Pioneering 4,11-Dioxo-4,11-dihydro-1H-anthra[2,3-d]imidazol-3-ium Compounds as Promising Survivin Inhibitors by Targeting ILF3/NF110 for Cancer Therapy

Q1 · MEDICINE

Article

Author: Zhang, Zhenfeng ; Gao, Feng ; Luo, Yanli ; Xia, Xuelin ; Yan, Deyue ; Yuan, Jing ; Dong, Yachun ; Zhang, Wanbin ; Liu, Zhanxiong ; Wang, Penghui

Survivin is a novel attractive target for cancer therapy; however, it is considered undruggable because it lacks enzymatic activities. Herein, we describe our efforts toward the discovery of a novel series of 4,11-dioxo-4,11-dihydro-1H-anthra[2,3-d]imidazol-3-ium derivatives as survivin inhibitors by targeting ILF3/NF110. Intensive structural modifications led us to identify a lead compound AQIM-I, which remarkably inhibited nonsmall cell lung cancer cells A549 with an IC₅₀ value of 9 nM and solid tumor cell proliferation with more than 700-fold selectivity against human normal cells. Further biological studies revealed that compound AQIM-I significantly inhibited survivin expression and colony formation and induced ROS production, apoptosis, cell cycle arrest, DNA damage, and autophagy. Furthermore, the promoter-luciferase reporter assay showed that AQIM-I attenuated the survivin promoter activity enhanced by the overexpression of ILF3/NF110 in a concentration-dependent manner, and specific binding (K_D = 163 nM) of AQIM-I to ILF3/NF110 was detected by surface plasmon resonance.

01 Jan 2007·Transplant InternationalQ2 · MEDICINE

Static normothermic preservation of renal allografts using a novel nonphosphate buffered preservation solution

Q2 · MEDICINE

Article

Author: Michael L. Nicholson ; Atul Bagul ; Helen L. Waller ; Simon J. F. Harper ; Douglas Rees ; Sarah A. Hosgood ; Mark D. Kay

The aim of this study was to assess the viability and function of renal allografts under normothermic conditions using a novel nonphosphate buffered preservation solution AQIXRS-I. Porcine kidneys were flushed at 30 degrees C with AQIXRS-I at 100 mmHg pressure after 5-10 min warm ischaemic time and stored statically at either 4 degrees C or 30 degrees C for 2 h (n = 6 per group). Assessment of renal function by physiological and biochemical parameters was performed by perfusing the organs with autologous blood at 37 degrees C, with an initial circulating serum creatinine concentration of 1000 mumol/l on an isolated organ perfusion system for 6 h. Although the hypothermic group demonstrated overall superior renal function, the normothermic stored kidneys displayed a statistically comparable acid-base balance (7.37 +/- 0.15 vs. 7.3 +/- 0.09, P = 0.24). Furthermore, renal function was still evident after 6 h perfusion with increasing oxygen consumption, renal blood flow and reduced renal vascular resistance. The effectiveness and versatility of AQIXRS-I as a preservation solution under both normothermic and hypothermic conditions has been demonstrated. Renal viability was maintained after 2 h static normothermic storage. This study provides a foundation for further analysis utilizing normothermic preservation.

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Indication	Highest Phase	Country/Location	Organization	Date
Solid tumor	Discovery	CN	Shanghai Jiao Tong University	11 Dec 2023

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