Department of Drug Radiation Research, National Center for Radiation Research and Technology (NCRRT), Egyptian Atomic Energy Authority (EAEA), Nasr City, P.O. Box 29, Cairo, Egypt.
Department of Drug Radiation Research, National Center for Radiation Research and Technology (NCRRT), Egyptian Atomic Energy Authority (EAEA), Nasr City, P.O. Box 29, Cairo, Egypt.
Bioorg Chem. 2019 Jul;88:102956. doi: 10.1016/j.bioorg.2019.102956. Epub 2019 Apr 27.
Multitargeted therapy is considered a successful approach to cancer treatment. The development of small molecule multikinase inhibitors through hybridization strategy can provide highly potent and selective anticancer agents. A library of N-alkyl-2-[(4-oxo-3-(4-sulfamoylphenyl)-3,4-dihydroquinazolin-2-yl)thio]acetamide derivatives 5-18 was designed and synthesized. The synthesized compounds were screened for cytotoxic activity against MDA-MB-231 breast cancer cell line and showed IC in the range of 0.34-149.10 µM. The inhibition percentage of VEGFR-2 was measured for all the compounds and found to be in the range of 90.09-20.44%. The promising compounds 8, 12, 13, 16 and 17 were selected to measure their possible multikinase inhibitory activity against VEGFR-2 and EGFR. IC of the promising compounds were in the range of 247-793 nM for VEGFR-2 in reference to sunitinib (IC 320 nM), and 369-725 nM for EGFR in reference to erlotinib (IC 568 nM). Compounds 12 and 13 showed the most potent activity towards VEGFR-2 & EGFR, respectively. Measuring the cytotoxicity of 12 and 13 against MCF-10 normal breast cell line indicates their relative safety to normal breast cells (IC 37 & 97 µM, respectively). As radiotherapy is considered the primary treatment for some types of solid tumors, the radiosensitizing ability of 12 and 13 was measured by subjecting the MDA-MB-231 cells to a single dose of 8 Gy of gamma radiation. IC of 12 and 13 decreased from 1.91 & 0.51 µM to 0.79 & 0.43 µM, respectively. Molecular docking was performed to gain insights into the ligand-binding interactions of 12 inside VEGFR-2 and EGFR binding sites in comparison to their co-crystallized ligands.
多靶点治疗被认为是癌症治疗的一种成功方法。通过杂交策略开发小分子多激酶抑制剂可以提供高效且选择性的抗癌药物。设计并合成了 N-烷基-2-[(4-氧代-3-(4-磺酰胺基苯基)-3,4-二氢喹唑啉-2-基)硫代]乙酰胺衍生物 5-18 的库。合成的化合物对 MDA-MB-231 乳腺癌细胞系进行了细胞毒性活性筛选，结果显示 IC 在 0.34-149.10 µM 范围内。测量了所有化合物对 VEGFR-2 的抑制百分比，发现范围在 90.09-20.44%之间。选择有前途的化合物 8、12、13、16 和 17 来测量它们对 VEGFR-2 和 EGFR 的可能多激酶抑制活性。与舒尼替尼（IC 320 nM）相比，有前途的化合物对 VEGFR-2 的 IC 在 247-793 nM 范围内，与厄洛替尼（IC 568 nM）相比，对 EGFR 的 IC 在 369-725 nM 范围内。化合物 12 和 13 对 VEGFR-2 和 EGFR 的活性最强。测量化合物 12 和 13 对 MCF-10 正常乳腺细胞系的细胞毒性表明它们对正常乳腺细胞相对安全（IC 37 和 97 µM，分别）。由于放射治疗被认为是某些类型实体瘤的主要治疗方法，因此通过将 MDA-MB-231 细胞暴露于 8 Gy 的伽马射线单次剂量来测量 12 和 13 的放射增敏能力。化合物 12 和 13 的 IC 从 1.91 和 0.51 µM 分别降低到 0.79 和 0.43 µM。进行分子对接以深入了解 12 与 VEGFR-2 和 EGFR 结合位点的配体结合相互作用，与它们共结晶的配体进行比较。
