Synthesis and Evaluation of Novel 2-Pyrrolidone-Fused (2-Oxoindolin-3-ylidene)methylpyrrole Derivatives as Potential Multi-Target Tyrosine Kinase Receptor Inhibitors
Abstract:Signaling pathways of VEGFs and PDGFs are crucial in tumor angiogenesis, which is essential in solid tumor progression and metastasis. This study reports our strategy for designing and synthesizing a series of novel 2-pyrrolidone-fused (2-oxoindolin-3-ylidene)methylpyrrole derivatives as potential multi-target tyrosine kinase receptor inhibitors. The target compounds were obtained by condensation of 5-substituted oxindoles with N-substituted 2-pyrrolidone aldehyde 7 in satisfactory yields. Of these, 11 and 12 … Show more
“…Given the high inhibitory potency of anlotinib toward VEGFR2 in enzymatic assays, we carried out a molecular docking approach to investigate the potential binding sites of anlotinib in VEGFR2 and its possible binding mode. According to previous reports, the ATP‐binding pocket of VEGFR2 is defined as including a hinge region and a hydrophobic region . As shown Figure B, residues of the hinge region (Cys919 and Glu917) can form hydrogen bonds with adenine mimics.…”
Abrogating tumor angiogenesis by inhibiting vascular endothelial growth factor receptor‐2 (VEGFR2) has been established as a therapeutic strategy for treating cancer. However, because of their low selectivity, most small molecule inhibitors of VEGFR2 tyrosine kinase show unexpected adverse effects and limited anticancer efficacy. In the present study, we detailed the pharmacological properties of anlotinib, a highly potent and selective VEGFR2 inhibitor, in preclinical models. Anlotinib occupied the ATP‐binding pocket of VEGFR2 tyrosine kinase and showed high selectivity and inhibitory potency (IC
50 <1 nmol/L) for VEGFR2 relative to other tyrosine kinases. Concordant with this activity, anlotinib inhibited VEGF‐induced signaling and cell proliferation in HUVEC with picomolar IC
50 values. However, micromolar concentrations of anlotinib were required to inhibit tumor cell proliferation directly in vitro. Anlotinib significantly inhibited HUVEC migration and tube formation; it also inhibited microvessel growth from explants of rat aorta in vitro and decreased vascular density in tumor tissue in vivo. Compared with the well‐known tyrosine kinase inhibitor sunitinib, once‐daily oral dose of anlotinib showed broader and stronger in vivo antitumor efficacy and, in some models, caused tumor regression in nude mice. Collectively, these results indicate that anlotinib is a well‐tolerated, orally active VEGFR2 inhibitor that targets angiogenesis in tumor growth, and support ongoing clinical evaluation of anlotinib for a variety of malignancies.
“…Given the high inhibitory potency of anlotinib toward VEGFR2 in enzymatic assays, we carried out a molecular docking approach to investigate the potential binding sites of anlotinib in VEGFR2 and its possible binding mode. According to previous reports, the ATP‐binding pocket of VEGFR2 is defined as including a hinge region and a hydrophobic region . As shown Figure B, residues of the hinge region (Cys919 and Glu917) can form hydrogen bonds with adenine mimics.…”
Abrogating tumor angiogenesis by inhibiting vascular endothelial growth factor receptor‐2 (VEGFR2) has been established as a therapeutic strategy for treating cancer. However, because of their low selectivity, most small molecule inhibitors of VEGFR2 tyrosine kinase show unexpected adverse effects and limited anticancer efficacy. In the present study, we detailed the pharmacological properties of anlotinib, a highly potent and selective VEGFR2 inhibitor, in preclinical models. Anlotinib occupied the ATP‐binding pocket of VEGFR2 tyrosine kinase and showed high selectivity and inhibitory potency (IC
50 <1 nmol/L) for VEGFR2 relative to other tyrosine kinases. Concordant with this activity, anlotinib inhibited VEGF‐induced signaling and cell proliferation in HUVEC with picomolar IC
50 values. However, micromolar concentrations of anlotinib were required to inhibit tumor cell proliferation directly in vitro. Anlotinib significantly inhibited HUVEC migration and tube formation; it also inhibited microvessel growth from explants of rat aorta in vitro and decreased vascular density in tumor tissue in vivo. Compared with the well‐known tyrosine kinase inhibitor sunitinib, once‐daily oral dose of anlotinib showed broader and stronger in vivo antitumor efficacy and, in some models, caused tumor regression in nude mice. Collectively, these results indicate that anlotinib is a well‐tolerated, orally active VEGFR2 inhibitor that targets angiogenesis in tumor growth, and support ongoing clinical evaluation of anlotinib for a variety of malignancies.
“…Lee and co-workers developed a novel class of multitarget inhibitors of VEGFR and PDGFR through condensation of 2-pyrrolidone aldehyde with oxindoles. 174 Two compounds (69, and 70) exhibited potent antiproliferative and enzymatic activities compared with sunitinib. They could be used as novel angiogenesis inhibitors in the treatment of cancers.…”
Section: Multitarget Rtkis As Antiangiogenic Agentsmentioning
confidence: 99%
“…It is under clinical assessment for the treatment of cancers. Lee and co‐workers developed a novel class of multitarget inhibitors of VEGFR and PDGFR through condensation of 2‐pyrrolidone aldehyde with oxindoles . Two compounds ( 69 , and 70 ) exhibited potent antiproliferative and enzymatic activities compared with sunitinib.…”
Section: Recent Advances In Small‐molecule Antiangiogenic Agentsmentioning
Pathological angiogenesis plays a crucial role in malignant neoplasia. Vascular normalization has been confirmed as a promising strategy to promote chemotherapy efficacy. However, compensatory activation of alternative angiogenic receptor tyrosine kinases (RTKs) reduces vascular normalization and induces resistance. Moreover, complexity and heterogeneity of angiogenesis make it difficult to treat with single-target agents. Accordingly, it has been proposed that multiplex inhibition of RTKs could enhance treatment efficacy and overcome resistance on the basis of the vascular normalization concept. Meanwhile, it is feasible to develop multiplex inhibitors against VEGFR-2/Tie-2/EphB4 because of their highly conserved ATP-binding pockets. These inhibitors possess the properties of not only stabilizing the vascular normalization "time window" but also preventing the occurrence of resistance. This novel strategy has yielded promising results in the discovery of antiangiogenic agents. This review highlights the recent progress on the development of such angiogenesis inhibitors.
“…Given the effectiveness of famitinib, our previous study successfully synthesized a series of novel five-membered-heterocycle derivatives of 2-pyrrolidone fused (2-oxoindolin-3-ylidene)methylpyrrole I (Fig. 1 ) [ 19 ]. In contrast to famitinib, our synthetic compounds possess a more rigid conformation than sunitinib and demonstrated superior inhibitory activity of VEGFR-2 and PDGFRβ to sunitinib.…”
Section: Introductionmentioning
confidence: 99%
“…In contrast to famitinib, our synthetic compounds possess a more rigid conformation than sunitinib and demonstrated superior inhibitory activity of VEGFR-2 and PDGFRβ to sunitinib. Among them, C(5)-Br 2-pyrrolidone-fused (2-oxoindolin-3-ylidene)methylpyrrole showed that potency against VEGFR-2 was fivefold higher in comparison to sunitinib [ 19 ]. Fig.…”
BackgroundTumor angiogenesis, essential for tumor growth and metastasis, is tightly regulated by VEGF/VEGFR and PDGF/PDGFR pathways, and therefore blocking those pathways is a promising therapeutic target. Compared to sunitinib, the C(5)-Br derivative of 2-pyrrolidone-fused (2-oxoindolin-3-ylidene)methylpyrrole has significantly greater in vitro activities against VEGFR-2, PDGFRβ, and tube formation.Results and discussionThe objective of this study was to perform further structural optimization, which revealed certain new products with even more potent anti-tumor activities, both cellularly and enzymatically. Of these, 15 revealed ten- and eightfold stronger potencies against VEGFR-2 and PDGFRβ than sunitinib, respectively, and showed selectivity against HCT116 with a favorable selective index (SI > 4.27). The molecular docking results displayed that the ligand–protein binding affinity to VEGFR-2 could be enhanced by introducing a hydrogen-bond-donating (HBD) substituent at C(5) of (2-oxoindolin-3-ylidene)methylpyrrole such as 14 (C(5)-OH) and 15 (C(5)-SH).ConclusionsAmong newly synthetic compounds, 7 and 13–15 exhibited significant inhibitory activities against VEGFR-2 and PDGFRβ. Of these, the experimental results suggest that 15 might be a promising anti-proliferative agent. Graphical abstractIC50 comparison of sunitinib, 14, and 15 against VEGFR-2 and PDGFRβ.
Electronic supplementary materialThe online version of this article (doi:10.1186/s13065-017-0301-5) contains supplementary material, which is available to authorized users.
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