Design, Synthesis and Pharmacological Evaluation of Novel 4-Phenoxyquinoline Derivatives as VEGFR2 Kinase Inhibitors for Tumor Treatment

doi:10.1007/s40242-024-4132-3

Abstract

Abstract: Vascular endothelial growth factor 2 (VEGFR2) plays a vital role in regulating of tumor metastasis and angiogenesis, which has emerged as one of the effective targets for clinical tumor therapy. Herein, a series of novel facilely accessible 4-phenoxyquinoline derivatives was prepared and assessed for their antitumor activity against three human tumor cell lines (SGC-7901, HepG2 and A549). Among these compounds, 6a, 6b and 6c show strong antitumor activity on HepG2 cells [the drug concentration of eliminating half of tumor cells (IC₅₀)=9.33, 1.84, 8.54 μmol/L]. Notably, compound 6b shows potent selective inhibitory activity against VEGFR2 kinase with an IC₅₀ value of 4.66 nmol/L. The excellent anti-angiogenesis capability of compound 6b was confirmed by tube formation and chick chorioallantoic membrane (CAM) assay. In vivo studies confirmed that compound 6b was able to inhibit tumor growth in HepG2 xenografts of BALB/c nude mice without obvious side or toxic effects. The results demonstrated that compound 6b exhibited remarkable anti-angiogenesis and tumor growth inhibitory effects with less toxicity in vitro and in vivo models. These findings highlighted the potential of compound 6b as a promising VEGFR2 kinase inhibitor for the development of antitumor drugs.

Key words: Vascular endothelial growth factor 2 (VEGFR2), 4-Phenoxyquinoline, Inhibitor, Anti-tumor, Angiogenesis

JIANG Wei, CHEN Jiayan, WANG Haifeng, XUE Aiqi, ZHANG Xinyang, GUAN Jichi, WEI Lulu, CAI Jianfeng, HU Yong, LIU Dan. Design, Synthesis and Pharmacological Evaluation of Novel 4-Phenoxyquinoline Derivatives as VEGFR2 Kinase Inhibitors for Tumor Treatment[J]. Chemical Research in Chinese Universities, 2025, 41(1): 66-78.

References

[1] Hendriks W., Bourgonje A., Leenders W., Pulido R., Molecules, 2018, 23, 395.
[2] Jiao Q., Bi L., Ren Y., Song S., Wang Q., Mol. Cancer., 2018, 17, 36.
[3] Bhanumathy K., Balagopal A., Vizeacoumar F. S., Vizeacoumar F. J., Freywald A., Giambra V., Cancers (Basel)., 2021, 13, 184.
[4] Patterson H., Nibbs R., McInnes I., Siebert S., Clin. Exp. Immunol., 2014, 176, 1.
[5] Ahn R., Ursini-Siegel J., Int. J. Mol. Sci., 2021, 22, 2608.
[6] Ebrahimi N., Fardi E., Ghaderi H., Palizdar S., Khorram R., Vafadar R., Ghanaatian V., Rezaei-Tazangi F., Baziyar P., Ahmadi A., Hamblin M. R., Aref A. R., Cell Mol. Life Sci., 2023, 80, 104.
[7] Jin H., Dan H.-G., Rao G.-W., Heterocyclic Communications, 2018, 24, 1.
[8] Yamaoka T., Kusumoto S., Ando K., Ohba M., Ohmori T., Int. J. Mol. Sci., 2018, 19, 3491.
[9] Liu Y., Li Y., Wang Y., Lin C., Zhang D., Chen J., Ouyang L., Wu F., Zhang J., Chen L., Journal of Hematology & Oncology, 2022, 15, 89.
[10] Qin S., Li A., Yi M., Yu S., Zhang M., Wu K., J. Hematol Oncol., 2019, 12, 27.
[11] Shaik F., Cuthbert G. A., Homer-Vanniasinkam S., Muench S. P., Ponnambalam S., Harrison M. A., Biomolecules, 2020, 10, 1673.
[12] Chen J.-C., Chang Y.-W., Hong C.-C., Yu Y.-H., Su J.-L., Int. J. Mol. Sci., 2012, 14, 88.
[13] Malekan M., Ebrahimzadeh M. A., Curr. Top. Med. Chem., 2022, 22, 891.
[14] Adel M., Serya R. A. T., Lasheen D. S., Abouzid K. A. M., Bioorg. Chem., 2018, 81, 612.
[15] Cheng K., Liu C.-F., Rao G.-W., Curr. Med. Chem., 2021, 28, 2540.
[16] Kaufman N. E. M., Dhingra S., Jois S. D., Molecules, 2021, 26, 1076.
[17] Falcon B. L., Chintharlapalli S., Uhlik M. T., Pytowski B., Pharmacol Ther., 2016, 164, 204.
[18] Mabeta P., Steenkamp V., Int. J. Mol. Sci., 2022, 23, 15585.
[19] Ntanasis-Stathopoulos I., Fotopoulos G., Tzanninis I.-G., Kotteas EA., Cancer Invest., 2016, 34, 313.
[20] Farghaly T. A., Al-Hasani W. A., Abdulwahab H. G., Expert Opin. Ther. Pat., 2021, 31, 989.
[21] Wang X., Bove A. M., Simone G., Ma B., Front Cell Dev. Biol., 2020, 8, 599281.
[22] Zhong L., Li Y., Xiong L., Wang W., Wu M., Yuan T., Yang W., Tian C., Miao Z., Wang T., Yang S., Sig. Transduct Target Ther., 2021, 6, 1.
[23] Auti P. S., George G., Paul A. T., RSC Adv., 2020, 10, 41353.
[24] Hameed A., Al-Rashida M., Uroos M., Ali S. A., Arshia., Ishtiaq M., Khan K. M., Expert Opin. Ther. Pat., 2018, 28, 281.
[25] Jafari E., Khajouei M. R., Hassanzadeh F., Hakimelahi G. H., Khodarahmi G. A., Research in Pharmaceutical Sciences, 2016, 11, 1.
[26] Peng F.-W., Liu D.-K., Zhang Q.-W., Xu Y.-G., Shi L., Expert Opin. Ther. Pat., 2017, 27, 987.
[27] Das R., Mehta D. K., Dhanawat M., Anticancer Agents Med. Chem., 2021, 21, 1350.
[28] Martorana A., La Monica G., Lauria A., Molecules, 2020, 25, 4279.
[29] Geller G., Laskin J., Cheung W. Y., Ho C., Thyroid Res., 2017, 10, 6.
[30] Xiao Z., Chu C., Zhou L., Zhou Z., Zhang Q., Yang F., Yang Z., Zheng P., Xu S., Zhu W., Bioorg. Med. Chem., 2020, 28, 115669.
[31] Momeny M., Alishahi Z., Eyvani H., Esmaeili F., Zaghal A., Ghaffari P., Tavakkoly-Bazzaz J., Alimoghaddam K., Ghavamzadeh A., Ghaffari SH., Cell Oncol. (Dordr.), 2020, 43, 81.
[32] Orbegoso C., Marquina G., George A., Banerjee S., Expert Opin. Pharmacother., 2017, 18, 1637.
[33] Zhao B., Lei F., Wang C., Zhang B., Yang Z., Li W., Zhu W., Xu S., Molecules, 2018, 23, 1553.
[34] Liu D., Luan T., Kong J., Zhang Y., Wang H.-F., Molecules, 2015, 21, E21.
[35] Liu D., Xue A., Liu Z., Zhang Y., Peng P., Wang H., Letters in Drug Design & Discovery., 2019, 16, 663.
[36] Wei H., Duan Y., Gou W., Cui J., Ning H., Li D., Qin Y., Liu Q., Li Y., Eur. J. Med Chem., 2019, 181, 111552.
[37] Berrino E., Michelet B., Martin-Mingot A., Carta F., Supuran C. T., Thibaudeau S., Angewandte Chemie International Edition, 2021, 60, 23068.
[38] Hevey R., Chemistry, 2021, 27, 2240.
[39] Richardson P., Expert Opin. Drug Discov., 2021, 16, 1261.
[40] Peng S., Wang Y., Peng H., Chen D., Shen S., Peng B., Chen M., Lencioni R., Kuang M., Hepatology, 2014, 60, 1264.
[41] Goel S., Chen F., Hong H., Valdovinos H. F., Hernandez R., Shi S., Barnhart T. E., Cai W., ACS Appl. Mater. Interfaces, 2014, 6, 21677.
[42] Li J., Wu Y., Wang D., Zou L., Fu C., Zhang J., Leung G. P. H., Pharmacol Res., 2019, 146, 104313.
[43] Ferrara N., Gerber H.-P., LeCouter J., Nat. Med., 2003, 9, 669.
[44] Olsson A.-K., Dimberg A., Kreuger J., Claesson-Welsh L., Nat. Rev. Mol. Cell Biol., 2006, 7, 359.