Site-Selective Synthesis of C-17 Ester Derivatives of Natural Andrographolide for Evaluation as a Potential Anticancer Agent

被引:6
|
作者
Kumar, Gulshan [1 ,2 ]
Thapa, Sonia [2 ,3 ]
Tali, Javeed Ahmad [1 ,2 ]
Singh, Davinder [1 ,2 ]
Sharma, Bhupesh Kumar [1 ,2 ]
Panda, Kamakshya Nath [4 ]
Singh, Shashank K. [2 ,3 ]
Shankar, Ravi [1 ,2 ]
机构
[1] CSIR, Indian Inst Integrat Med, Nat Prod & Med Chem Div, Jammu 180001, India
[2] Acad Sci & Innovat Res AcSIR, Ghaziabad 201002, India
[3] CSIR, Indian Inst Integrat Med, Pharmacol Div, Jammu 180001, India
[4] Indian Inst Technol Roorkee, Dept Chem, Roorkee 247667, Uttaranchal, India
来源
ACS OMEGA | 2023年 / 8卷 / 06期
关键词
BIOLOGICAL EVALUATION; PANICULATA; ANALOGS;
D O I
10.1021/acsomega.3c00036
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
A library of 57 compounds of natural andrographolide was designed, synthesized, and screened for in vitro studies against four human cancer cell lines: A594, PC-3, MCF-7, and HCT-116. Most of the synthesized compounds displayed better cytotoxic profile against all tested cells compared to the parent andrographolide (1). The tested semisynthetic derivatives of andrographolide were found to be more sensitive toward lung carcinoma (A594) and prostate carcinoma (PC-3) cell lines. Among the synthesized compounds, the C-17 p-methoxy phenyl ester analog 8s inhibited cell proliferation effectively in A549 (IC50: 6.6 mu M) and PC-3 (IC50: 5.9 mu M) cell variants, and compound 9s exhibited the most potent activity against the A594 cell line, with an IC50 value of 3.5 mu M. Further anticancer mechanistic investigation demonstrated that compound 9s displayed nuclear morphological changes and increased reactive oxygen species (ROS) with disturbed mitochondrial membrane potential (MMP) that can lead to apoptosis. To know the exact structure confirmation of intermediate compounds 4 and 5, single X-ray crystallography was performed, which supported the complete reaction design of this work.
引用
收藏
页码:6099 / 6123
页数:25
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