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受海洋启发合成多面性DNA损伤螺环氧化吲哚以对抗非小细胞肺癌及相关细菌感染

Synthesis of Marine-Inspired Multifaceted DNA Damaging Spirooxindoles Combating NSCLC and Associated Bacterial Infection.

作者信息

Islam Mohammad Shahidul, Barakat Assem, Alayyaf Abdul Majeed Abdullah, Haukka Matti, Verma Ved Prakash, Abu-Serie Marwa M, El-Yazbi Amira F, Shehat Michael G, Alseqely Mustafa, Teleb Mohamed

机构信息

Department of Chemistry, College of Science, King Saud University, P. O. Box 2455, Riyadh 11451, Saudi Arabia.

Department of Chemistry, University of Jyväskylä, P. O. Box 35, FI-40014 Jyväskylä, Finland.

出版信息

ACS Med Chem Lett. 2025 Apr 18;16(5):819-828. doi: 10.1021/acsmedchemlett.5c00014. eCollection 2025 May 8.

Abstract

Targeted therapeutics have gained prominence in combating non-small cell lung carcinoma (NSCLC) and opportunistic bacterial infections like (). This study explores dual-acting marine-inspired spirooxindoles to limit NSCLC and opportunistic bacteria. Pharmacophoric motifs from antitumor and antibacterial marine products were merged into a new series of pyrazole-clubbed spirooxindoles via a stereoselective [3 + 2] cycloaddition reaction. MTT screening identified , , and - as potent cytotoxic agents, with showing exceptional activity (IC = 0.042 μM) and tumor selectivity (SI = 58.28). exhibited antibacterial efficacy against (MIC = 25 μg/mL). DNA damage studies using a terbium(III) chloride biosensor revealed 's ability to damage both calf thymus and DNA at low concentrations. Docking simulations presumed that binds between DNA strands, while apoptosis studies indicated it induced G1/S phase cell cycle arrest and increased A549 apoptosis by 33.65%. These findings highlight as a promising lead for further studies.

摘要

靶向治疗在对抗非小细胞肺癌(NSCLC)和诸如()等机会性细菌感染方面已崭露头角。本研究探索具有双重作用的受海洋启发的螺环氧化吲哚,以抑制NSCLC和机会性细菌。通过立体选择性[3 + 2]环加成反应,将来自抗肿瘤和抗菌海洋产物的药效基团合并到一系列新的吡唑连接的螺环氧化吲哚中。MTT筛选确定了,和为有效的细胞毒性剂,其中表现出卓越的活性(IC = 0.042 μM)和肿瘤选择性(SI = 58.28)。对表现出抗(MIC = 25 μg/mL)的抗菌功效。使用氯化铽生物传感器进行的DNA损伤研究表明,在低浓度下能够损伤小牛胸腺和DNA。对接模拟推测在DNA链之间结合,而凋亡研究表明它诱导G1/S期细胞周期停滞,并使A549细胞凋亡增加33.65%。这些发现突出了作为进一步研究的有前景的先导物。

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An overview of spirooxindole as a promising scaffold for novel drug discovery.螺环氧化吲哚作为新型药物发现有前景的骨架的概述。
Expert Opin Drug Discov. 2020 May;15(5):603-625. doi: 10.1080/17460441.2020.1733526. Epub 2020 Feb 28.

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