Andrzej Błauż, Karolina Rózga, Małgorzata Nosek, Anna Makal, Błażej Rychlik, Damian Plażuk
{"title":"二茂铁-环-(Gly - l- Pro)杂合体使多药耐药癌细胞对抗癌药物敏感的设计、合成和生物学评价。","authors":"Andrzej Błauż, Karolina Rózga, Małgorzata Nosek, Anna Makal, Błażej Rychlik, Damian Plażuk","doi":"10.1021/acsmedchemlett.5c00256","DOIUrl":null,"url":null,"abstract":"<p><p>Ferrocenyl-cyclo-(Gly-l-Pro) hybrids as novel inhibitors of ABCB1 and ABCG2 transporters were developed. These organometallic compounds were virtually nontoxic to colon cancer cells, their multidrug-resistant (MDR) variants, and normal fibroblasts. Derivatives bearing <i>o</i>-, <i>m</i>-, or <i>p</i>-ferrocenylphenyl groups significantly sensitized ABCB1- and ABCG2-overexpressing cells to chemotherapeutics such as vincristine, mitoxantrone, and doxorubicin, reducing IC<sub>50</sub> values by up to 12.7- and 10.3-fold, respectively. Notably, (<i>S</i>,<i>Z</i>)-<b>4b</b>, (<i>S</i>,<i>Z</i>)-<b>4c</b>, and (<i>S</i>,<i>Z</i>)-<b>4d</b> showed the strongest effects. Drug combination studies revealed synergistic interactions, particularly in vincristine-, mitoxantrone-, and etoposide-resistant cells (synergy scores: 13.6-17.05). Accumulation assays confirmed ABC transporter inhibition, with (<i>S</i>,<i>Z</i>)-<b>4b</b> and (<i>S</i>,<i>Z</i>)-<b>4d</b> increasing intracellular retention of calcein and pheophorbide A up to 3.4- and 2.9-foldcomparable to those of verapamil and Ko143. Antibody-binding assays further indicated that these hybrids act as substrates of ABCB1 and ABCG2.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 7","pages":"1391-1400"},"PeriodicalIF":3.5000,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12257394/pdf/","citationCount":"0","resultStr":"{\"title\":\"Design, Synthesis, and Biological Evaluation of Ferrocenyl-Cyclo-(Gly‑l‑Pro) Hybrids Sensitizing Multidrug-Resistant Cancer Cells to Anticancer Agents.\",\"authors\":\"Andrzej Błauż, Karolina Rózga, Małgorzata Nosek, Anna Makal, Błażej Rychlik, Damian Plażuk\",\"doi\":\"10.1021/acsmedchemlett.5c00256\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Ferrocenyl-cyclo-(Gly-l-Pro) hybrids as novel inhibitors of ABCB1 and ABCG2 transporters were developed. These organometallic compounds were virtually nontoxic to colon cancer cells, their multidrug-resistant (MDR) variants, and normal fibroblasts. Derivatives bearing <i>o</i>-, <i>m</i>-, or <i>p</i>-ferrocenylphenyl groups significantly sensitized ABCB1- and ABCG2-overexpressing cells to chemotherapeutics such as vincristine, mitoxantrone, and doxorubicin, reducing IC<sub>50</sub> values by up to 12.7- and 10.3-fold, respectively. Notably, (<i>S</i>,<i>Z</i>)-<b>4b</b>, (<i>S</i>,<i>Z</i>)-<b>4c</b>, and (<i>S</i>,<i>Z</i>)-<b>4d</b> showed the strongest effects. Drug combination studies revealed synergistic interactions, particularly in vincristine-, mitoxantrone-, and etoposide-resistant cells (synergy scores: 13.6-17.05). Accumulation assays confirmed ABC transporter inhibition, with (<i>S</i>,<i>Z</i>)-<b>4b</b> and (<i>S</i>,<i>Z</i>)-<b>4d</b> increasing intracellular retention of calcein and pheophorbide A up to 3.4- and 2.9-foldcomparable to those of verapamil and Ko143. Antibody-binding assays further indicated that these hybrids act as substrates of ABCB1 and ABCG2.</p>\",\"PeriodicalId\":20,\"journal\":{\"name\":\"ACS Medicinal Chemistry Letters\",\"volume\":\"16 7\",\"pages\":\"1391-1400\"},\"PeriodicalIF\":3.5000,\"publicationDate\":\"2025-06-16\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12257394/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"ACS Medicinal Chemistry Letters\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1021/acsmedchemlett.5c00256\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/7/10 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q2\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Medicinal Chemistry Letters","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1021/acsmedchemlett.5c00256","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/7/10 0:00:00","PubModel":"eCollection","JCR":"Q2","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
Design, Synthesis, and Biological Evaluation of Ferrocenyl-Cyclo-(Gly‑l‑Pro) Hybrids Sensitizing Multidrug-Resistant Cancer Cells to Anticancer Agents.
Ferrocenyl-cyclo-(Gly-l-Pro) hybrids as novel inhibitors of ABCB1 and ABCG2 transporters were developed. These organometallic compounds were virtually nontoxic to colon cancer cells, their multidrug-resistant (MDR) variants, and normal fibroblasts. Derivatives bearing o-, m-, or p-ferrocenylphenyl groups significantly sensitized ABCB1- and ABCG2-overexpressing cells to chemotherapeutics such as vincristine, mitoxantrone, and doxorubicin, reducing IC50 values by up to 12.7- and 10.3-fold, respectively. Notably, (S,Z)-4b, (S,Z)-4c, and (S,Z)-4d showed the strongest effects. Drug combination studies revealed synergistic interactions, particularly in vincristine-, mitoxantrone-, and etoposide-resistant cells (synergy scores: 13.6-17.05). Accumulation assays confirmed ABC transporter inhibition, with (S,Z)-4b and (S,Z)-4d increasing intracellular retention of calcein and pheophorbide A up to 3.4- and 2.9-foldcomparable to those of verapamil and Ko143. Antibody-binding assays further indicated that these hybrids act as substrates of ABCB1 and ABCG2.
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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