Napabucasin and Related Heterocycle-Fused Naphthoquinones as STAT3 Inhibitors with Antiproliferative Activity against Cancer Cells

Journal of Natural Products
Hauke LöckenKlaus Müller

Abstract

Napabucasin (6) and its angularly anellated isomer (7), for which the synthesis is described, together with related plant-derived naphthoquinones, were evaluated in vitro against human breast cancer (MDA-MB-231) and chronic myelogenous leukemia (K562) cells. As observed for β-lapachone (3), the active naphthoquinones all induced apoptosis in a cell-cycle-independent fashion. In contrast to the pyran-fused β-lapachone (3), however, the most potent furan-fused naphthoquinones were able to redox cycle and generate superoxide in cell-based assays, which was independent of NAD(P)H:quinone oxido-reductase 1. In a homogeneous time-resolved fluorescence (HTRF) assays with MDA-MB-231 cells, both napabucasin (6) and isonapabucasin (7) were identified as targeting STAT3 phosphorylation. In addition, drug affinity responsive target stability assays were performed to validate a direct interaction of the naphthoquinones with STAT3. Isonapabucasin (7) turned out to be twice as potent against STAT3 as napabucasin (6) in the HTRF assay, with an EC50 in the submicromolar range, which was in excellent agreement with the potency of both agents to inhibit the growth of MDA-MB-231 cells. Moreover, molecular docking experiments predicted different bi...Continue Reading

References

Sep 10, 1999·Journal of Natural Products·K MüllerW Wiegrebe
Feb 22, 2000·The Journal of Biological Chemistry·J J PinkD A Boothman
May 18, 2001·Journal of Medicinal Chemistry·R A UrbanekM J Chapdelaine
Apr 5, 2007·Nature Protocols·Carlo Riccardi, Ildo Nicoletti
May 29, 2007·Breast Cancer Research : BCR·Marjan BerishajJacqueline F Bromberg
Jul 5, 2007·Proceedings of the National Academy of Sciences of the United States of America·Erik A BeyDavid A Boothman
Nov 11, 2008·Journal of Ethnopharmacology·J Rubén Gómez CastellanosMichael Heinrich
Dec 5, 2008·Expert Opinion on Investigational Drugs·Peibin Yue, James Turkson
Apr 29, 2009·Journal of Computational Chemistry·Garrett M MorrisArthur J Olson
Aug 25, 2009·Bioorganic & Medicinal Chemistry·Chih-Hua TsengYeh-Long Chen
Dec 10, 2009·Proceedings of the National Academy of Sciences of the United States of America·Brett LomenickJing Huang
Jun 2, 2012·Journal of Medicinal Chemistry·Bikash DebnathNouri Neamati
Jul 17, 2012·Analytical Biochemistry·Nadine C L ZembruskiJohanna Weiss
Oct 8, 2013·European Journal of Medicinal Chemistry·Solange L de CastroEufrânio N da Silva Júnior
Oct 25, 2014·Nature Reviews. Cancer·Simran S Sabharwal, Paul T Schumacker
Jan 22, 2015·Proceedings of the National Academy of Sciences of the United States of America·Youzhi LiChiang J Li
Jan 27, 2015·Methods in Molecular Biology·Melody Y PaiJing Huang
Oct 8, 2015·Accounts of Chemical Research·Elizabeth I Parkinson, Paul J Hergenrother
Nov 13, 2015·International Journal of Cancer. Journal International Du Cancer·Kasturi Banerjee, Haluk Resat
Jan 6, 2016·ACS Chemical Biology·Steffanie L FurtekPhilip Reigan
Jun 21, 2016·Expert Opinion on Investigational Drugs·Catherine Cafferkey, Ian Chau
Jan 31, 2017·Journal of Medicinal Chemistry·Allimuthu T Dharmaraja
Apr 22, 2017·Trends in Molecular Medicine·Iok In Christine Chio, David A Tuveson
Jun 7, 2017·Expert Opinion on Therapeutic Patents·Hidayat Hussain, Ivan R Green
Feb 6, 2018·Journal of Natural Products·Md Abdullah Al NomanKhondaker Miraz Rahman

❮ Previous
Next ❯

Citations

May 10, 2020·Cancer·Ganji Purnachandra NagarajuBassel F El-Rayes
Jul 7, 2019·Journal of Experimental & Clinical Cancer Research : CR·Dongfeng HanDehua Jiang
Mar 13, 2019·International Journal of Molecular Sciences·Renata Novak KujundžićKoraljka Gall Trošelj
Dec 24, 2018·Nature Reviews. Cancer·Jennifer HuynhMatthias Ernst
Mar 1, 2020·Cell Communication and Signaling : CCS·Jia-Hui MaXia Li
Dec 12, 2019·Biochimica Et Biophysica Acta. Bioenergetics·Gabriel N ValérioAlejandro K Samhan-Arias
Jan 29, 2021·Journal of Medicinal Chemistry·Maha HanafiNouri Neamati
Oct 30, 2020·Molecular & Cellular Proteomics : MCP·Niels M LeijtenSimone Lemeer
Feb 18, 2021·Molecular & Cellular Proteomics : MCP·Niels M LeijtenSimone Lemeer
Jan 13, 2021·Journal of Natural Products·David G I Kingston
Jun 22, 2021·European Journal of Medicinal Chemistry·Li ZhangYuning Song

❮ Previous
Next ❯

Related Concepts

Related Feeds

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis

Apoptosis in Cancer

Apoptosis is an important mechanism in cancer. By evading apoptosis, tumors can continue to grow without regulation and metastasize systemically. Many therapies are evaluating the use of pro-apoptotic activation to eliminate cancer growth. Here is the latest research on apoptosis in cancer.