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5-Hydroxy-7-azaindolin-2-one, a novel hybrid of pyridinol and sunitinib: design, synthesis and cytotoxicity against cancer cells

Title
5-Hydroxy-7-azaindolin-2-one, a novel hybrid of pyridinol and sunitinib: design, synthesis and cytotoxicity against cancer cells
Author
남태규
Keywords
GASTROINTESTINAL STROMAL TUMORS; RECEPTOR TYROSINE KINASES; ENDOTHELIAL GROWTH-FACTOR; ANTITUMOR-ACTIVITY; AMINOPYRIDINOL ANTIOXIDANTS; ANGIOGENESIS INHIBITORS; ANTIANGIOGENIC ACTIVITY; BIOLOGICAL EVALUATION; DRUG DISCOVERY; INDOLIN-2-ONE
Issue Date
2016-06
Publisher
ROYAL SOC CHEMISTRY
Citation
ORGANIC & BIOMOLECULAR CHEMISTRY, v. 14, No. 21, Page. 4829-4841
Abstract
Angiogenesis plays important roles in tumor growth and metastasis. Sunitinib (Sutent (R)) is an antitumor agent targeting receptor tyrosine kinases which are involved in angiogenesis as well as cancer cell growth and survival. Using the pyridin-3-ol scaffold, which was previously reported as an excellent antioxidant and antiangiogenic platform, we have synthesized sunitinib mimics 6 by hybridizing bicyclic pyridinol 4 as a key scaffold and pyrrole-2-carbaldehydes 7 as side chains. Cytotoxicity assays showed that compounds 6 have comparable to better anticancer activity than sunitinib against five different cancer cell tines. In addition, compounds 6 showed even lower levels of cytotoxicity against normal cells, resulting in up to 26-fold better safety windows, than sunitinib. Signaling pathway-associated transcription factor reporter assay and western blot analyses revealed that apoptosis induction in MDA-MB-231 human breast cancer cells by 6F is mainly mediated through the p53 increase and down-regulation of phospho-signal transducer and activator of transcription 3 (STAT3) and its target gene products, cyclin D, Bcl-2, and survivin. The data strongly suggest that our hybrid compounds can provide a novel anticancer scaffold with improved and safer cytotoxicity profiles than sunitinib.
URI
http://pubs.rsc.org/-/content/articlehtml/2016/ob/c6ob00406ghttp://repository.hanyang.ac.kr/handle/20.500.11754/102524
ISSN
1477-0520; 1477-0539
DOI
10.1039/c6ob00406g
Appears in Collections:
COLLEGE OF PHARMACY[E](약학대학) > PHARMACY(약학과) > Articles
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