Integrated Biosciences Graduate Program, University of Minnesota, Duluth, MN, 55812, USA.
Department of Chemistry and Biochemistry, University of Minnesota Duluth, Duluth, MN, 55812, USA.
Sci Rep. 2020 Oct 21;10(1):17969. doi: 10.1038/s41598-020-74572-1.
Novel N-phenylindazole based diarylureas have been designed, synthesized and evaluated as potential anticancer agents. In vitro cell viability studies of these derivatives illustrate good potency with IC values in the range of 0.4-50 μM in several cancer cell lines including murine metastatic breast cancer 4T1, murine glioblastoma GL261, human triple negative breast cancer MDA-MB-231, human pancreatic cancer MIAPaCa-2, and human colorectal cancer cell line WiDr. The ester group in the lead compound 8i was modified to incorporate amino-amides to increase solubility and stability while retaining biological activity. Further in vitro studies reveal that lead candidates inhibit tube length in HUVEC cells. In vivo systemic toxicity studies indicate that these candidate compounds are well tolerated in mice without any significant side effects. Anticancer efficacy studies in WiDr tumor xenograft and 4T1 tumor syngraft models demonstrate that the lead candidate 11 exhibits significant antitumor properties as a single agent in these tumor models.
新型 N-苯基吲唑类二芳基脲类化合物被设计、合成并评估为有潜力的抗癌药物。这些衍生物的体外细胞活力研究表明，它们在几种癌细胞系中具有良好的活性，IC 值在 0.4-50 μM 范围内，包括鼠转移性乳腺癌 4T1、鼠神经胶质瘤 GL261、人三阴性乳腺癌 MDA-MB-231、人胰腺癌细胞 MIAPaCa-2 和人结直肠癌细胞 WiDr。先导化合物 8i 中的酯基被修饰为氨基酰胺，以增加化合物的溶解性和稳定性，同时保持生物活性。进一步的体外研究表明，先导候选化合物抑制 HUVEC 细胞的管长度。体内全身毒性研究表明，这些候选化合物在小鼠中耐受性良好，没有明显的副作用。在 WiDr 肿瘤异种移植和 4T1 肿瘤同系移植模型中的抗癌功效研究表明，先导候选化合物 11 在这些肿瘤模型中作为单一药物具有显著的抗肿瘤特性。
