Synthesis, kinase activity and molecular modeling of a resorcylic acid lactone incorporating an amide and a trans-enone in the macrocycle

Details for the synthesis of a resorcylic acid lactone (RAL) incorporating a trans-enone and an amide in the macrocyclic ring are provided herein. The sequence included the assembly of three fragments by esterification, olefination, and lactamization. The RAL with the lactam was less potent as an in...

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Veröffentlicht in:	Tetrahedron 2012-07, Vol.68 (27-28), p.5533-5540
Hauptverfasser:	Napolitano, Carmela, Palwai, Viraja R., Eriksson, Leif A., Murphy, Paul V.
Format:	Artikel
Sprache:	eng
Schlagworte:	1983 1991 activation Amides Assembly cancer Chemical Sciences Chemistry Exact sciences and technology force-field Fysikalisk kemi Heterocyclic compounds Heterocyclic compounds with n hetero atom and also o and/or s, se, te hetero atoms Heterocyclic compounds with o, s, se, te hetero atom and condensed derivatives Heterocyclic compounds with only one n hetero atom and condensed derivatives Human in-vitro Inhibitors journal of organic chemistry journal of the american chemical society Kemi Kinase inhibitors Kinases Lactamization Lactones Macrocyclic compounds methoxybenzyl pmb ethers Molecular Biology Molekylärbiologi Olefination Organic Chemistry Organisk kemi p4155 p7277 phosphorylation Physical Chemistry potent Preparations and properties Resorcylic acid lactones secondary alcohols Simulation ss db Synthesis Teoretisk kemi Theoretical Chemistry tyrosine v113 v48
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Zusammenfassung:	Details for the synthesis of a resorcylic acid lactone (RAL) incorporating a trans-enone and an amide in the macrocyclic ring are provided herein. The sequence included the assembly of three fragments by esterification, olefination, and lactamization. The RAL with the lactam was less potent as an inhibitor of kinases than other RALs investigated. The biological results were rationalized by docking and molecular dynamics simulations of the lactam bound to human ERK2 and comparison with hypothemycin. [Display omitted]
ISSN:	0040-4020 1464-5416 1464-5416
DOI:	10.1016/j.tet.2012.04.082