title: 5-Hydroxy-7-azaindolin-2-one, a novel hybrid of pyridinol and sunitinib: design, synthesis and cytotoxicity against cancer cells.
abstract: Angiogenesis plays important roles in tumor growth and metastasis. Sunitinib (Sutent®) 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 lines. 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.
authors.affiliation: College of Pharmacy and Institute for Drug Research, Yeungnam University, Gyeongsan 38541, Republic of Korea. jakim@yu.ac.kr jeongb@ynu.ac.kr.
authors.forename: Sajita
authors.initials: S
authors.lastname: Shah
authors.forename: Chaemin
authors.initials: C
authors.lastname: Lee
authors.forename: Hyukjae
authors.initials: H
authors.lastname: Choi
authors.forename: Jaya
authors.initials: J
authors.lastname: Gautam
authors.forename: Hyeonjin
authors.initials: H
authors.lastname: Jang
authors.forename: Geum Jin
authors.initials: GJ
authors.lastname: Kim
authors.forename: Yu-Jeong
authors.initials: YJ
authors.lastname: Lee
authors.forename: Chhabi Lal
authors.initials: CL
authors.lastname: Chaudhary
authors.forename: Sang Won
authors.initials: SW
authors.lastname: Park
authors.forename: Tae-Gyu
authors.initials: TG
authors.lastname: Nam
authors.forename: Jung-Ae
authors.initials: JA
authors.lastname: Kim
authors.forename: Byeong-Seon
authors.initials: BS
authors.lastname: Jeong
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D015536:Down-Regulation / Q000187:drug effects; D015195:Drug Design; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D021381:Protein Transport / Q000187:drug effects; D011725:Pyridines / Q000737:chemistry*; D011758:Pyrroles / Q000737:chemistry*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000077210:Sunitinib; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C000626209:5-hydroxy-7-azaindolin-2-one; D000970:Antineoplastic Agents; D007211:Indoles; D011725:Pyridines; D011758:Pyrroles; D050796:STAT3 Transcription Factor; D016159:Tumor Suppressor Protein p53; D000077210:Sunitinib