- Identification of azepinone fused tetracyclic heterocycles as new chemotypes with protein kinase inhibitory activities
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The design and synthesis of small tetracyclic heterocycles which bear two new regioisomeric 2-carboxyethyl-1H-pyrrole-annulated indoloazepinone scaffolds is described. An azepinone motif, which is inherent in the structures of many well studied protein kinase inhibitors, serves as prominent structural feature of the new compounds. Concise access to the new regioisomeric tetracyclic derivatives was accomplished through amide coupling of appropriate pyrrole and indole precursors followed by an intramolecular Heck coupling reaction of the intermediate amide conjugates. Preliminary evaluation of newly synthesized tetracyclic molecules against a panel of protein kinases indicated their inhibitory activities and revealed promising selectivity profiles. The new compounds displayed no significant antiproliferative activity against MCF-7 cancer cells. Interestingly, derivative 19a exhibited selective TAK1 kinase inhibitory activity and figures as a promising chemotype for the discovery of new TAK1 inhibitors.
- Psarra, Vassiliki,Fousteris, Manolis A.,Hennig, Lothar,Bantzi, Marina,Giannis, Athanassios,Nikolaropoulos, Sotiris S.
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supporting information
p. 2376 - 2385
(2016/04/26)
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- Synthesis, biological evaluation and molecular modelling of N-heterocyclic dipeptide aldehydes as selective calpain inhibitors
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A series of N-heterocyclic dipeptide aldehydes 4-13 have been synthesised and evaluated as inhibitors of ovine calpain 1 (o-CAPN1) and ovine calpain 2 (o-CAPN2). 5-Formyl-pyrrole 9 (IC50 values of 290 and 25 nM against o-CAPN1 and o-CAPN2, respectively) was the most potent and selective o-CAPN2 inhibitor, displaying >11-fold selectivity. The amino acid sequences of o-CAPN1 and o-CAPN2 have been determined. Because of the lack of available structural information on the ovine calpains, in silico homology models of the active site cleft of o-CAPN1 and o-CAPN2 were developed based on human calpain 1 (h-CAPN1) X-ray crystal structure (PDB code 1ZCM). These models were used to rationalise the observed SAR for compounds 4-13 and the selectivity observed for 9. The o-CAPN2 selective inhibitor 9 (CAT0059) was assayed in an in vitro ovine lens culture system and shown to successfully protect the lens from calcium-induced opacification.
- Jones, Matthew A.,Morton, James D.,Coxon, James M.,McNabb, Stephen B.,Lee, Hannah Y.-Y.,Aitken, Steven G.,Mehrtens, Janna M.,Robertson, Lucinda J.G.,Neffe, Axel T.,Miyamoto, Shigeru,Bickerstaffe, Roy,Gately, Karl,Wood, Jacqueline M.,Abell, Andrew D.
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p. 6911 - 6923
(2008/12/22)
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- 5-sulfonamido-substituted indolinone compounds as protein kinase inhibitors
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The present invention relates to 5-sulfonamido substituted indolinones that modulate the activity of protein kinases (“PKs”). The compounds of this invention are therefore useful in treating disorders related to abnormal PK activity. Pharmaceutical compositions comprising these compounds, methods of treating diseases utilizing pharmaceutical compositions comprising these compounds and methods of preparing them are also disclosed.
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Page/Page column 16
(2010/02/08)
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- Sulfonamide substituted indolinones as inhibitors of DNA dependent protein kinase (DNA-PK)
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The present invention relates generally to the field of radiosensitizing agents which are capable of enhancing radiotherapy by inhibiting DNA-PK (DNA-protein kinase). In particular, it relates to sulfonamide substituted indolinones which inhibit DNA-PK.
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- SUBSTITUTED PYRAZOLE ANGIOTENSIN II ANTAGONISTS
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Substituted pyrazoles such as STR1 and their pharmaceutically suitable salts are useful as antihypertensive agents and for treatment of congestive heart failure.
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- Rational Tetraarylporphyrin Syntheses: Tetraarylporphyrins from the MacDonald Route
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Four new synthetic routes to meso-tetraarylporphyrins using a MacDonald-type 2 + 2 condensation are described.Self-condensation of a 5-arylpyrromethane (e.g., 17) with an aryl-substituted one-carbon bridging unit affords a mixture of tetraarylporphyrins due to acid-catalyzed redistribution reactions.The second and third methods presented here show wide applicability for the preparation of 5,10,15,20-tetraaryl-substituted porphyrins (e.g., 31, 37, 48, 49) with 2-fold rotational symmetry and involve self-condensation of 5-aryl-1-aryldipyrromethanecarbinols.Finally, the fourth approach involves a 2 + 2 approach in which one of the two dipyrromethanes bears both of the bridging carbons in the porphyrin products, affording porphyrin 50 which possesses three different aryl rings, with one pair of uniquely opposite identical aryl groups.The last two 2 + 2 methods are further extended to give a tetraarylporphyrin 38 bearing four different aryl groups in a predesignated array, the structure of which is confirmed by a single-crystal X-ray study.
- Wallace, David M.,Leung, Sam H.,Senge, Mathias O.,Smith, Kevin M.
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p. 7245 - 7257
(2007/10/02)
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- TREATMENT OF HYPERTENSION WITH 1,2,4-ANGIOTENSIN II ANTAGONISTS
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Substituted pyrroles, pyrazoles and traizoles such as STR1 and their pharmaceutically suitable salts are useful as antihypertensive agents and for treatment of congestive heart failure.
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