- Substitution at the indole 3 position yields highly potent indolecombretastatins against human tumor cells
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Resistance to combretastatin A-4 is mediated by metabolic modification of the phenolic hydroxyl and ether groups of the 3-hydroxy-4-methoxyphenyl (B ring). Replacement of the B ring of combretastatin A-4 by a N-methyl-5-indolyl reduces tubulin polymerization inhibition (TPI) and cytotoxicity against human cancer cell lines but cyano, methoxycarbonyl, formyl, and hydroxyiminomethyl substitutions at the indole 3-position restores potent TPI and cytotoxicity against sensitive human cancer cell lines. These highly potent substituted derivatives displayed low nanomolar cytotoxicity against several human cancer cell lines due to tubulin inhibition, as shown by cell cycle analysis, confocal microscopy, and tubulin polymerization inhibitory activity studies, and promoted cell killing mediated by caspase-3 activation. Binding at the colchicine site was suggested by molecular modeling studies. Substituted combretastatins displayed higher potencies than the isomeric isocombretastatins and the highest potencies were achieved for the hydroxyiminomethyl (21) and cyano (23) groups, with TPI values in the submicromolar range and cytotoxicities in the nanomolar and subnanomolar range. Dose-response and time-course studies showed that drug concentrations as low as 1 nM (23) or 10 nM (21) led to a complete G2/M cell cycle arrest after 15 h treatment followed by a high apoptosis-like cell response after 48–72 h treatment. The P-glycoprotein antagonist verapamil increased 21 and 23 cytotoxicity to IC50 values of 10?10 M, and highly potentiated the cytotoxic activity in 100-fold of the CHO derivative (17), in A-549 human non-small cell lung cancer cells. The cyano substituted indolecombretastatin 23 is by itself highly potent against rather resistant HT-29 and A-549 cell lines. A 3,4,5-trimethoxyphenyl ring always afforded more potent derivatives than a 2,3,4-trimethoxyphenyl ring.
- álvarez, Raquel,Gajate, Consuelo,Puebla, Pilar,Mollinedo, Faustino,Medarde, Manuel,Peláez, Rafael
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Read Online
- ISOINDOLINE COMPOUND, AND PREPARATION METHOD, PHARMACEUTICAL COMPOSITION, AND APPLICATION OF ISOINDOLINE COMPOUND
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The present invention relates to an isoindoline compound as represented by general formula (I) and used as a CRBN regulator, and a preparation method, a pharmaceutical composition, and an application of the isoindoline compound. Specifically, a class of polysubstituted isoindoline compound provided in the present invention, as a class of CRL4CRBN E3 ubiquitin ligase regulator having a novel structure, has good anti-tumor activity and immunoregulatory activity, and can be used for preparing drugs for treating diseases associated with a CRL4CRBN E3 ubiquitin ligase.
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Paragraph 0157-0158
(2021/10/22)
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- Multi-target inhibitor acting on QC and GSK-3[beta]
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The invention discloses a multi-target inhibitor acting on QC and GSK-3[beta], wherein the multi-target inhibitor has the structural general formula shown in the specification; according to active center crystal structures of target QC and GSK-3[beta] zymoprotein, with synthesis of multiple high-activity pharmacophores, the multi-target inhibitor capable of acting on QC and GSK-3[beta] at the sametime is prepared through skeletal transition and recombination design; the multi-target inhibitor is a high-activity molecule with multiple target points, the molecular structure diversity of a leaddrug is remarkably expanded, and research and development of innovative anti-AD drugs and AD diagnostic kits are actively promoted.
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- Preparation method and application of multi-target inhibitor acting on QC and GSK-3beta
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The invention discloses a preparation method and application of a multi-target inhibitor acting on QC and GSK-3 beta. The structural general formula of the multi-target inhibitor prepared by the method is shown in the specification. According to the invention, according to active center crystal structures of target QC and GSK-3 beta zymoprotein, multiple high-activity pharmacophores are integrated, the multi-target inhibitor capable of acting on QC and GSK-3 beta at the same time is prepared through framework transition and recombination design, the multi-target inhibitor is molecules with multiple target points and high activity, the molecular structure diversity of a lead drug is remarkably expanded, and the research and development of innovative anti-AD drugs and AD diagnostic kits areactively promoted, and the preparation method of the multi-target inhibitor provided by the invention is simple and easy to operate.
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- Substituted Pyran Derivatives
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Certain 3,6-disubstituted and 2, 4, 5-trisubstituted pyran derivatives that exhibit potent activity on monoamine transport systems are provided. The 3, 6 and 2, 4, 5 pyrans are useful in probing the effects of their binding to monoamine transporter system
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Paragraph 0163; 0164
(2014/10/29)
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- PROTEASE ACTIVATED RECEPTOR 2 (PAR2) ANTAGONISTS
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A compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate thereof (I) Wherein Y, Z, R3, U, R4, m and n are as defined in the claims.
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Page/Page column 29
(2012/08/08)
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- A facile synthesis of 5(6)-(chloromethyl)benzimidazoles: Replacement of a sulfonic acid functionality by chlorine
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(Chemical Equation Presented) Valuable new synthetic intermediates, 5(6)-(chloromethyl)benzimidazoles, were prepared by the facile elimination of sulfur dioxide under the influence of thionyl chloride from benzimidazole-5(6)- methanesulfonic acids easily
- Pete, Bela,Szokol, Balint,Toke, Laszlo
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p. 343 - 347
(2008/09/20)
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- HETEROARYL COMPOUNDS, COMPOSITIONS THEREOF, AND USE THEREOF AS PROTEIN KINASE INHIBITORS
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Provided herein are Heteroaryl Compounds having the following structure: (I) wherein R1, R2, L, X, Y, Z, Q, A and B are as defined herein, compositions comprising an effective amount of a Heteroaryl Compound and methods for treating or preventing cancer, inflammatory conditions, immunological conditions, metabolic conditions and conditions treatable or preventable by inhibition of a kinase pathway comprising administering an effective amount of a Heteroaryl Compound to a patient in need thereof.
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Page/Page column 124
(2008/12/05)
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- NOVEL JNK INHIBITORS
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Disclosed are substituted imidazo[1,2-a]pyridines, imidazo[1,2-a]pyrazines, imidazo[1,2-c]pyrimidines and imidazo[1,2-d]triazines compounds of the formula: (1.0) Also disclosed are methods for treating JNK1 and ERK mediated diseases using the compounds of formula 1.0.
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Page/Page column 97
(2008/12/07)
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- OXIME COMPOUNDS AND THE USE THEREOF
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The invention relates to oxime compounds of Formula (I) and pharmaceutically acceptable salts, prodrugs, or solvates thereof, wherein X is hydrogen, optionally substituted aryl, optionally substituted heteroaryl or the like; Y is CO, SO2, CRsu
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Page/Page column 364
(2008/06/13)
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- NOVEL INHIBITORS OF GLUTAMINYL CYCLASE
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Compounds of formula (I), combinations and uses thereof for disease therapy, or a pharmaceutically acceptable salt, solvate or polymorph thereof, including all tautomers and stereoisomers thereof wherein: A represents and B, R1, R2,
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Page/Page column 28-29
(2008/12/04)
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- NOVEL INHIBITORS OF GLUTAMINYL CYCLASE
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Compounds of formula (I), combinations and uses thereof for disease therapy, or a pharmaceutically acceptable salt, solvate or polymorph thereof, including all tautomers and stereoisomers thereof wherein: R1 represents and R2, R
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Page/Page column 36
(2008/12/04)
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- THERAPEUTIC AGENTS, AND METHODS OF MAKING AND USING THE SAME
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In part, the present invention is directed to antibacterial compounds
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Page/Page column 181-182
(2010/11/27)
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- THIAZOLONES FOR USE AS PI3 KINASE INHIBITORS
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Invented is a method of inhibiting the activity/function of PI3 kinases using substituted thiazolones. Also invented is a method of treating one or more disease states selected from: autoimmune disorders, inflammatory diseases, cardiovascular diseases, ne
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Page/Page column 111
(2008/06/13)
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- Novel potent antagonists of transient receptor potential channel, vanilloid subfamily member 1: Structure-activity relationship of 1,3-diarylalkyl thioureas possessing new vanilloid equivalents
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Recently, 1,3-diarylalkyl thioureas have merged as one of the promising nonvanilloid TRPV1 antagonists possessing excellent therapeutic potential in pain regulation. In this paper, the full structure-activity relationship for TRPV1 antagonism of a novel series of 1,3-diarylalky thioureas is reported. Exploration of the structure-activity relationship, by systemically modulating three essential pharmacophoric regions, led to six examples of 1,3-dibenzyl thioureas, which exhibit Ca2+ uptake inhibition in rat DRG neuron with IC50 between 10 and 100 nM.
- Suh, Young-Ger,Lee, Yong-Sil,Min, Kyung-Hoon,Park, Ok-Hui,Kim, Jin-Kwan,Seung, Ho-Sun,Seo, Seung-Yong,Lee, Bo-Young,Nam, Yeon-Hee,Lee, Kwang-Ok,Kim, Hee-Doo,Park, Hyeung-Geun,Lee, Jeewoo,Oh, Uhtaek,Lim, Ju-Ok,Kang, Sang-Uk,Kil, Min-Jung,Koo, Jae-Yeon,Shin, Song Seok,Joo, Yung-Hyup,Kim, Jin Kwan,Jeong, Yeon-Su,Kim, Sun-Young,Park, Young-Ho
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p. 5823 - 5836
(2007/10/03)
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- NOVEL CHEMICAL COMPOUNDS
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This invention relates to newly identified compounds for inhibiting hYAK3 proteins and methods for treating diseases associated with the imbalance or inappropriate activity of hYAK3 proteins.
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Page/Page column 91
(2010/02/13)
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- Thrombin inhibitors
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Compounds of the invention are useful in inhibiting thrombin and associated thrombotic occlusions having the following structure: or a pharmaceutically acceptable salt thereof, wherein b is NY or O; c is CY2or N; d is CY3or N; e is CY4or N; f is CY5or N; g is CY6or N; Y4, Y5, and Y6are independently hydrogen, C1-4alkyl, or halogen; Y1and Y2are independently hydrogen, C1-4alkyl, C3-7cycloalkyl, halogen, NH2, OH or C1-4alkoxy, and Y3is hydrogen, C1-4alkyl, C3-7cycloalkyl, halogen, —CN, NH2, OH or C1-4alkoxy; A is and W, W1, R1, R3, R4, R5, X and Z are defined in the specification.
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- Pyrrolo[2.1-a]isoquinoline derivatives
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The present invention relates to pyrrolo[2.1-a]isoquinolines which are inhibitors of phosphodiesterase 10a, a process for preparing these compounds and a method of treating cancer in humans and animals by administering these compounds.
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- New analogs of nitrobenzylthioinosine
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This invention relates to new analogs or derivatives of nitrobenzylthioinosine, use of these new analogs of nitrobenzylthioinosine for the treatment of pain and various other diseases as well as pharmaceuticals comprising at least on new analog of nitrobenzylthioinosine.
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Page/Page column 30; 38
(2010/11/29)
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- Inhibition of nucleoside transport by new analogues of nitrobenzylthioinosine
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Nitrobenzylthioinosine (NBTI, 1) was systematically modified by attachment of substituents at positions C6 and N9, and also by substitution of N1 with C. These modifications were chosen to reduce the polarity of the new compounds. Incorporation of the nitro functionality into a benzoxadiazole ring system was considered first. These new nucleosides showed high affinity (1.5-10 nM) towards the nucleoside transport protein as present on human erythrocyte ghosts. Next, modification of this benzoxadiazole ring system with C, S and O in different positions produced a number of less polar nucleosides with affinity in the higher nanomolar range. Modification of N9 was achieved with different alkyl and alcohol substituents. An n-butyl substituent proved best, although all variations yielded substantial decreases in affinity. Replacement of N1 by a carbon atom in combination with a 2-Cl substituent also resulted in a relatively potent NBTI derivative (47 nM).
- Deghati, Paymaneh Y. F.,Borghini, Alice,Van Den Nieuwendijk, Adrianus M. C. H.,Dissen-de Groote, Miriam,IJzerman, Adriaan P.
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p. 899 - 908
(2007/10/03)
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- Thrombin inhibitors
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Compounds of the invention are useful in inhibiting thrombin and treating blood coagulation and cardiovascular disorders and have the following structure: wherein R3 is hydrogen or halogen, and u is N or CH.
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- Synthesis and evaluation of terbenzimidazoles as topoisomerase I inhibitors
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The synthesis and pharmacological activity of a series of terbenzimidazoles are described. The ability of these derivatives to induce DNA cleavage in the presence of topoisomerase I was evaluated in vitro. These analogs were also assayed for their cytotoxicity in RPMI 8402 cells and the camptothecin-resistant CPT-K5 cells. In addition the potential for these compounds to serve as substrates for MDR1 was also determined. Several terbenzimidazoles exhibited similar cytotoxicity against variants of human tumor cells that either overexpress MDR1 or are camptothecin-resistant.
- Sun,Gatto,Yu,Liu,Liu,LaVoie
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p. 3638 - 3644
(2007/10/03)
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- HETEROCYCLIC COMPOUNDS
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Compounds of Formula I are described STR1 in which X and Y are independently--NH--,--O--or--S--; Z may be a pyrimidine, triazine, triazole, thiazole, thiadiazole ring. The methods of preparation are described. The compounds are useful as antipeptic ulcer agents.
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