Mohammad Shahidul Islam, Assem Barakat*, Abdul Majeed Abdullah Alayyaf, Matti Haukka, Ved Prakash Verma, Marwa M. Abu-Serie, Amira F. El-Yazbi, Michael G. Shehat, Mustafa Alseqely and Mohamed Teleb*,
{"title":"抗非小细胞肺癌和相关细菌感染的海洋多面DNA损伤螺菌吲哚的合成","authors":"Mohammad Shahidul Islam, Assem Barakat*, Abdul Majeed Abdullah Alayyaf, Matti Haukka, Ved Prakash Verma, Marwa M. Abu-Serie, Amira F. El-Yazbi, Michael G. Shehat, Mustafa Alseqely and Mohamed Teleb*, ","doi":"10.1021/acsmedchemlett.5c0001410.1021/acsmedchemlett.5c00014","DOIUrl":null,"url":null,"abstract":"<p >Targeted therapeutics have gained prominence in combating non-small cell lung carcinoma (NSCLC) and opportunistic bacterial infections like <i>Staphylococcus aureus</i> (<i>S. aureus</i>). 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 <b>4e</b>, <b>4i</b>, and <b>4p</b>–<b>4s</b> as potent cytotoxic agents, with <b>4p</b> showing exceptional activity (IC<sub>50</sub> = 0.042 μM) and tumor selectivity (SI = 58.28). <b>4p</b> exhibited antibacterial efficacy against <i>S. aureus</i> (MIC = 25 μg/mL). DNA damage studies using a terbium(III) chloride biosensor revealed <b>4p</b>’s ability to damage both calf thymus and <i>S. aureus</i> DNA at low concentrations. Docking simulations presumed that <b>4p</b> 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 <b>4p</b> as a promising lead for further studies.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 5","pages":"819–828 819–828"},"PeriodicalIF":3.5000,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Synthesis of Marine-Inspired Multifaceted DNA Damaging Spirooxindoles Combating NSCLC and Associated Bacterial Infection\",\"authors\":\"Mohammad Shahidul Islam, Assem Barakat*, Abdul Majeed Abdullah Alayyaf, Matti Haukka, Ved Prakash Verma, Marwa M. Abu-Serie, Amira F. El-Yazbi, Michael G. Shehat, Mustafa Alseqely and Mohamed Teleb*, \",\"doi\":\"10.1021/acsmedchemlett.5c0001410.1021/acsmedchemlett.5c00014\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >Targeted therapeutics have gained prominence in combating non-small cell lung carcinoma (NSCLC) and opportunistic bacterial infections like <i>Staphylococcus aureus</i> (<i>S. aureus</i>). 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 <b>4e</b>, <b>4i</b>, and <b>4p</b>–<b>4s</b> as potent cytotoxic agents, with <b>4p</b> showing exceptional activity (IC<sub>50</sub> = 0.042 μM) and tumor selectivity (SI = 58.28). <b>4p</b> exhibited antibacterial efficacy against <i>S. aureus</i> (MIC = 25 μg/mL). DNA damage studies using a terbium(III) chloride biosensor revealed <b>4p</b>’s ability to damage both calf thymus and <i>S. aureus</i> DNA at low concentrations. Docking simulations presumed that <b>4p</b> 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 <b>4p</b> as a promising lead for further studies.</p>\",\"PeriodicalId\":20,\"journal\":{\"name\":\"ACS Medicinal Chemistry Letters\",\"volume\":\"16 5\",\"pages\":\"819–828 819–828\"},\"PeriodicalIF\":3.5000,\"publicationDate\":\"2025-04-18\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"ACS Medicinal Chemistry Letters\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://pubs.acs.org/doi/10.1021/acsmedchemlett.5c00014\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Medicinal Chemistry Letters","FirstCategoryId":"3","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acsmedchemlett.5c00014","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
Synthesis of Marine-Inspired Multifaceted DNA Damaging Spirooxindoles Combating NSCLC and Associated Bacterial Infection
Targeted therapeutics have gained prominence in combating non-small cell lung carcinoma (NSCLC) and opportunistic bacterial infections like Staphylococcus aureus (S. aureus). 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 4e, 4i, and 4p–4s as potent cytotoxic agents, with 4p showing exceptional activity (IC50 = 0.042 μM) and tumor selectivity (SI = 58.28). 4p exhibited antibacterial efficacy against S. aureus (MIC = 25 μg/mL). DNA damage studies using a terbium(III) chloride biosensor revealed 4p’s ability to damage both calf thymus and S. aureus DNA at low concentrations. Docking simulations presumed that 4p 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 4p as a promising lead for further studies.
期刊介绍：
ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to:
Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics)
Biological characterization of new molecular entities in the context of drug discovery
Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc.
Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry
Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources
Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response
Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic
Mechanistic drug metabolism and regulation of metabolic enzyme gene expression
Chemistry patents relevant to the medicinal chemistry field.
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