Abstract
Marine animals and plants provide abundant secondary metabolites with antitumor activity. Itampolin A is a brominated natural tyrosine secondary metabolite that is isolated from the sponge Iotrochota purpurea. Recently, we have achieved the first total synthesis of this brominated tyrosine secondary metabolite, which was found to be a potent p38α inhibitor exhibiting anticancer effects. A fragment-based drug design (FBDD) was carried out to optimize itampolin A. Forty-five brominated tyrosine derivatives were synthesized with interesting biological activities. Then, a QSAR study was carried out to explore the structural determinants responsible for the activity of brominated tyrosine skeleton p38α inhibitors. The lead compound was optimized by a FBDD method, then three series of brominated tyrosine derivatives were synthesized and evaluated for their inhibitory activities against p38α and tumor cells. Compound 6o (IC50 = 0.66 μM) exhibited significant antitumor activity against non-small cell lung A549 cells (A549). This also demonstrated the feasibility of the FBDD method of structural optimization.
Highlights
Sponges are the most abundant source of bioactive compounds in marine invertebrates [1]
The total synthesis of itampolin A was achieved for the first time
An FBDD‐based BREED technique was adopted as as a novel fragment-based drug design method, which was based on sets of aligned 3D ligand a novel fragment‐based drug design method, which was based on sets of aligned 3D ligand structures structures to the same target family
Summary
Sponges are the most abundant source of bioactive compounds in marine invertebrates [1]. Relative to type I inhibitors that compete directly with ATP, type II inhibitors bind to the inactive DFG-out conformation of kinase induced by the conformational transition of DFG-loop This opened up a second hydrophobic subcavity formed by the catalytic amino acid triad. Fragment-based drug design (FBDD) is widely used in academia and industry to obtain small molecule inhibitors for adrug given target. Active pocketsFinding of the drug target are made up linking of multiple subcavities, theleads fragments are units that combine compounds [15].with these subcavities. Finding these fragments and linking them together often leads to For higher compounds [15].
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