Structural modifications of indolinones bearing a pyrrole moiety and discovery of a multi-kinase inhibitor with potent antitumor activity
Graphical abstract
Introduction
Angiogenesis is an indispensable physiological process during embryonic development and wound healing.1, 2, 3 However, considerable studies demonstrated that the progression of primary tumor is angiogenesis-dependent, which provide necessary nutrient for further growth and metastasis of tumor cells.4, 5
Angiogenesis is regulated by several endogenous molecules. Vascular endothelial growth factor receptors (VEGFRs) are transmembrane tyrosine kinases consisting of three structurally related isoforms. The binding of VEGFR with its cognate ligand activates several downstream signal cascades, which are responsible for cell proliferation and survival.2 VEGFR-2 is considered the major mediator, and is a valid target for drug discovery.6, 7, 8 In addition, increasing studies indicate that VEGFR-1 and VEGFR-3 are independently up-regulated in several human malignancies, such as prostate, lung, and colorectal tumors. Higher levels of these receptors are commonly correlated with formation of metastasis.9, 10, 11 These findings highlighted the importance of VEGFR family in tumorigenesis. Platelet-derived growth factor (PDGF) and its cognate receptor mediate an essential signaling for growth of perivascular smooth muscle and pericytes, which are important for neovascularization.12 Aberrant PDGFRs activation has been documented in clinical samples of tumor such as glioma and prostate cancer, making PDGFRs as druggable therapeutic targets.13 Upon sustained blockade of VEGF-driven pathway, several other molecules may involve, such as fibroblast growth factor receptor (FGFR), providing a compensatory mechanism to facilitate tumor angiogenesis.14
Considering the complicated regulation of tumor angiogenesis, combination therapy and multi-target inhibitors are considered promising strategies to inhibit tumor growth and circumvent drug resistance. On the other hand, the high degree of structural similarities between VEGFR, PDGFR, and FGFR kinases creates possibility to identify inhibitors with synergistic activity. Nintedanib is an authorized inhibitor of VEGFR, PDGFR, and FGFR, with excellent in vivo activity in various tumor models.15 It contains an indolinone scaffold, where by the lactam group forms pivotal hydrogen bonds with the amino acid residues of target proteins.16, 17
In our previous study, we have disclosed two 6-methoxycarbonyl indolinones (1 and 2) as angiokinases inhibitors.18 Here, our recent work regarding the structural optimizations of these precursors is reported (Fig. 1), which ultimately leads to the discovery of methyl (Z)-3-(((4-(2-methyl-5-((4-methylpiperazin-1-yl)methyl)-1H-pyrrol-1-yl)phenyl)amino)(phenyl)methylene)-2-oxoindoline-6-carboxylate (7h), a more potent multi-kinase inhibitor with excellent antitumor activity.
Section snippets
Chemistry
The synthetic route for preparation of compounds 7a–7l is outlined in Scheme 1. Briefly, the fluoro benzene or heterocycle 3 underwent a nucleophilic coupling with pyrrole or 2-methyl-1H-pyrrole to generate intermediates 4a–4e, which were converted to intermediates 5a–5l via Mannich reaction followed by hydrogenation reaction as previously reported.18 Finally, Michael addition reactions were employed by reacting intermediates 5a–5l with commercially available intermediate methyl (E
Conclusions
In summary, structural modifications of compound 2, an angiokinase inhibitor reported previously were performed in this study, which generated a potent multi-kinase inhibitor, 7h, for the treatment of tumor. Compound 7h exhibited excellent potency against angiokinases, with IC50 values ranging 6.3–31 nM. Also, it displayed potent activity against other kinases correlated with tumor growth, such as LYN and c-KIT kinases. In cells, 7h effectively attenuated the phosphorylation of AKT and ERK
Chemistry
Reagents and solvents were obtained from commercial sources and used without further purification. All the reactions were monitored by TLC using silica gel GF/UV 254. Flash chromatography was performed using silica gel (300–400 mesh). The purity of the synthesized compounds was measured by high performance liquid chromatography (HPLC, Agilent, USA), and was confirmed to be higher than 95%. Melting points were determined on a Büchi Melting Point B-540 apparatus (Büchi Labortechnik, Flawil,
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
This work was supported by China Postdoctoral Science Foundation (2018M633720) and Liaoning Revitalization Talents Program (XLYC1808037).
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