterocycles catalysis is specific.The reactivity of amines in the cleavage of azetidines is linearly dependent on their pKa values, primary and secondary amines comprising separate reaction series.
- Bobylev, V. A.,Veselkov, N. Yu.,Dalin, A. R.,Sharikov, F. Yu.
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p. 1700 - 1713
(2007/10/02)
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- Anti-arrhythmic agents
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A series of 5-endo-(1-naphthoyloxy)-N-[amino-(lower)alkyl]bicyclo[2.2.1]heptane-2,3-di-endo-carboxylic acid imides have been found to possess unique prophylactic and therapeutic activity as anti-arrhythmia agents. An example of such a compound possessing excellent activity is 5-endo-(1-naphthoyloxy)-N-(3-dimethylaminopropyl)bicyclo[2.2.1]heptane-2,3-di-endo-carboxylic acid imide hydrochloride.
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