Discovery of a potent, metabolically stabilized resorcylic lactone as an anti-inflammatory lead

Design, synthesis and biological evaluation of FLT3 covalent inhibitors with a resorcylic acid core

“…We then investigated an alternative route in which substituted maleimides were prepared by cyclisation of a maleic monoamide (Scheme 4), 46 which proved to be successful in our synthesis. For example, maleic acid monoamides 47 were obtained by ring-opening amidation of maleic anhydride with amines (35,(37)(38)(39)(40)(41)(45)(46). The monoamide intermediates were then subjected to ring-closing dehydration in refluxing acetic anhydride to provide the maleimides 12, accompanied by O-acetylation of the 2-phenolic group.…”

“…In addition, the cis-enone moiety present in these molecules is prone to isomerisation to the less active trans-form. [39][40][41] In continuation of our work on enamide RAL analogues as covalent inhibitors of kinases, 21 we report herein the development of a series of simplified, easily accessible ring-opened RAL derivatives bearing suitably positioned Michael acceptors as irreversible or reversible FLT3 kinase inhibitors. It is noted that during the course of our study, Zambaldo et al reported that resorcinol derivatives with a Michael acceptor at the C-5 position of the aryl ring were inhibitors of EGFR and ERBB2.…”

Cis-enone Resorcylic Acid Lactones (RALs) as Irreversible Protein Kinase Inhibitors

“…Evaluation of LL-Z1640-2 (3) revealed a short plasma half life of 61 min in mice [44]. Analysis of the metabolites indicated that cis-to-trans isomerization of the enone is the major deactivating process, the trans-isomer 35 was approximately 30-fold less potent (IC 50 : 349 nM) than the corresponding cis-isomer LL-Z1640-2 (11 nM) [45]. (7) [45]).…”

Kinase Inhibition by Deoxy Analogues of the Resorcylic Lactone L-783277

“…The data for E analogue 2 provide broad confirmation for the substantially reduced activity of C7 0 -C8 0 E-configured RL-based kinase inhibitors, which had been reported previously for the C7 0 -C8 0 E isomers of L-783277 and LL-Z1640-2 against MEK2 29 and TAK1, 31 respectively, and also for E-LL-Z1640-2 in a cellular reporter assay for TNFR signaling. 18 There appears to be a trend for 3 to be more potent than 2, but additional data are required to consolidate this conclusion. It should also be noted that the significant difference in activity between 3 and 1 does not necessarily imply the 4 0 -(mono)-deoxy analogue of L-783277 to be less active than 1.…”

“…However, on the basis of work by Kosan, the second order rate constant for the reaction of hypothemycin with glutathione at pH 7.5 is 6.6 M -1 s -1 vs an apparent second order rate constant (k inact /K i ) of 1.2 Â 10 5 for the reaction with MEK1, thus indicating a high degree of specificity. 8 Structure-activity relationship (SAR) studies around hypothemycin 11 and LL-Z1640-2 (also called f152A1 or 5Z-7-oxozeaenol) [12][13][14][15][16][17][18][19] have included modifications of both the aliphatic and the aromatic portion of the structures, and analogues have been identified with in vivo activity in tumor 20 as well as inflammatory disease 14,18 models; one compound, Eisai's E6201, has been advanced to clinical trials in humans 13 in cancer and plaque type psoriasis (according to the Thomson Reuters Integrity database). With the exception of their clinical candidate E6201, 17 however, no kinase inhibition data have been reported by the Eisai group on the numerous LL-Z1640-2 analogues that were prepared as part of the work leading to the discovery of E6201.…”