Key analogs of a uniquely potent synthetic vinblastine that contain modifications of the C20′ ethyl substituent
| Autor: | Dale L. Boger, Manuela M. Brütsch, Aleksandar Radakovic, R. Matthew Cross, Oliver Allemann |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
Stereochemistry
Clinical Biochemistry Substituent Pharmaceutical Science Antineoplastic Agents Molecular Dynamics Simulation 010402 general chemistry Crystallography X-Ray Vinblastine 01 natural sciences Biochemistry Article Tubulin binding chemistry.chemical_compound Structure-Activity Relationship Tubulin Drug Discovery medicine Side chain Potency Humans Ethyl group Molecular Biology Alkyl chemistry.chemical_classification Binding Sites biology 010405 organic chemistry Organic Chemistry HCT116 Cells 0104 chemical sciences chemistry biology.protein Molecular Medicine medicine.drug Protein Binding |
| Popis: | A key series of vinblastine analogs 7 – 13 , which contain modifications to the C20′ ethyl group, was prepared with use of two distinct synthetic approaches that provide modifications of the C20′ side chain containing linear and cyclized alkyl groups or added functionalized substituents. Their examination revealed the unique nature of the improved properties of the synthetic vinblastine 6 , offers insights into the origins of its increased tubulin binding affinity and 10-fold improved cell growth inhibition potency, and served to probe a small hydrophobic pocket anchoring the binding of vinblastine with tubulin. Especially noteworthy were the trends observed with substitution of the terminal carbon of the ethyl group that, with the exception of 9 (R = F vs H, equipotent), led to remarkably substantial reductions in activity (>10-fold): R = F (equipotent with H) > N 3 , CN (10-fold) > Me (50-fold) > Et (100-fold) > OH (inactive). This is in sharp contrast to the maintained ( 7 ) or enhanced activity ( 6 ) observed with its incorporation into a cyclic C20′/C15′-fused six-membered ring. |
| Databáze: | OpenAIRE |
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