Identification of inhibitors for mycobacterial protein tyrosine phosphatase B (MptpB) by biology-oriented synthesis (BIOS).
Protein phosphatases have recently emerged as important targets for research in chemical biology and medicinal chemistry, and new classes of phosphatase inhibitors are in high demand. BIOS (biology-oriented synthesis) employs the criteria of relevance to nature and biological prevalidation for the design and synthesis of compound collections. In an application of the BIOS principle, an efficient solid-phase synthesis of highly substituted indolo[2,3-a]quinolizidines by using a vinylogous Mannich-Michael reaction in combination with phosgene- or acid-mediated ring closure was developed. Screening of this library for phosphatase inhibitors yielded a new inhibitor class for the Mycobacterium tuberculosis phosphatase MptpB.
Max Planck Institute of Molecular Physiology, Department of Chemical Biology, D-44367 Dortmund, Germany.
Ivan R
IR
Corrêa
Andrea
A
Nören-Müller
Horst-Dieter
HD
Ambrosi
Sven
S
Jakupovic
Krishna
K
Saxena
Harald
H
Schwalbe
Markus
M
Kaiser
Herbert
H
Waldmann
D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D001688:Biological Products / Q000737:chemistry; D003500:Cyclization; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D009161:Mycobacterium / Q000201:enzymology*; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*; D011807:Quinolizines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
D001426:Bacterial Proteins; D001688:Biological Products; D004791:Enzyme Inhibitors; C414465:MptpA protein, Mycobacterium tuberculosis; D011807:Quinolizines; D017027:Protein Tyrosine Phosphatases