TY - JOUR
T1 - Discovery of Novel Cinchona-Alkaloid-Inspired Oxazatwistane Autophagy Inhibitors
AU - Laraia, Luca
AU - Ohsawa, Kosuke
AU - Konstantinidis, Georgios
AU - Robke, Lucas
AU - Wu, Yao Wen
AU - Kumar, Kamal
AU - Waldmann, Herbert
N1 - Publisher Copyright:
© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2017/2/13
Y1 - 2017/2/13
N2 - The cinchona alkaloids are a privileged class of natural products and are endowed with diverse bioactivities. However, for compounds with the closely-related oxazatricyclo[4.4.0.0]decane (“oxazatwistane”) scaffold, which are accessible from cinchonidine and quinidine by means of ring distortion and modification, biological activity has not been identified. We report the synthesis of an oxazatwistane compound collection through employing state-of-the-art C−H functionalization, and metal-catalyzed cross-coupling reactions as key late diversity-generating steps. Exploration of oxazatwistane bioactivity in phenotypic assays monitoring different cellular processes revealed a novel class of autophagy inhibitors termed oxautins, which, in contrast to the guiding natural products, selectively inhibit autophagy by inhibiting both autophagosome biogenesis and autophagosome maturation.
AB - The cinchona alkaloids are a privileged class of natural products and are endowed with diverse bioactivities. However, for compounds with the closely-related oxazatricyclo[4.4.0.0]decane (“oxazatwistane”) scaffold, which are accessible from cinchonidine and quinidine by means of ring distortion and modification, biological activity has not been identified. We report the synthesis of an oxazatwistane compound collection through employing state-of-the-art C−H functionalization, and metal-catalyzed cross-coupling reactions as key late diversity-generating steps. Exploration of oxazatwistane bioactivity in phenotypic assays monitoring different cellular processes revealed a novel class of autophagy inhibitors termed oxautins, which, in contrast to the guiding natural products, selectively inhibit autophagy by inhibiting both autophagosome biogenesis and autophagosome maturation.
KW - alkaloids
KW - autophagy
KW - inhibitors
KW - medicinal chemistry
KW - natural products
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U2 - 10.1002/anie.201611670
DO - 10.1002/anie.201611670
M3 - Article
C2 - 28097798
AN - SCOPUS:85009740903
VL - 56
SP - 2145
EP - 2150
JO - Angewandte Chemie - International Edition
JF - Angewandte Chemie - International Edition
SN - 1433-7851
IS - 8
ER -