Synthesis and biological evaluation of novel hybrids of phenylsulfonyl furoxan and phenstatin derivatives as potent anti-tumor agents.

Autor: Huang X; Anhui Province Key Laboratory of Inflammation and Immune Diseases, School of Pharmacy, Anhui Medical University, Hefei, 230032, Anhui Province, PR China; Department of Pharmacy, Maanshan People's Hospital, Maanshan, 243009, Anhui Province, PR China., Wang YS; Anhui Province Key Laboratory of Inflammation and Immune Diseases, School of Pharmacy, Anhui Medical University, Hefei, 230032, Anhui Province, PR China., Ma D; Anhui Province Key Laboratory of Inflammation and Immune Diseases, School of Pharmacy, Anhui Medical University, Hefei, 230032, Anhui Province, PR China., Wang YY; Anhui Province Key Laboratory of Inflammation and Immune Diseases, School of Pharmacy, Anhui Medical University, Hefei, 230032, Anhui Province, PR China., Bian SD; Anhui Province Key Laboratory of Inflammation and Immune Diseases, School of Pharmacy, Anhui Medical University, Hefei, 230032, Anhui Province, PR China., Zhang B; Anhui Province Key Laboratory of Inflammation and Immune Diseases, School of Pharmacy, Anhui Medical University, Hefei, 230032, Anhui Province, PR China., Qiao Y; Anhui Province Key Laboratory of Inflammation and Immune Diseases, School of Pharmacy, Anhui Medical University, Hefei, 230032, Anhui Province, PR China., He ZR; The First Clinical Medical College, Anhui Medical University, Hefei, 230032, Anhui Province, PR China., Lv M; The First Clinical Medical College, Anhui Medical University, Hefei, 230032, Anhui Province, PR China., Cai GL; The First Clinical Medical College, Anhui Medical University, Hefei, 230032, Anhui Province, PR China., Wang ZX; The First Clinical Medical College, Anhui Medical University, Hefei, 230032, Anhui Province, PR China., Liu XS; Anhui Province Key Laboratory of Inflammation and Immune Diseases, School of Pharmacy, Anhui Medical University, Hefei, 230032, Anhui Province, PR China. Electronic address: chemxsliu@126.com., Shi JB; Anhui Province Key Laboratory of Inflammation and Immune Diseases, School of Pharmacy, Anhui Medical University, Hefei, 230032, Anhui Province, PR China. Electronic address: sjbo616@126.com., Liu MM; Anhui Province Key Laboratory of Inflammation and Immune Diseases, School of Pharmacy, Anhui Medical University, Hefei, 230032, Anhui Province, PR China. Electronic address: lmm@ahmu.edu.cn.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2022 Feb 15; Vol. 230, pp. 114112. Date of Electronic Publication: 2022 Jan 11.
DOI: 10.1016/j.ejmech.2022.114112
Abstrakt: Hybridization of nitric oxide (NO) donors with known anti-cancer agents have been emerged as a strategy to achieve improved therapeutic effect and to overcome chemo-resistance in cancer therapy. In this study, furoxan moiety as an efficient NO donor was introduced to phenstatin, a microtubule-interfering agent (MIA), leading to the design and synthesis of a series of furoxan-based NO-releasing arylphenones derivatives. In biological evaluation, the synthesized compounds showed moderate to potent anti-tumor activities against several human cancer cell lines. Among them, compound 15h showed the most potent activities against both chemo-sensitive and resistant cancer cell lines with IC 50 values ranging from 0.008 to 0.021 μM. Further mechanistic studies revealed that 15h worked as a bifunctional agent exhibiting both tubulin polymerized inhibition and NO-releasing activities, resulting in potent anti-angiogenesis, colony formation inhibition, cell cycle arrest and apoptosis induction effects. In the nude mice xenograft model, 15h significantly inhibited the paclitaxel-resistant tumor growth with low toxicity, demonstrating the promising potential for further preclinical evaluation as a therapeutic agent, particularly for the treatment of chemo-resistant cancers.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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Databáze: MEDLINE
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