Design, Synthesis, Activity and Docking Study of Sorafenib Analogs Bearing Sulfonylurea Unit

Wu, Chunjiang; Wang, Min; Tang, Qidong; Luo, Rong; Chen, Le; Zheng, Pengwu; Zhu, Wufu

doi:10.3390/molecules201019361

Cited by 35 publications

(18 citation statements)

References 12 publications

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“…There were also some pi-pi interactions between YLL545 and Phe1407 and hydrophobic interactions with the Ile898, Val899, Ile892, and Val899 residues in the allosteric pocket. These results indicate that YLL545 has a similar binding mode to that of sorafenib [21], demonstrating the effectiveness of our ring closure design strategy.…”

Section: Resultsmentioning

confidence: 76%

The novel VEGF receptor 2 inhibitor YLL545 inhibits angiogenesis and growth in breast cancer

et al. 2016

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Their antiangiogenic effects make vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors useful for cancer treatment. However, most of these drugs have unexpected adverse side effects. Here, we show that the novel VEGFR2 inhibitor YLL545 suppressed tumor angiogenesis and growth in triple-negative breast cancer without adverse effects. YLL545 treatment also markedly inhibited proliferation, migration, invasion, and tube formation by human umbilical vascular endothelial cells (HUVECs) in vitro. These effects of YLL545 were equal to or greater than those seen with sorafenib. In addition, YLL545 inhibited VEGF-induced phosphorylation of VEGFR2 and activation of downstream signaling regulators, such as phospho-STAT3 and phospho-ERK1/2, in HUVECs. Embryonic angiogenesis assays in zebrafish and Matrigel plug assays in mice demonstrated that YLL545 inhibits angiogenesis in vivo. YLL545 also inhibited proliferation and induced apoptosis in MDA-MB-231 breast cancer cells both in vitro and in vivo, and 50 mg/kg/d YLL545 inhibited human tumor xenograft growth by more than 50% in BALB/c nude mice. These observations suggest YLL545 is a potentially useful anticancer drug candidate.

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Section: Resultsmentioning

confidence: 76%

The novel VEGF receptor 2 inhibitor YLL545 inhibits angiogenesis and growth in breast cancer

et al. 2016

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“…The mean percent VEGFR-2 inhibition of the investigated compounds on VEGFR-2 at 10 μM concentration are shown in Figs 6 , 7 and 8 . (Sorafenib as a lead compound showed 95% VEGFR-2 inhibition) 36 .…”

Section: Resultsmentioning

confidence: 99%

Discovery of Potent VEGFR-2 Inhibitors based on Furopyrimidine and Thienopyrimidne Scaffolds as Cancer Targeting Agents

Aziz

Serya

Lasheen

et al. 2016

Sci Rep

144

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Vascular endothelial growth factor receptor-2 (VEGFR-2) plays a crucial role in cancer angiogenesis. In this study, a series of novel furo[2,3-d]pyrimidine and thieno[2,3-d]pyrimidine based-derivatives were designed and synthesized as VEGFR-2 inhibitors, in accordance to the structure activity relationship (SAR) studies of known type II VEGFR-2 inhibitors. The synthesized compounds were evaluated for their ability to in vitro inhibit VEGFR-2 kinase enzyme. Seven compounds (15b, 16c, 16e, 21a, 21b, 21c and 21e) demonstrated highly potent dose-related VEGFR-2 inhibition with IC50 values in nanomolar range, of which the thieno[2,3-d]pyrimidine based-derivatives (21b, 21c and 21e) exhibited IC50 values of 33.4, 47.0 and 21 nM respectively. Moreover, furo[2,3-d]pyrimidine-based derivative (15b) showed the strongest inhibition of human umbilical vein endothelial cells (HUVEC) proliferation with 99.5% inhibition at 10 μM concentration. Consistent with our in vitro findings, compounds (21b and 21e) orally administered at 5 and 10 mg/kg/day for 8 consecutive days demonstrated potent anticancer activity in Erhlich ascites carcinoma (EAC) solid tumor murine model. Such compounds blunted angiogenesis in EAC as evidenced by reduced percent microvessel via decreasing VEGFR-2 phosphorylation with subsequent induction of apoptotic machinery. Furthermore, Miles vascular permeability assay confirmed their antiangiogenic effects in vivo. Intriguingly, such compounds showed no obvious toxicity.

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“…The selected compounds ( 16d , 18d , and 20d ) are tested for their activity against one or several tyrosine kinases (c‐Met, Flt‐3, VEGFR‐2, c‐Kit, and EGFR kinases) through the mobility shift assay . (The rationale of measuring the activity of different types of tyrosine kinases: The tyrosine kinase can catalyze the phosphorylation of the substrate, and this process requires the involvement of ATP.…”

Section: Methodsmentioning

confidence: 99%

Discovery of novel pyrrolopyrimidine/pyrazolopyrimidine derivatives bearing 1,2,3‐triazole moiety as c‐Met kinase inhibitors

et al. 2018

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Six series of pyrrolo[2,3-d]pyrimidine and pyrazolo[3,4-d]pyrimidine derivatives bearing 1,2,3-triazole moiety were designed and synthesized, and some bio-evaluation was also carried out. As a result, four points can be summarized: Firstly, some of compounds exhibited excellent cytotoxicity activity and selectivity with the IC values in single-digit μm level. In particular, the most promising compound 16d showed equal activity to lead compound foretinib against A549, HepG2, and MCF-7 cell lines, with the IC values of 4.79 ± 0.82, 2.03 ± 0.39, and 2.90 ± 0.43 μm, respectively. Secondly, the SARs and docking studies indicated that the in vitro antitumor activity of pyrrolo[2,3-d]pyrimidine derivatives bearing 1,2,3-triazole moiety was superior to the pyrazolo[3,4-d]pyrimidine derivatives bearing 1,2,3-triazole moiety. Thirdly, three selected compounds (16d, 18d, and 20d) were further evaluated for inhibitory activity against the c-Met kinase, and the 16d could inhibit the c-Met kinase selectively by experiments of enzyme-based selectivity. What is more, 16d could induce apoptosis of HepG2 cells and inhibitor the cell cycle of HepG2 on G2/M phase by acridine orange staining and cell cycle experiments, respectively.

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Design, Synthesis, Activity and Docking Study of Sorafenib Analogs Bearing Sulfonylurea Unit

Cited by 35 publications

References 12 publications

The novel VEGF receptor 2 inhibitor YLL545 inhibits angiogenesis and growth in breast cancer

The novel VEGF receptor 2 inhibitor YLL545 inhibits angiogenesis and growth in breast cancer

Discovery of Potent VEGFR-2 Inhibitors based on Furopyrimidine and Thienopyrimidne Scaffolds as Cancer Targeting Agents

Discovery of novel pyrrolopyrimidine/pyrazolopyrimidine derivatives bearing 1,2,3‐triazole moiety as c‐Met kinase inhibitors

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