Design, synthesis and biological evaluation of dual HDAC and VEGFR inhibitors as multitargeted anticancer agents.
Summary: Herein, a novel series of dual histone deacetylase (HDAC) and vascular endothelial growth factor receptor (VEGFR) inhibitors were designed, synthesized and biologically evaluated based on previously reported pazopanib-based HDAC and VEGFR dual inhibitors. Most target compounds showed signif...
| Publicado en: | Investigational New Drugs Vol. 40; no. 1; pp. 10 - 21 |
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| Autores principales: | , , , , , , , , , , |
| Formato: | pictorial research tables/charts Journal Article |
| Publicado: |
Springer Nature
Feb2022
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=154714711&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 154714711 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 01676997 OH2 jtl: Investigational New Drugs issn: 01676997 maglogo: N pubinfo: dt: Feb2022 vid: 40 iid: 1 pid: 237 pub: Springer Nature place: New York, New York artinfo: ui: 154714711 152182042 154714711 154714711 10.1007/s10637-021-01169-4 154714711 ppf: 10 ppct: 11 formats: tig: atl: Design, synthesis and biological evaluation of dual HDAC and VEGFR inhibitors as multitargeted anticancer agents. aug: au: Xue, Xia Zhang, Yingjie Liao, Yongxiang Sun, Deqing Li, Lina Liu, Ying Wang, Yongjie Jiang, Wen Zhang, Jian Luan, Yun Zhao, Xiaogang affil: Department of Pharmacy, The Second Hospital, Cheeloo College of Medicine, Shandong University, 250012, Jinan, Shandong, PR China sug: subj: Histone Deacetylases Antagonists and Inhibitors Vascular Endothelial Growth Factors Antagonists and Inhibitors Polypharmacy Antineoplastic Agents Pharmacodynamics Drug Design Tyrosine Kinase Inhibitors Pharmacodynamics Human Cell Line Animal Studies Animals Rats In Vitro Studies Blotting, Western Funding Source ab: Summary: Herein, a novel series of dual histone deacetylase (HDAC) and vascular endothelial growth factor receptor (VEGFR) inhibitors were designed, synthesized and biologically evaluated based on previously reported pazopanib-based HDAC and VEGFR dual inhibitors. Most target compounds showed significant HDAC1, HDAC6 and VEGFR2 inhibition, which contributed to their potent antiproliferative activities against multiple cancer cell lines and significant antiangiogenic potencies in both human umbilical vein endothelial cell (HUVEC) tube formation assays and rat thoracic aorta ring assays. Further HDAC selectivity evaluations indicated that hydroxamic acids 5 and 9e possessed HDAC isoform selectivity profiles similar to that of the approved HDAC inhibitor suberoylanilide hydroxamic acid(SAHA), while hydrazide12 presented an HDAC isoform selectivity profilesimilar to that of the clinical HDAC inhibitor MS-275. The VEGFR inhibition profiles of 5, 9e and 12 were similar to that of the approved VEGFR inhibitor pazopanib. The intracellular target engagements of Compounds 5 and 12 were confirmed by western blot analysis. The metabolic stabilities of 5, 9e and 12 in mouse liver microsomes were inferior to that of pazopanib. These dual HDAC and VEGFR inhibitors provide lead compounds for further structural optimization to obtainpolypharmacological anticancer agents. pubtype: Academic Journal doctype: pictorial research tables/charts Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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