- NOVEL COMPOUNDS WITH THYMINE SKELETON FOR USE IN MEDICINE
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The present invention relates to novel compounds as new chemical entities with thymine skeleton, these compounds for use as in medicine, especially in the treatment of carcinoma, HSP27-associated diseases and cystic fibrosis; and a pharmaceutical product
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Paragraph 0128-0130
(2021/05/07)
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- A focused fragment library targeting the antibiotic resistance enzyme - Oxacillinase-48: Synthesis, structural evaluation and inhibitor design
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β-Lactam antibiotics are of utmost importance when treating bacterial infections in the medical community. However, currently their utility is threatened by the emergence and spread of β-lactam resistance. The most prevalent resistance mechanism to β-lactam antibiotics is expression of β-lactamase enzymes. One way to overcome resistance caused by β-lactamases, is the development of β-lactamase inhibitors and today several β-lactamase inhibitors e.g. avibactam, are approved in the clinic. Our focus is the oxacillinase-48 (OXA-48), an enzyme reported to spread rapidly across the world and commonly identified in Escherichia coli and Klebsiella pneumoniae. To guide inhibitor design, we used diversely substituted 3-aryl and 3-heteroaryl benzoic acids to probe the active site of OXA-48 for useful enzyme-inhibitor interactions. In the presented study, a focused fragment library containing 49 3-substituted benzoic acid derivatives were synthesised and biochemically characterized. Based on crystallographic data from 33 fragment-enzyme complexes, the fragments could be classified into R1 or R2 binders by their overall binding conformation in relation to the binding of the R1 and R2 side groups of imipenem. Moreover, binding interactions attractive for future inhibitor design were found and their usefulness explored by the rational design and evaluation of merged inhibitors from orthogonally binding fragments. The best inhibitors among the resulting 3,5-disubstituted benzoic acids showed inhibitory potential in the low micromolar range (IC50 = 2.9 μM). For these inhibitors, the complex X-ray structures revealed non-covalent binding to Arg250, Arg214 and Tyr211 in the active site and the interactions observed with the mono-substituted fragments were also identified in the merged structures.
- Akhter, Sundus,Lund, Bjarte Aarmo,Ismael, Aya,Langer, Manuel,Isaksson, Johan,Christopeit, Tony,Leiros, Hanna-Kirsti S.,Bayer, Annette
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supporting information
p. 634 - 648
(2018/01/19)
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- Suzuki-Miyaura and related cross-couplings in aqueous solvents catalyzed by di(2-pyridyl)methylamine-palladium dichloride complexes
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Di(2-pyridyl)methylamine-based palladium dichloride complexes 4 are versatile catalysts for different types of cross-coupling reactions in water or aqueous solvents under aerobic conditions. The Suzuki-Miyaura reaction of arylboronic acids can be performed with bromoarenes under water reflux using K2CO3 as base or at room temperature or 60°C in aqueous methanol using KOH as base. For aryl chlorides the corresponding cross-couplings with arylboronic acids can be carried out in refluxing water with K2CO3 as base and TBAB as additive to provide biaryls and heterobiaryls. Arylboronic acids react with benzylic chlorides and allylic substrates such as chlorides, acetates or carbonates also in refluxing water with K2CO3 as base or at room temperature in aqueous acetone and KOH as base, to give diarylmethanes and arylpropenes. Trimethylboroxine and alkylboronic acids are coupled with bromo- and chloroarenes under water at reflux with K2CO3 as base and TBAB as additive to furnish methyl- and butylarenes. These cross-couplings have also been performed in shorter times under microwave irradiation. Several important intermediates such as, 4′-methylbiphenyl-2-carbonitrile, 4-biphenylacetic acid, 3-(3-methylphenyl)benzoic acid, 4,5-diphenyl-2-methyl- 3(2H)pyridazinone and 2-(4′-fluorobenzyl)thiophene have been prepared under aqueous and aerobic conditions in good yields.
- Najera, Carmen,Gil-Molto, Juan,Karlstroem, Sofia
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p. 1798 - 1811
(2007/10/03)
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- Inhibitors of prenyl transferases
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Compounds which inhibit prenyl transferases, particularly farnysyltransferase and geranylgeranyl transferase I, processes for preparing the compounds, pharmaceutical compositions containing the compounds, and methods of use.
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- Design and synthesis of non-peptide Ras CAAX mimetics as potent farnesyltransferase inhibitors
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Cysteine farnesylation of the ras oncogene product Ras is required for its transforming activity and is catalyzed by farnesyltransferase (FTase). The Ras carboxyl terminal tetrapeptide CAAX (C is cysteine, A is any aliphatic amino acid, X is methionine or serine) is the minimum sequence for FTase recognition. We report here the design, synthesis, and biological characterization of Ras CAAX non-peptide mimetics in which the cysteine is linked through a reduced pseudopeptide bond to 4-amino-3'-carboxybiphenyl. These non-peptide mimetics are potent inhibitors of FTase (IC50 = 40 nM for the most potent inhibitor) and are highly selective for FTase over GGTase I (geranylgeranyltransferase I). They are not substrates for farnesylation, do not have peptidic features, and have no hydrolyzable bonds. Structure- activity studies reveal the importance of the position of the carboxylic acid on the aryl ring as well as the reduction of the cysteine amide bond. Substitution at the 2-position of 4-amino-3'-carboxybiphenyl increases inhibitory potency, while the removal of the carboxylic acid results in a 10- fold loss of inhibitory activity.
- Qian, Yimin,Vogt, Andreas,Sebti, Sa?d M.,Hamilton, Andrew D.
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p. 217 - 223
(2007/10/03)
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