Insa Klemt, Viktor Reshetnikov, Subrata Dutta, Galyna Bila, Rostyslav Bilyy, Itziar Cossío Cuartero, Andrés Hidalgo, Adrian Wünsche, Maximilian Böhm, Marit Wondrak, Leoni A. Kunz-Schughart, Rainer Tietze, Frank Beierlein, Petra Imhof, Sabrina Gensberger-Reigl, Monika Pischetsrieder, Marlies Körber, Tina Jost and Andriy Mokhir
{"title":"基于低聚物控制酯基反应性的双反应原药概念:提高喜树碱对癌细胞和中性粒细胞的选择性","authors":"Insa Klemt, Viktor Reshetnikov, Subrata Dutta, Galyna Bila, Rostyslav Bilyy, Itziar Cossío Cuartero, Andrés Hidalgo, Adrian Wünsche, Maximilian Böhm, Marit Wondrak, Leoni A. Kunz-Schughart, Rainer Tietze, Frank Beierlein, Petra Imhof, Sabrina Gensberger-Reigl, Monika Pischetsrieder, Marlies Körber, Tina Jost and Andriy Mokhir","doi":"10.1039/D3MD00609C","DOIUrl":null,"url":null,"abstract":"<p >Many known chemotherapeutic anticancer agents exhibit neutropenia as a dose-limiting side effect. In this paper we suggest a prodrug concept solving this problem for camptothecin (HO-cpt). The prodrug is programmed according to Boolean “AND” logic. In the absence of H<small><sub>2</sub></small>O<small><sub>2</sub></small> (trigger T1), <em>e.g.</em> in the majority of normal cells, it exists as an inactive oligomer. In cancer cells and in primed neutrophils (high H<small><sub>2</sub></small>O<small><sub>2</sub></small>), the oligomer is disrupted forming intermediate (inactive) lipophilic cationic species. These are accumulated in mitochondria (Mit) of cancer cells, where they are activated by hydrolysis at mitochondrial pH 8 (trigger T2) with formation of camptothecin. In contrast, the intermediates remain stable in neutrophils lacking Mit and therefore a source of T2. In this paper we demonstrated a proof-of-concept. Our prodrug exhibits antitumor activity both <em>in vitro</em> and <em>in vivo</em>, but is not toxic to normal cell and neutrophils in contrast to known single trigger prodrugs and the parent drug HO-cpt.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":null,"pages":null},"PeriodicalIF":3.5970,"publicationDate":"2024-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2024/md/d3md00609c?page=search","citationCount":"0","resultStr":"{\"title\":\"A concept of dual-responsive prodrugs based on oligomerization-controlled reactivity of ester groups: an improvement of cancer cells versus neutrophils selectivity of camptothecin†\",\"authors\":\"Insa Klemt, Viktor Reshetnikov, Subrata Dutta, Galyna Bila, Rostyslav Bilyy, Itziar Cossío Cuartero, Andrés Hidalgo, Adrian Wünsche, Maximilian Böhm, Marit Wondrak, Leoni A. Kunz-Schughart, Rainer Tietze, Frank Beierlein, Petra Imhof, Sabrina Gensberger-Reigl, Monika Pischetsrieder, Marlies Körber, Tina Jost and Andriy Mokhir\",\"doi\":\"10.1039/D3MD00609C\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >Many known chemotherapeutic anticancer agents exhibit neutropenia as a dose-limiting side effect. In this paper we suggest a prodrug concept solving this problem for camptothecin (HO-cpt). The prodrug is programmed according to Boolean “AND” logic. In the absence of H<small><sub>2</sub></small>O<small><sub>2</sub></small> (trigger T1), <em>e.g.</em> in the majority of normal cells, it exists as an inactive oligomer. In cancer cells and in primed neutrophils (high H<small><sub>2</sub></small>O<small><sub>2</sub></small>), the oligomer is disrupted forming intermediate (inactive) lipophilic cationic species. These are accumulated in mitochondria (Mit) of cancer cells, where they are activated by hydrolysis at mitochondrial pH 8 (trigger T2) with formation of camptothecin. In contrast, the intermediates remain stable in neutrophils lacking Mit and therefore a source of T2. In this paper we demonstrated a proof-of-concept. Our prodrug exhibits antitumor activity both <em>in vitro</em> and <em>in vivo</em>, but is not toxic to normal cell and neutrophils in contrast to known single trigger prodrugs and the parent drug HO-cpt.</p>\",\"PeriodicalId\":88,\"journal\":{\"name\":\"MedChemComm\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":3.5970,\"publicationDate\":\"2024-01-31\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://pubs.rsc.org/en/content/articlepdf/2024/md/d3md00609c?page=search\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"MedChemComm\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://pubs.rsc.org/en/content/articlelanding/2024/md/d3md00609c\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"Pharmacology, Toxicology and Pharmaceutics\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"MedChemComm","FirstCategoryId":"1085","ListUrlMain":"https://pubs.rsc.org/en/content/articlelanding/2024/md/d3md00609c","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"Pharmacology, Toxicology and Pharmaceutics","Score":null,"Total":0}
A concept of dual-responsive prodrugs based on oligomerization-controlled reactivity of ester groups: an improvement of cancer cells versus neutrophils selectivity of camptothecin†
Many known chemotherapeutic anticancer agents exhibit neutropenia as a dose-limiting side effect. In this paper we suggest a prodrug concept solving this problem for camptothecin (HO-cpt). The prodrug is programmed according to Boolean “AND” logic. In the absence of H2O2 (trigger T1), e.g. in the majority of normal cells, it exists as an inactive oligomer. In cancer cells and in primed neutrophils (high H2O2), the oligomer is disrupted forming intermediate (inactive) lipophilic cationic species. These are accumulated in mitochondria (Mit) of cancer cells, where they are activated by hydrolysis at mitochondrial pH 8 (trigger T2) with formation of camptothecin. In contrast, the intermediates remain stable in neutrophils lacking Mit and therefore a source of T2. In this paper we demonstrated a proof-of-concept. Our prodrug exhibits antitumor activity both in vitro and in vivo, but is not toxic to normal cell and neutrophils in contrast to known single trigger prodrugs and the parent drug HO-cpt.
期刊介绍:
Research and review articles in medicinal chemistry and related drug discovery science; the official journal of the European Federation for Medicinal Chemistry.
In 2020, MedChemComm will change its name to RSC Medicinal Chemistry. Issue 12, 2019 will be the last issue as MedChemComm.