Tandem MS-Based Metabolite Profiling of 19,20-Epoxycytochalasin C Reveals the Importance of a Hydroxy Group at the C7 Position for Biological Activity,ACS Omega

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Tandem MS-Based Metabolite Profiling of 19,20-Epoxycytochalasin C Reveals the Importance of a Hydroxy Group at the C7 Position for Biological Activity
ACS Omega ( IF 3.7 ) Pub Date : 2021-01-25 , DOI: 10.1021/acsomega.0c05307
Manoj Kushwaha _{1,

2} , Arem Qayum _{3,

4} , Shreyans K. Jain ₅ , Jasvinder Singh _{3,

4} , Amit Kumar Srivastava ₆ , Shubham Srivastava ₇ , Nisha Sharma _{1,

4} , Vidushi Abrol ₁ , Ruchi Malik ₇ , Shashank K. Singh ₃ , Ram A. Vishwakarma ₈ , Sundeep Jaglan _{1,

4}

Affiliation

Seven cytochalasins, 19,20-epoxycytochalasin N, cytochalasin P1, deacetyl 19,20-epoxycytochalasin C, 19,20-epoxycytochalasin D, 19,20-epoxycytochalasin C, cytochalasin D, and cytochalasin C, were isolated from a fungal (Rosellinia sanctae-cruciana) crude extract. A cytotoxicity assay (sulforhodamine B) was performed on a series of cancer cell lines: HT-29, A-549, PC-3, HCT-116, SW-620, and MCF-7. Simultaneously, the liquid chromatography–mass spectrometry (LC–MS)/MS profile of 19,20-epoxycytochalasin C-treated cell lines revealed that 19,20-epoxycytochalasin C (m/z 524.25) oxidized to a metabolite of m/z 522.25 Da (−2 Da (−2H) from 19,20-epoxycytochalasin C). Further chemical oxidation of 19,20-epoxycytochalasin C using the Dess–Martin reagent produced an identical metabolite. It has been noticed that the parent molecule (19,20-epoxycytochalasin C) showed an IC₅₀ of 650 nM (on HT-29), whereas for the oxidized metabolite (m/z 522.24) of 19,20-epoxycytochalasin C, the IC₅₀ was >10 μM. It is clear that the parent molecule had 16 times higher cytotoxic potential as compared to the oxidized metabolite. The spectroscopic investigation indicated that the oxidation of the hydroxyl (−OH) group occurred at the C7 position in 19,20-epoxycyctochalsin C and led to the inactivation of 19,20-epoxycytochalasin C. Further, cell cycle analysis and histopathological evidence support the findings, and CDK2 could be a possible target of 19,20-epoxycyctochalasin C.

中文翻译：

基于串联MS的19,20-环氧细胞松弛素C代谢产物分析揭示了C7位置生物活性的羟基基团的重要性。

七个细胞松弛素，19,20-epoxycytochalasin N，细胞松驰素P1，脱乙酰19,20-epoxycytochalasin C，19,20-epoxycytochalasin d，19,20-epoxycytochalasin C，细胞松驰素d，细胞松弛素和C，从真菌中分离（Rosellinia sanctae -cruciana）粗提物。在一系列癌细胞系HT-29，A-549，PC-3，HCT-116，SW-620和MCF-7上进行了细胞毒性试验（磺胺多巴胺B）。同时，液相色谱-质谱法（LC-MS）/ MS分析了19,20-环氧细胞松弛素C处理的细胞系，发现19,20-环氧细胞松弛素C（m / z 524.25）被氧化为m / z的代谢产物522.25 Da（来自19,20-环氧细胞松弛素C的-2 Da（-2H））。使用Dess-Martin试剂对19,20-环氧细胞松弛素C进行进一步的化学氧化可产生相同的代谢物。已经注意到，母体分子（19,20-环氧细胞松弛素C）的IC ₅₀为650 nM（在HT-29上），而对于19,20-环氧细胞松弛素C的氧化代谢物（m / z 522.24）， IC ₅₀> 10μM。显然，母体分子的细胞毒性潜力是氧化代谢产物的16倍。光谱研究表明，羟基（-OH）的氧化发生在19,20-环氧胞苷C中的C7位置，并导致19,20-环氧胞松弛素C失活。此外，细胞周期分析和组织病理学证据支持研究发现，CDK2可能是19,20-环氧环瓜氨酸C的可能靶标。

更新日期：2021-02-09

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