Synthesis of a Resorcylic Acid Lactone (RAL) Library Using Fluorous‐Mixture Synthesis and Profile of its Selectivity Against a Panel of Kinases

Abstract

A library of resorcylic acid lactones (RAL) containing a cis-enone moiety targeting kinases bearing a cysteine residue within the ATP-binding pocket was prepared using a fluorous-mixture synthesis and evaluated against a panel of 19 kinases thus providing important structure-activity trends. Two new analogues were then profiled for their selectivity against a panel of 402 kinases providing the broadest evaluation of this pharmacophores' selectivity.

Comprehensive Survey of Chemical Libraries for Drug Discovery and Chemical Biology: 2008

“…329 Natural resorcylic acid lactones (RAL) containing a cis-enone moiety such as radicicol A, L-783277, and LL-Z1640-2 are known to be potent and irreversible kinase inhibitors. For QSAR studies, the Winssinger group developed a fluorous mixture synthesis (FMS) method based on the previously reported fluorous total synthesis of radicicol A and synthesized a compound library containing 51 analogs (Figure 18).…”

“…For QSAR studies, the Winssinger group developed a fluorous mixture synthesis (FMS) method based on the previously reported fluorous total synthesis of radicicol A and synthesized a compound library containing 51 analogs (Figure 18). 329 In the FMS, three propargyl alcohols were used each attached to a different p-methoxybenzyl aldehydes 192(a-c) to afford compounds 194(d-f) Selective noradrenaline reuptake inhibitors. 73 …”

Polyubiquitination of Transforming Growth Factor β (TGFβ)-associated Kinase 1 Mediates Nuclear Factor-κB Activation in Response to Different Inflammatory Stimuli

“…Chloro-radicicol A was dissolved in dimethyl sulfoxide as a 10 mM stock solution and further diluted into buffer. Broad profiling of this pharmacophore against a panel of 401 kinases showed it to be a potent and irreversible inhibitor of the following kinases: TAK1, VEGFR, FLT3, GAK, KIT, MEK, MKNK, PDGFR, PRKD, STK36, TGFR (18). The p38␣ and ␤ inhibitor, SB203580, were purchased from Calbiochem and used at a concentration of 10 M.…”

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

“…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.…”

“…cKIT, MK5, ERK2, and TYK2, although they do contain the requisite Cys residue, are inhibited with much lower potency, thus indicating that L-783277 (as other RL-based kinase inhibitors) 8,15 does not indiscriminately inhibit all potentially susceptible kinases with the same potency. IC 50 values of ca.…”