Kinase Chemodiversity from the Arctic: The Breitfussins

Abstract

In this work, we demonstrate that the indole-oxazole-pyrrole framework of the breitfussin family of natural products is a promising scaffold for kinase inhibition. Six new halogenated natural products, breitfussin C-H (3-8) were isolated and characterized from the Arctic, marine hydrozoan Thuiaria breitfussi. The structures of two of the new natural products were also confirmed by total synthesis. Two of the breitfussins (3 and 4) were found to selectively inhibit the survival of several cancer cell lines, with the lowest IC50 value of 340 nM measured against the drug-resistant triple negative breast cancer cell line MDA-MB-468, while leaving the majority of the tested cell lines not or significantly less affected. When tested against panels of protein kinases, 3 gave IC50 and Kd values as low as 200 and 390 nM against the PIM1 and DRAK1 kinases, respectively. The activity was confirmed to be mediated through ATP competitive binding in the ATP binding pocket of the kinases. Furthermore, evaluation of potential off-target and toxicological effects, as well as relevant in vitro ADME parameters for 3 revealed that the breitfussin scaffold holds promise for the development of selective kinase inhibitors.

Unequivocal structure confirmation of a breitfussin analog by anisotropic NMR measurements

“…In comparison, the average 13 C chemical shi for a series of six non-iodinated breitfussins analogs was 122.4 ppm. 38 In contrast, only a small difference of 0.5 ppm was observed for C5 0 .…”

Total Synthesis of Phorbazole B

“…We thus envisioned that 2 could be obtained by chlorination of compound 13 , where the oxazole 4-position is protected. Access to 13 was planned through Suzuki Miyaura coupling on diiodide 14 , which we planned to obtain from the Van Leusen methyl isocyanide synthon [ 8 ] after cyclisation to the oxazole and subsequent deiodination as we have reported for the breitfussin syntheses [ 5 , 6 ].…”

“…Breitfussin A–H ( 5 – 12 , Figure 2 ) constitute the second class of marine natural products containing the pyrrole-oxazole motif [ 4 , 5 ]. Like the phorbazoles, the breitfussins are highly halogenated natural products derived from dipeptide precursors, but with tryptophan instead of tyrosine.…”

“…We have earlier reported on the total syntheses of 5 – 8 , which were based on the utilization of two palladium-catalyzed cross couplings to install the indole and pyrrole onto the oxazole core, followed by halogenation of the pyrrole at a late stage in the case of 6 [ 5 , 6 ]. An alternative synthesis of 6 (and by coincidence also 8 ) based on application of the Robinson–Gabriel cyclodehydration to form the oxazole ring combined with a late stage bromination strategy [ 7 ], has also been reported.…”

Antimicrobial Activity of Small Synthetic Peptides Based on the Marine Peptide Turgencin A: Prediction of Antimicrobial Peptide Sequences in a Natural Peptide and Strategy for Optimization of Potency

“…The human melanoma cell line A2058 (ATTC CRL-11144) and the non-malignant human lung fibroblast cell line MRC-5 (ATTC CCL-171) were assayed for sensitivity against StAMP-1-11 at ranging concentrations between 100 and 5 µg/mL in a two-fold dilution series. The assays were performed as previously described [ 55 ]. Both assays were performed in triplicate in two independent experiments.…”