scholarly journals The isolation, total synthesis and structure elucidation of chlorofusin, a natural product inhibitor of the p53–MDM2 protein–protein interaction

2009 ◽  
Vol 26 (4) ◽  
pp. 465 ◽  
Author(s):  
Ryan C. Clark ◽  
Sang Yeul Lee ◽  
Mark Searcey ◽  
Dale L. Boger
Keyword(s):  
Total Synthesis ◽  
Natural Product ◽  
Protein Interaction ◽  
Structure Elucidation ◽  
Mdm2 Protein ◽  
Protein Protein Interaction

A Fluorescent Probe for Imaging p53-MDM2 Protein-Protein Interaction

2014 ◽  
Vol 85 (4) ◽  
pp. 411-417 ◽  
Author(s):  
Zhenzhen Liu ◽  
Zhenyuan Miao ◽  
Jin Li ◽  
Kun Fang ◽  
Chunlin Zhuang ◽  
...  
Keyword(s):  
Fluorescent Probe ◽  
Protein Interaction ◽  
Mdm2 Protein ◽  
Protein Protein Interaction

The Structure Elucidation of Haprolid

Synthesis ◽  
2017 ◽  
Vol 50 (03) ◽  
pp. 529-538 ◽  
Author(s):  
Markus Kalesse ◽  
Jun Li ◽  
Jun Xing ◽  
Daniel Lücke ◽  
Dennis Lübken ◽  
...  
Keyword(s):  
Total Synthesis ◽  
Natural Product ◽  
Structure Elucidation ◽  
Carcinoma Cell ◽  
Hidden Markov ◽  
Biological Evaluation ◽  
Terminal Olefin ◽  
Carcinoma Cell Lines ◽  
Hepatocellular Carcinoma Cell ◽  
Key Steps

The assignment of two stereocenters of the natural product haprolid through the application of a profile hidden Markov model (HMM) and its confirmation through total synthesis of the natural product and of two of its diastereomers are reported. The structure elucidation of this polyketide-peptide hybrid natural product is a telling showcase of how difficult it can be to determine the absolute configuration of isolated stereocenters and the benefits of a gene cluster analysis for structure determination. The key steps of the synthesis are a selective epoxidation of a terminal olefin and the stereodivergent macrolactonization strategy. Furthermore, the biological evaluation of all products showed that all diastereomers are potent inhibitors of hepatocellular carcinoma cell lines.

scholarly journals Conformational control of the bacterial Clp protease by natural product antibiotics

2017 ◽  
Vol 34 (7) ◽  
pp. 815-831 ◽  
Author(s):  
I. T. Malik ◽  
H. Brötz-Oesterhelt
Keyword(s):  
Natural Products ◽  
Natural Product ◽  
Protein Interaction ◽  
Long Distance ◽  
Clp Protease ◽  
Conformational Control ◽  
Protein Protein Interaction

Natural products targeting the bacterial Clp protease unravel key interfaces for protein–protein–interaction and long-distance conformational control.

scholarly journals Ultrapotent vinblastines in which added molecular complexity further disrupts the target tubulin dimer–dimer interface

2016 ◽  
Vol 113 (35) ◽  
pp. 9691-9698 ◽  
Author(s):  
Daniel W. Carney ◽  
John C. Lukesh ◽  
Daniel M. Brody ◽  
Manuela M. Brütsch ◽  
Dale L. Boger
Keyword(s):  
Natural Products ◽  
Total Synthesis ◽  
Natural Product ◽  
Biological Properties ◽  
Dimer Interface ◽  
Protein Protein Interaction ◽  
Conformational Constraints ◽  
Biological Target ◽  
Molecular Complexity ◽  
Target Binding

Approaches to improving the biological properties of natural products typically strive to modify their structures to identify the essential pharmacophore, or make functional group changes to improve biological target affinity or functional activity, change physical properties, enhance stability, or introduce conformational constraints. Aside from accessible semisynthetic modifications of existing functional groups, rarely does one consider using chemical synthesis to add molecular complexity to the natural product. In part, this may be attributed to the added challenge intrinsic in the synthesis of an even more complex compound. Herein, we report synthetically derived, structurally more complex vinblastines inaccessible from the natural product itself that are a stunning 100-fold more active (IC50 values, 50–75 pM vs. 7 nM; HCT116), and that are now accessible because of advances in the total synthesis of the natural product. The newly discovered ultrapotent vinblastines, which may look highly unusual upon first inspection, bind tubulin with much higher affinity and likely further disrupt the tubulin head-to-tail α/β dimer–dimer interaction by virtue of the strategic placement of an added conformationally well-defined, rigid, and extended C20′ urea along the adjacent continuing protein–protein interface. In this case, the added molecular complexity was used to markedly enhance target binding and functional biological activity (100-fold), and likely represents a general approach to improving the properties of other natural products targeting a protein–protein interaction.

Total synthesis and characterization of thielocin B1 as a protein–protein interaction inhibitor of PAC3 homodimer

2014 ◽  
Vol 5 (5) ◽  
pp. 1860-1868 ◽  
Author(s):  
Takayuki Doi ◽  
Masahito Yoshida ◽  
Kosuke Ohsawa ◽  
Kazuo Shin-ya ◽  
Motoki Takagi ◽  
...  
Keyword(s):  
Total Synthesis ◽  
Protein Interaction ◽  
Synthesis And Characterization ◽  
Protein Protein Interaction

We have characterized the inhibition of the protein–protein interaction of the homodimer of proteasome assembling chaperone (PAC) 3 with thielocin B1.

scholarly journals Stereochemical Assignment of the Protein-Protein Interaction Inhibitor JBIR-22 by Total Synthesis

2015 ◽  
Vol 54 (13) ◽  
pp. 4046-4050 ◽  
Author(s):  
Alan R. Healy ◽  
Miho Izumikawa ◽  
Alexandra M. Z. Slawin ◽  
Kazuo Shin-ya ◽  
Nicholas J. Westwood
Keyword(s):  
Total Synthesis ◽  
Protein Interaction ◽  
Stereochemical Assignment ◽  
Protein Protein Interaction
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