1. BODIPY-Appended Pt(II) Complexes with High Toxicities and Anti-chemoresistance Performances in a Cisplatin Resistant In Vivo Model
- Author
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Hualing Li, Zhonghua Shi, Hang Yao, Chengyin Wang, Guoxiu Wang, Ting Z’hang, Xichen Chen, Qi Tao, Chuan Tan, Di Yang, Cunhui Zhai, Aijian Qin, Chengxin Fei, Siyu Fang, Hui Chong, Hongying Fan, Hongxia Shao, Xiaohui Yuan, and Jinzhi Li
- Subjects
Cisplatin ,010405 organic chemistry ,DNA damage ,010402 general chemistry ,01 natural sciences ,0104 chemical sciences ,Inorganic Chemistry ,chemistry.chemical_compound ,chemistry ,Downregulation and upregulation ,In vivo ,Toxicity ,medicine ,Unfolded protein response ,Biophysics ,Physical and Theoretical Chemistry ,BODIPY ,DNA ,medicine.drug - Abstract
Two novel fluorophore (BODIPY)-bearing complexes, pyriplatin (mCBP) and pyrimidine-chelated cisplatin (dCBP), were synthesized and characterized. The additional BODIPY-pyridine/pyridimine motifs of the two Pt(II) complexes resulted in stronger interactions with DNA in comparison with those of cisplatin. mCBP and cisplatin caused relative decreases in life span and body length in a cisplatin resistant in vivo model, N2 (wild-type) Caenorhabditis elegans. In contrast, dCBP resulted in a dramatic reduction in the two physiological parameters in N2 C. elegans, indicating high toxicity and sensitivity. The resistance factors (RF) of cisplatin, mCBP, and dCBP were determined to be 2.46, 1.04, and 0.91, respectively. The increasing RF folds for mCBP and dCBP against cisplatin were 2.36 and 2.70, respectively. This suggested they were featured with improved anti-chemoresistance capabilities. It is noteworthy that dCBP showed lowest lethal concentration (LC50) values of 0.56 and 0.61 mM in cisplatin resistant and sensitive in vivo models, respectively. Upregulation of several evolutionary conservation genes that regulate cisplatin chemoresistance through cisplatin effluxing, the DNA damage response, the unfolded protein response, and detoxification (asna-1, parp-1, enpl-1, and skn-1) was observed upon exposure to cisplatin but not to mCBP and dCBP. This could explain the improved anti-chemoresistance performances of synthesized Pt(II) complexes.
- Published
- 2021