448-40-8Relevant academic research and scientific papers
Fluorination as tool to improve bioanalytical sensitivity and COX-2-selective antitumor activity of cobalt alkyne complexes
Baecker, Daniel,Obermoser, Victoria,Kirchner, Elisabeth Anna,Hupfauf, Andrea,Kircher, Brigitte,Gust, Ronald
supporting information, p. 15856 - 15868 (2019/11/11)
The cobalt alkyne complex [(prop-2-ynyl)-2-acetoxybenzoate]dicobalthexacarbonyl (Co-ASS) is an auspicious lead, which exhibits its anticancer activity mainly by inhibition of both cyclooxygenases (COX-1 and COX-2). Since COX-2 participates in carcinogenesis, a selective inhibition of that isoenzyme is aimed. To study if fluorination increases the COX-2/COX-1 inhibition ratio of the lead, substitution was respectively performed in the positions 3, 4, 5, and 6 of the aromatic moiety. The complexes 3/4/5F-Co-ASS and to a much lower extent also 6F-Co-ASS showed cytotoxic, antimetabolic, and apoptotic effects in COX-1/2-positive HT-29 and MDA-MB-231 cells and remarkably less activity in the COX-1/2-negative MCF-7 cell line. The metabolic activity in MCF-7 cells was even unaffected up to a concentration of 40 μM. With exception of 6F-Co-ASS, the complexes strongly reduced the PGE2 synthesis in HT-29 cells and all complexes inhibited COX-2 more effectively than COX-1 in an assay at isolated enzymes. These findings point to an interference in the COX cascade as part of the mode of antitumor action. The limited cellular effects of 6F-Co-ASS are related to its poor uptake as determined by HR CS AAS/MAS. Moreover, the cellular uptake studies confirm fluorination as beneficial tool for bioanalytical labeling. The higher quantification of fluorine by HR CS MAS makes this method about 5-fold more sensitive than HR CS AAS measuring cobalt. As a further positive result, 3/4/5/6-Co-ASS demonstrated high selectivity to tumor cells due to lack of antimetabolic activity against the non-tumorigenic bone marrow stromal cell line HS-5.
Conformation-constrained entirely-synthetic macrocyclic compounds
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Paragraph 1406, (2016/10/07)
The invention relates to conformation-constrained entirely-synthetic macrocyclic compounds. A conformation-constrained, space-defined 12-30-member macrocyclic system (I) which is as shown in the description comprises three different constitution units: an aromatic template a, a confor1ation regulator b and a spaced part c, which are illustrated in the description and the claims. The macrocyclic compounds (I) can be easily prepared according to a parallel synthesis method or a combinatorial chemistry method, and are designed for realizing interaction with a specific biological target. Particularly, the compounds show agonistic or antagonistic activity to the following matters: a motilin receptor (MR), a 5-hydroxytryptamine receptor (5-HT2B receptor) of a subtype 5-HT2B, and a prostaglandin F2alpha receptor (FP receptor). Thus, the compounds are effectively used for treating gastrointestinal tract hypomotility disorder such as diabetic gastroparesis and constipation-predominant irritable bowel syndrome, CNS-related diseases such as migraine, schizophrenia, psychosis and depression, ocular hypertension such as glaucoma-related ocular hypertension, and premature delivery.
COMPOUNDS USEFUL IN THE TREATMENT OF NEOPLASTIC DISEASES
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Page/Page column 28, (2015/04/15)
The present invention refers to compounds of formula: (formula A), wherein R1 is selected from (formula I), (formula II), (formula (III), (formula IV), (formula V), or (formula B), and wherein R2, R3, R4 and Rs
CONFORMATIONALLY CONSTRAINED, SYNTHETIC MACROCYCLIC COMPOUNDS
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Paragraph 0103, (2016/10/10)
PROBLEM TO BE SOLVED: To provide a novel macrocyclic compound showing agonistic or antagonistic activity on a motilin receptor, a serotonin receptor and a prostaglandin F2A receptor. SOLUTION: This invention provides a macrocyclic compound incorporating building blocks A, B and C, represented by formula (I). The compound is useful for the treatment of motility disorders of the gastrointestinal tract, CNS-related disease and ocular hypertension. COPYRIGHT: (C)2015,JPO&INPIT
Synthesis, biological evaluation and 3D-QSAR studies of 3-keto salicylic acid chalcones and related amides as novel HIV-1 integrase inhibitors
Sharma, Horrick,Patil, Shivaputra,Sanchez, Tino W.,Neamati, Nouri,Schinazi, Raymond F.,Buolamwini, John K.
experimental part, p. 2030 - 2045 (2011/05/05)
HIV-1 integrase is one of the three most important enzymes required for viral replication and is therefore an attractive target for anti retroviral therapy. We herein report the design and synthesis of 3-keto salicylic acid chalcone derivatives as novel HIV-1 integrase inhibitors. The most active compound, 5-bromo-2-hydroxy-3-[3-(2,3,6-trichlorophenyl)acryloyl]benzoic acid (25) was selectively active against integrase strand transfer, with an IC 50 of 3.7 μM. While most of the compounds exhibited strand transfer selectivity, a few were nonselective, such as 5-bromo-3-[3-(4- bromophenyl)acryloyl]-2-hydroxybenzoic acid (15), which was active against both 3′-processing and strand transfer with IC50 values of 11 ± 4 and 5 ± 2 μM, respectively. The compounds also inhibited HIV replication with potencies comparable with their integrase inhibitory potencies. Thus, 5-bromo-2-hydroxy-3-[3-(2,3,6-trichlorophenyl)acryloyl]benzoic acid (25) and 5-bromo-3-[3-(4-bromophenyl)acryloyl]-2-hydroxybenzoic acid (15) inhibited HIV-1 replication with EC50 values of 7.3 and 8.7 μM, respectively. A PHASE pharmacophore hypothesis was developed and validated by 3D-QSAR, which gave a predictive r2 of 0.57 for an external test set of ten compounds. Phamacophore derived molecular alignments were used for CoMFA and CoMSIA 3D-QSAR modeling. CoMSIA afforded the best model with q2 and r2 values of 0.54 and 0.94, respectively. This model predicted all the ten compounds of the test set within 0.56 log units of the actual pIC50 values; and can be used to guide the rational design of more potent novel 3-keto salicylic acid integrase inhibitors.
Synthesis and structure-activity relationships of carboxylated chalcones: A novel series of CysLT1 (LTD4) receptor antagonists
Zwaagstra, Mari?l E.,Timmerman, Hendrik,Tamura, Masahiro,Tohma, Tsutomu,Wada, Yasushi,Onogi, Kazuhiro,Zhang, Ming-Qiang
, p. 1075 - 1089 (2007/10/03)
The synthesis and CysLT1 antagonistic activities of a new series of 2- , 3-, and 4-(2-quinolinylmethoxy)- and 3- and 4-[2-(2-quinolinyl)ethenyl]- substituted, 2'-, 3'-, 4'-, or 5'-carboxylated chalcones are described. Structure-activity relationship studies indicate a preference for the presence of a negatively charged (acidic) moiety, although in some cases nitrile or ester analogues also exhibit moderate activity. The quinoline moiety may be substituted at either the 3- or the 4-position. Replacement of this heterocycle by other aromatic groups results in compounds with comparable affinities [2-(7-chloroquinoline), 1-(1-methyl-2-benzimidazole), or 1-(2-benzothiazole)] or substantially lower activities [1-(1- ethoxyethyl)-2-benzimidazole, 2-naphthyl, or phenyl]. The quinoline and chalcone moieties may be connected by either an ethenyl or a methoxy spacer. The acidic moiety at the chalcone B ring may be attached to the 2'-, 3'-, 4'- , or 5'-position, for both the 3- and 4-substituted chalcones. There are no general patterns to specify which substitution positions gave the most potent compounds. The series contains several potent CysLT1 receptor antagonists, with K(D) values approaching the nanomolar range, as measured by the displacement of [3H]LTD4 from guinea pig lung membranes. Antagonism of LTD4-induced contraction of guinea pig ileum, the inhibition of antigen- induced contraction of guinea pig trachea in vitro, and the inhibition of LTD4-induced increase of vascular permeability in vivo are determined for chalcones with high CysLT1 receptor affinities (K(D) values below 0.1μM). 2'-Hydroxy-4-(2-quinolinylmethoxy)-5'-(5-tetrazolyl)chalcone (14, VUF 4819) showed good activity in both in vitro and in vivo assays and has been selected for further evaluation.
