کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
10584065 | 981318 | 2013 | 70 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Synthesis and evaluation of heteroaryl substituted diazaspirocycles as scaffolds to probe the ATP-binding site of protein kinases
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کلمات کلیدی
PKBSpirocycleHeavy atomAGCDIBAL-HCaMK9-BBNpKaCbzRCMdFG - DFGSNAr - SPEEDYAdenosine Triphosphate - آدنوزین تری فسفاتATP - آدنوزین تری فسفات یا ATPSelectivity - انتخابیbenzyloxycarbonyl - بنزیلوسیکروبنیلTyrosine kinase - تیروزین کینازNucleophilic aromatic substitution - جایگزینی معطر NucleophilicRing-closing metathesis - حلقه بسته شدن metateesisKinase inhibitor - مهارکننده کیناز Diisobutylaluminium hydride - هیدرید دیسیوبوتیل آلومینیومProtein kinase - پروتئین کینازprotein kinase A - پروتئین کیناز Aprotein kinase B - پروتئین کیناز BLigand efficiency - کارایی لیگاند
موضوعات مرتبط
مهندسی و علوم پایه
شیمی
شیمی آلی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
With the success of protein kinase inhibitors as drugs to target cancer, there is a continued need for new kinase inhibitor scaffolds. We have investigated the synthesis and kinase inhibition of new heteroaryl-substituted diazaspirocyclic compounds that mimic ATP. Versatile syntheses of substituted diazaspirocycles through ring-closing metathesis were demonstrated. Diazaspirocycles directly linked to heteroaromatic hinge binder groups provided ligand efficient inhibitors of multiple kinases, suitable as starting points for further optimization. The binding modes of representative diazaspirocyclic motifs were confirmed by protein crystallography. Selectivity profiles were influenced by the hinge binder group and the interactions of basic nitrogen atoms in the scaffold with acidic side-chains of residues in the ATP pocket. The introduction of more complex substitution to the diazaspirocycles increased potency and varied the selectivity profiles of these initial hits through engagement of the P-loop and changes to the spirocycle conformation, demonstrating the potential of these core scaffolds for future application to kinase inhibitor discovery.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Bioorganic & Medicinal Chemistry - Volume 21, Issue 18, 15 September 2013, Pages 5707-5724
Journal: Bioorganic & Medicinal Chemistry - Volume 21, Issue 18, 15 September 2013, Pages 5707-5724
نویسندگان
Charlotte E. Allen, Chiau L. Chow, John J. Caldwell, Isaac M. Westwood, Rob L. M. van Montfort, Ian Collins,