作者: Wu, Jiale ; Wang, Haijun ; Guo, Xiaoshan ; Bu, Ming ; Han, Yinglong ; Deng, Siqi ; Zhou, Jianwen ; Wang, Lu ; Han, Cuicui ; Lin, Yu ; Ren, Wenkang ; Tian, Shuang

Ergosterol peroxide (EP) is a natural steroid compound that has been reported to have significant antitumor activity. However, its poor water solubility and cellular uptake mean that it has weak efficacy against tumor cells. Herein, we designed and synthesized a series of EP derivatives with mitochondrial targeting properties. Of these, compound 15a showed an IC₅₀ value of 0.32 μM against MCF-7 cells, which was 67-fold higher than that of the parental EP (IC₅₀ = 21.46 μM), and was better than cisplatin (IC₅₀ = 4.23 μM), had a selectivity index of 25.28 (IC₅₀MCF-10A/IC₅₀MCF-7). Additionally, compound 15a promoted an increase in intracellular reactive oxygen species levels and a decrease in mitochondrial membrane potential, and blocked the cell cycle in the G0/G1 phase. In a mouse model of breast cancer, 15a showed 89.85 % tumor inhibition at a dose of 20 mg/kg, which is similar to the therapeutic effect of the cisplatin. On the basis of these results, 15a could be considered for further preclinical evaluation for cancer therapy.

2024-05-01·Saudi Pharmaceutical Journal

Synthesis, in silico ADMET prediction analysis, and pharmacological evaluation of sulfonamide derivatives tethered with pyrazole or pyridine as anti-diabetic and anti-Alzheimer's agents

Article

作者: Alkahtani, Hamad M ; Almehizia, Abdulrahman A ; Abdelazeem, Nagwa M ; Aboulthana, Wael M ; Naglah, Ahmed M ; Hassan, Ashraf S

Based on previous developments of our research programs in trying to find new compounds with multiple biological targets such as antioxidant, anti-diabetic, anti-Alzheimer's, and anti-arthritic agents. In the context, a novel series of sulfonamide derivatives based on the pyrazole or pyridine moieties 3a, b, 7-9, 11-13, 15a, b, and 16 were synthesized from amine compounds with sulfonyl chloride derivatives. The structures of sulfonamide derivatives were elucidated via spectroscopy (¹H and ¹³C NMR). The sulfonamide derivatives were biologically assessed in vitro for their anti-diabetic (α-amylase and α-glucosidase inhibition) and anti-Alzheimer's (acetylcholinesterase inhibition) activities. The biological results revealed that compound 15a is a powerful enzyme inhibitor for α-amylase and α-glucosidase. Also, compound 15b demonstrated inhibitor activity against the acetylcholinesterase enzyme. The structure-activity relationship study of sulfonamide derivatives was accomplished. Furthermore, complementary in silico molecular properties, drug-likeness, ADMET prediction, and surface properties of the two more powerful derivatives 15a and 15b were fulfilled and computed. These studies recommend 15a and 15b as candidates with modifications in their structures before the in vivo assays.

2024-02-08·Journal of Medicinal Chemistry1区 · 医学

Discovery of Novel Coumarin-quinolinium Derivatives as Pan-KRAS Translation Inhibitors by Targeting 5′-UTR RNA G-Quadruplexes

1区 · 医学

Article

作者: Huang, Zhi-Shu ; Yan, Jia-Tong ; Gao, Zhuo-Yu ; Chen, Xiu-Cai ; Xu, Shu-Min ; Chen, Shuo-Bin ; Dai, Le-Tian ; Li, Mao-Lin ; Tan, Jia-Heng

Hyperactivated KRAS mutations fuel tumorigenesis and represent attractive targets for cancer treatment. While covalent inhibitors have shown clinical benefits against the KRAS^G12C mutant, advancements for non-G12C mutants remain limited, highlighting the urgent demand for pan-KRAS inhibitors. RNA G-quadruplexes (rG4s) in the 5'-untranslated region of KRAS mRNA can regulate KRAS translation, making them promising targets for pan-KRAS inhibitor development. Herein, we designed and synthesized 50 novel coumarin-quinolinium derivatives, leveraging our previously developed rG4-specific ligand, QUMA-1. Notably, several compounds exhibited potent antiproliferative activity against cancer cells as pan-KRAS translation inhibitors. Among them, 15a displayed exceptional capability in stabilizing KRAS rG4s, suppressing KRAS translation, and consequently modulating MAPK and PI3K-AKT pathways. 15a induced cell cycle arrest, prompted apoptosis in KRAS-driven cancer cells, and effectively inhibited tumor growth in a KRAS mutant xenograft model. These findings underscore the potential of 15a as a pan-KRAS translation inhibitor, offering a novel and promising approach to target various KRAS-driven cancers.

100 项与 15-a 相关的药物交易

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