From Synthetic Simplified Marine Metabolite Analogues to New Selective Allosteric Inhibitor of Aurora B Kinase

Abstract

Significant inhibition of Aurora B was achieved by the synthesis of simplified fragments of benzosceptrins and oroidin belonging to the marine pyrrole-2-aminoimidazoles metabolites isolated from sponges. Evaluation of kinase inhibition enabled the discovery of a synthetically accessible rigid acetylenic structural analog EL-228 (1), whose structure could be optimized into the potent CJ2-150 (37. Here we present the synthesis of new inhibitors of Aurora B kinase which is an important target for cancer therapy through mitosis regulation. The biologically oriented synthesis yielded several nanomolar inhibitors. The optimized compound CJ2-150 (37) showed a non-ATP competitive allosteric mode of action in a mixed-type inhibition for Aurora B kinase. Molecular docking identified a probable binding mode in the allosteric site "F" and highlighted the key interactions with the protein. We describe the improvement of the inhibitory potency and specificity of the novel scaffold as well as the characterization of the mechanism of action.

Syntheses and Preliminary Biological Evaluations of the Dibromopyrrole‐Containing Marine Natural Products Agesasine A, Agesasine B, Longamide E and Various Congeners

“…The outcomes of the preliminary biological evaluations of the compounds ( S )‐ 1 , ( R )‐ 1 , (±)‐ 1 , ( S )‐ 2 , ( R )‐ 2 , (±)‐ 3 to (±)‐ 6 , (±)‐ 11 to (±)‐ 15 , 16 , (±)‐ 22 , (±)‐ 28 , (±)‐ 29 , (±)‐ 30 and (±)‐ 31 presented in the preceding section reveals an interesting structure activity relationship profile for a significant cross‐section of the family of bromopyrrole‐containing marine natural products. These results reinforce the notion that this scaffold represents something of a privileged structure for the purposes of drug development [7–13] . Again, our work in this area is ongoing and results will be reported in due course.…”

“…These results reinforce the notion that this scaffold represents something of a privileged structure for the purposes of drug development. [7][8][9][10][11][12][13] Again, our work in this area is ongoing and results will be reported in due course.…”

“…The results of these studies are detailed below. A further motivation for undertaking this work was that a number of bromopyrrole alkaloids have served as the inspiration for various drug development programs including ones focused on identifying and optimizing inhibitors of PIM kinases, [7] indoleamine 2,3‐dioxygenase [8] and Aurora B kinase [9] . Others have served as starting points for the development of anti‐fungal agents, [10] the identification of antiprotozoal drugs, [11] of anti‐fouling agents, [12] and of anti‐microbial agents [13] …”

On the Biological Importance, Preparation, and Uses of Imidazo[1,2-b]pyridazine-Based Compounds

“…Juillet and colleagues tried to vary the flexibility of the molecules and first replaced the acetylene linker with an alkene moiety. The preparation of the alkene series is depicted in Scheme 9 (39).…”

Exploration of the structural requirements of Aurora Kinase B inhibitors by a combined QSAR, modelling and molecular simulation approach

“…These inhibitors are derivatives of indole, bis-indole, pyrrolopyrazole, pyrimidine, thiazolo-quinazoline, quinazolin, pyrazoloquinazoline, fused tricyclic structures, and some other structures 42 . In addition, the prospect of designing potent allosteric inhibitors for AK-B appears very promising from the clinical perspective, because it may generate selective inhibitors 43 . Recently, Colombo and colleagues proposed a new possibility in pursuit of designing selective chemical tools by perturbing the intermolecular interaction between chaperone and kinases thus, targeting protein folding and rendering it inactive 44 .…”