Synthesis and in vivo SAR study of indolin-2-one-based multi-targeted inhibitors as potential anticancer agents

• Published in: European journal of medicinal chemistry Vol. 82; pp. 139 - 151
• Main Authors: Zhang, Long, Zheng, Qingmei, Yang, Yingying, Zhou, Haojie, Gong, Xingjiang, Zhao, Shuyong, Fan, Chuanwen
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 23.07.2014; Elsevier
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Line, Tumor; Cell Proliferation - drug effects; Chemistry, Medicinal; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; HT29 Cells; Humans; In-vivo SAR; Indoles - chemical synthesis; Indoles - chemistry; Indoles - pharmacology; Indolin-2-one analogues; Life Sciences & Biomedicine; Mice; Molecular Structure; Multi-targeted inhibitors; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - pathology; PDGFR-β; Pharmacology & Pharmacy; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Protein Kinases - metabolism; Pyrroles - pharmacology; Science & Technology; Structure-Activity Relationship; VEGFR-2; PDGFR-β; NSKYYUZMAXEZIR-AQTBWJFISA-N; Multi-targeted inhibitors; Indolin-2-one analogues; In-vivo SAR; VEGFR-2; PDGFR-beta; DESIGN; VEGF; SUNITINIB MALATE; SU11248; HYPOTHYROIDISM; DISCOVERY; THERAPY; TYROSINE KINASE INHIBITOR; ANTIPROLIFERATIVE EVALUATION
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2014.05.051

A series of indolin-2-one analogues were designed and synthesized, and all of them exhibited excellent in vitro potency. The structure and in vivo activity or toxicity relationship (in-vivo SAR) investigation of indolin-2-one structural analogues was carried out. In vivo efficacy studies indicated that 3b significantly suppressed tumor growth in HT-29 and NCI-H460 xenografts without causing significant loss of body weight. Kinase assay showed that compound 3b effectively inhibited the VEGFR-2, VEGFR-3, FLT3, Ret and PDGFR-β kinases, but had little effect on the VEGFR-1 kinase. Besides, 3b showed higher selectivity for VEGFR-2 compared with PDGFR-β. On the basis of its selectivity and safety properties, 3b was identified as a drug candidate for the treatment of cancer. [Display omitted] •Series of indolin-2-one analogues with potent anti-angiogenesis were synthesized.•The in-vivo SAR of these indolin-2-one analogues was described.•Compared with sunitinib, a safer multi-targeted inhibitor 3b had been discovered.•3b was an effective inhibitor of VEGFR-2, VEGFR-3, FLT3, Ret and PDGFR-β.•3b exhibited higher selectivity for the VEGFR-2 compared with PDGFR-β or VEGFR-1.