TY - JOUR
T1 - Synthesis, biological activity evaluation and mechanism of action of novel bis-isatin derivatives as potential anti-liver cancer agents
AU - Li, Zhifen
AU - Ma, Jingbo
AU - Tian, Ming
AU - Xia, Peng
AU - Lv, Xiannian
AU - Hou, Rui
AU - Jiang, Yuke
AU - Xu, Xiaolong
AU - Jia, Zhifang
AU - Wang, Jigang
AU - Li, Zhijie
PY - 2024/2/1
Y1 - 2024/2/1
N2 - A series of bis-isatin conjugates with lysine linker were synthesized with the aim of probing their antiproliferative potential. All the newly synthesized derivatives (0–100 μM) were first screened against liver cancer cell lines(Huh1, H22, Huh7, Hepa1-6, HepG2, Huh6 and 97H) using CCK-8 assay. Results indicated that the derivative 4d exhibited the most potent activity against Huh1 (IC50 = 17.13 µM) and Huh7(IC50 = 8.265 µM). In vivo anti-tumor study showed that compound 4d effectively inhibited tumor growth in Huh1-induced xenograft mouse model; the anti-tumor effect of compound 4d (15 mg/kg) was comparable with sorafenib (20 mg/kg). H&E staining analysis and routine blood test and blood serum biochemistry examination was performed to confirm the safety of compound 4d in xenograft models. The mechanism of action of 4d on tumor growth inhibition was further investigated by RNA-Seq analysis, which indicates a positive regulation of autophagy signaling pathway, which was further confirmed with key biomarker expression of autophagy after 4d treatment. Our results suggest that the bis-isatin conjugate compound 4d is a promising tumor inhibitory agent for some liver cancer.
AB - A series of bis-isatin conjugates with lysine linker were synthesized with the aim of probing their antiproliferative potential. All the newly synthesized derivatives (0–100 μM) were first screened against liver cancer cell lines(Huh1, H22, Huh7, Hepa1-6, HepG2, Huh6 and 97H) using CCK-8 assay. Results indicated that the derivative 4d exhibited the most potent activity against Huh1 (IC50 = 17.13 µM) and Huh7(IC50 = 8.265 µM). In vivo anti-tumor study showed that compound 4d effectively inhibited tumor growth in Huh1-induced xenograft mouse model; the anti-tumor effect of compound 4d (15 mg/kg) was comparable with sorafenib (20 mg/kg). H&E staining analysis and routine blood test and blood serum biochemistry examination was performed to confirm the safety of compound 4d in xenograft models. The mechanism of action of 4d on tumor growth inhibition was further investigated by RNA-Seq analysis, which indicates a positive regulation of autophagy signaling pathway, which was further confirmed with key biomarker expression of autophagy after 4d treatment. Our results suggest that the bis-isatin conjugate compound 4d is a promising tumor inhibitory agent for some liver cancer.
KW - Cancer therapy
KW - Isatin derivatives
KW - Liver cancer
KW - RNA-seq
UR - http://www.scopus.com/inward/record.url?scp=85182550408&partnerID=8YFLogxK
U2 - 10.1016/j.bmcl.2024.129613
DO - 10.1016/j.bmcl.2024.129613
M3 - Article
C2 - 38224754
AN - SCOPUS:85182550408
SN - 0960-894X
VL - 99
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
M1 - 129613
ER -