Design, Synthesis, and in Vitro Biological Evaluation of 14-Hydroxytylophorine-dichloroacetate Co-drugs as Antiproliferative Agents
Co-drug, or mutual-prodrug, is a drug design approach consisting of covalently linking two active drugs so as to improve the pharmacokinetics and/or pharmacodynamics properties of one or both drugs. Co-drug strategy has proven good success in overcoming undesirable properties such as absorption, poo...
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| Veröffentlicht in: | Chemical & pharmaceutical bulletin 2019/11/01, Vol.67(11), pp.1208-1210 |
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| creator | Omran, Ziad Alarja, Mohamed Abdalla, Ashraf N. Ibrahim, Munjed M. Hossain, Mohammad A. Chen, Linwei Liu, Yuxiu Wang, Qingmin |
| description | Co-drug, or mutual-prodrug, is a drug design approach consisting of covalently linking two active drugs so as to improve the pharmacokinetics and/or pharmacodynamics properties of one or both drugs. Co-drug strategy has proven good success in overcoming undesirable properties such as absorption, poor bioavailability, nonspecificity, and gastrointestine tract (GIT) side effects. In this work, we successfully developed a co-drug of 14-hydroxytylophorine, a phenanthroindolizidine derivative with remarkable antiproliferative activity, and dichloroacetate, a known inhibitor of pyruvate dehydrogenase kinase. Dichloroacetate steers tumour cell metabolism from glycolysis back to glucose oxidation, which in turn reverses the Warburg effect and renders tumour cells with a proliferative disadvantage. The obtained co-drugs retained the cytotoxicity of 14-hydroxytylophorine. However, they showed similar unselectivity towards normal cells. |
| doi_str_mv | 10.1248/cpb.c19-00520 |
| format | Article |
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Co-drug strategy has proven good success in overcoming undesirable properties such as absorption, poor bioavailability, nonspecificity, and gastrointestine tract (GIT) side effects. In this work, we successfully developed a co-drug of 14-hydroxytylophorine, a phenanthroindolizidine derivative with remarkable antiproliferative activity, and dichloroacetate, a known inhibitor of pyruvate dehydrogenase kinase. Dichloroacetate steers tumour cell metabolism from glycolysis back to glucose oxidation, which in turn reverses the Warburg effect and renders tumour cells with a proliferative disadvantage. The obtained co-drugs retained the cytotoxicity of 14-hydroxytylophorine. However, they showed similar unselectivity towards normal cells.</description><identifier>ISSN: 0009-2363</identifier><identifier>EISSN: 1347-5223</identifier><identifier>DOI: 10.1248/cpb.c19-00520</identifier><identifier>PMID: 31495803</identifier><language>eng</language><publisher>Japan: The Pharmaceutical Society of Japan</publisher><subject>Animals ; Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Antiproliferatives ; Bioavailability ; cancer ; Cell Line ; Cell Proliferation - drug effects ; CHO Cells ; co-drug ; Cricetulus ; Cytotoxicity ; dichloroacetate ; Dichloroacetic acid ; Dose-Response Relationship, Drug ; Drug Design ; Drug development ; Drug Screening Assays, Antitumor ; Drugs ; Enzyme inhibitors ; Glycolysis ; Humans ; Indoles - chemical synthesis ; Indoles - chemistry ; Indoles - pharmacology ; Kinases ; Metabolism ; Molecular Structure ; Oxidation ; Pharmacodynamics ; Pharmacokinetics ; Pharmacology ; Phenanthrenes - chemical synthesis ; Phenanthrenes - chemistry ; Phenanthrenes - pharmacology ; phenanthroindolizidine ; Prodrugs - chemical synthesis ; Prodrugs - chemistry ; Prodrugs - pharmacology ; Pyruvic acid ; Side effects ; Solubility ; Structure-Activity Relationship ; Toxicity ; Tumors</subject><ispartof>Chemical and Pharmaceutical Bulletin, 2019/11/01, Vol.67(11), pp.1208-1210</ispartof><rights>2019 The Pharmaceutical Society of Japan</rights><rights>Copyright Japan Science and Technology Agency 2019</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c703t-6bc025014b5438e2e7935ecb0ae0922f4bf727be772ba6f8199a974e63ced1a43</citedby><cites>FETCH-LOGICAL-c703t-6bc025014b5438e2e7935ecb0ae0922f4bf727be772ba6f8199a974e63ced1a43</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,1877,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31495803$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Omran, Ziad</creatorcontrib><creatorcontrib>Alarja, Mohamed</creatorcontrib><creatorcontrib>Abdalla, Ashraf N.</creatorcontrib><creatorcontrib>Ibrahim, Munjed M.</creatorcontrib><creatorcontrib>Hossain, Mohammad A.</creatorcontrib><creatorcontrib>Chen, Linwei</creatorcontrib><creatorcontrib>Liu, Yuxiu</creatorcontrib><creatorcontrib>Wang, Qingmin</creatorcontrib><creatorcontrib>aCollege of Pharmacy</creatorcontrib><creatorcontrib>Umm Al-Qura University</creatorcontrib><creatorcontrib>College of Chemistry</creatorcontrib><creatorcontrib>bState Key Laboratory of Elemento-Organic Chemistry</creatorcontrib><creatorcontrib>Collaborative Innovation Center of Chemical Science and Engineering (Tianjin</creatorcontrib><creatorcontrib>Nankai University</creatorcontrib><title>Design, Synthesis, and in Vitro Biological Evaluation of 14-Hydroxytylophorine-dichloroacetate Co-drugs as Antiproliferative Agents</title><title>Chemical & pharmaceutical bulletin</title><addtitle>Chem. Pharm. Bull.</addtitle><description>Co-drug, or mutual-prodrug, is a drug design approach consisting of covalently linking two active drugs so as to improve the pharmacokinetics and/or pharmacodynamics properties of one or both drugs. Co-drug strategy has proven good success in overcoming undesirable properties such as absorption, poor bioavailability, nonspecificity, and gastrointestine tract (GIT) side effects. In this work, we successfully developed a co-drug of 14-hydroxytylophorine, a phenanthroindolizidine derivative with remarkable antiproliferative activity, and dichloroacetate, a known inhibitor of pyruvate dehydrogenase kinase. Dichloroacetate steers tumour cell metabolism from glycolysis back to glucose oxidation, which in turn reverses the Warburg effect and renders tumour cells with a proliferative disadvantage. The obtained co-drugs retained the cytotoxicity of 14-hydroxytylophorine. However, they showed similar unselectivity towards normal cells.</description><subject>Animals</subject><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Antiproliferatives</subject><subject>Bioavailability</subject><subject>cancer</subject><subject>Cell Line</subject><subject>Cell Proliferation - drug effects</subject><subject>CHO Cells</subject><subject>co-drug</subject><subject>Cricetulus</subject><subject>Cytotoxicity</subject><subject>dichloroacetate</subject><subject>Dichloroacetic acid</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Design</subject><subject>Drug development</subject><subject>Drug Screening Assays, Antitumor</subject><subject>Drugs</subject><subject>Enzyme inhibitors</subject><subject>Glycolysis</subject><subject>Humans</subject><subject>Indoles - chemical synthesis</subject><subject>Indoles - chemistry</subject><subject>Indoles - pharmacology</subject><subject>Kinases</subject><subject>Metabolism</subject><subject>Molecular Structure</subject><subject>Oxidation</subject><subject>Pharmacodynamics</subject><subject>Pharmacokinetics</subject><subject>Pharmacology</subject><subject>Phenanthrenes - chemical synthesis</subject><subject>Phenanthrenes - chemistry</subject><subject>Phenanthrenes - pharmacology</subject><subject>phenanthroindolizidine</subject><subject>Prodrugs - chemical synthesis</subject><subject>Prodrugs - chemistry</subject><subject>Prodrugs - pharmacology</subject><subject>Pyruvic acid</subject><subject>Side effects</subject><subject>Solubility</subject><subject>Structure-Activity Relationship</subject><subject>Toxicity</subject><subject>Tumors</subject><issn>0009-2363</issn><issn>1347-5223</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdUU1vEzEUtBCIhsCRK7LEhUO3-GN3vT6GtLRIlTjwcbW83reJI8cOtrciZ_44TlJSCcl6z9Ibz4zfIPSWkivK6u6j2fVXhsqKkIaRZ2hGeS2qhjH-HM0IIbJivOUX6FVKG0JYQwR_iS44rWXTET5Df64h2ZW_xN_2Pq_LPV1i7QdsPf5pcwz4kw0urKzRDt88aDfpbIPHYcS0ru72Qwy_93nvwm4dovVQDdasXYhBG8g6A16GaojTKmGd8MJnu4vB2RFioXkAvFiBz-k1ejFql-DNY5-jH59vvi_vqvuvt1-Wi_vKCMJz1fbm8AFa903NO2AgJG_A9EQDkYyNdT8KJnoQgvW6HTsqpZaihpYbGKiu-Rx9OPEWE78mSFltbTLgnPYQpqQY60TDGS9njt7_B92EKfriTjFOKeOS17KgqhPKxJBShFHtot3quFeUqEM6qqSjSjrqmE7Bv3tknfotDGf0vzgK4PYEKNPDyoN3ZalP2iYJs4atVYwcSVtB6aEVMdKVQguHlG17sHZ9YtqkrFdwltIxW-PgaKwVqjwv9ezwabzWUYHnfwHkgLpw</recordid><startdate>20191101</startdate><enddate>20191101</enddate><creator>Omran, Ziad</creator><creator>Alarja, Mohamed</creator><creator>Abdalla, Ashraf N.</creator><creator>Ibrahim, Munjed M.</creator><creator>Hossain, Mohammad A.</creator><creator>Chen, Linwei</creator><creator>Liu, Yuxiu</creator><creator>Wang, Qingmin</creator><general>The Pharmaceutical Society of Japan</general><general>Pharmaceutical Society of Japan</general><general>Japan Science and Technology Agency</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>H94</scope><scope>7X8</scope></search><sort><creationdate>20191101</creationdate><title>Design, Synthesis, and in Vitro Biological Evaluation of 14-Hydroxytylophorine-dichloroacetate Co-drugs as Antiproliferative Agents</title><author>Omran, Ziad ; Alarja, Mohamed ; Abdalla, Ashraf N. ; Ibrahim, Munjed M. ; Hossain, Mohammad A. ; Chen, Linwei ; Liu, Yuxiu ; Wang, Qingmin</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c703t-6bc025014b5438e2e7935ecb0ae0922f4bf727be772ba6f8199a974e63ced1a43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Animals</topic><topic>Antineoplastic Agents - chemical synthesis</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Antiproliferatives</topic><topic>Bioavailability</topic><topic>cancer</topic><topic>Cell Line</topic><topic>Cell Proliferation - drug effects</topic><topic>CHO Cells</topic><topic>co-drug</topic><topic>Cricetulus</topic><topic>Cytotoxicity</topic><topic>dichloroacetate</topic><topic>Dichloroacetic acid</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Design</topic><topic>Drug development</topic><topic>Drug Screening Assays, Antitumor</topic><topic>Drugs</topic><topic>Enzyme inhibitors</topic><topic>Glycolysis</topic><topic>Humans</topic><topic>Indoles - chemical synthesis</topic><topic>Indoles - chemistry</topic><topic>Indoles - pharmacology</topic><topic>Kinases</topic><topic>Metabolism</topic><topic>Molecular Structure</topic><topic>Oxidation</topic><topic>Pharmacodynamics</topic><topic>Pharmacokinetics</topic><topic>Pharmacology</topic><topic>Phenanthrenes - chemical synthesis</topic><topic>Phenanthrenes - chemistry</topic><topic>Phenanthrenes - pharmacology</topic><topic>phenanthroindolizidine</topic><topic>Prodrugs - chemical synthesis</topic><topic>Prodrugs - chemistry</topic><topic>Prodrugs - pharmacology</topic><topic>Pyruvic acid</topic><topic>Side effects</topic><topic>Solubility</topic><topic>Structure-Activity Relationship</topic><topic>Toxicity</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Omran, Ziad</creatorcontrib><creatorcontrib>Alarja, Mohamed</creatorcontrib><creatorcontrib>Abdalla, Ashraf N.</creatorcontrib><creatorcontrib>Ibrahim, Munjed M.</creatorcontrib><creatorcontrib>Hossain, Mohammad A.</creatorcontrib><creatorcontrib>Chen, Linwei</creatorcontrib><creatorcontrib>Liu, Yuxiu</creatorcontrib><creatorcontrib>Wang, Qingmin</creatorcontrib><creatorcontrib>aCollege of Pharmacy</creatorcontrib><creatorcontrib>Umm Al-Qura University</creatorcontrib><creatorcontrib>College of Chemistry</creatorcontrib><creatorcontrib>bState Key Laboratory of Elemento-Organic Chemistry</creatorcontrib><creatorcontrib>Collaborative Innovation Center of Chemical Science and Engineering (Tianjin</creatorcontrib><creatorcontrib>Nankai University</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Chemical & pharmaceutical bulletin</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Omran, Ziad</au><au>Alarja, Mohamed</au><au>Abdalla, Ashraf N.</au><au>Ibrahim, Munjed M.</au><au>Hossain, Mohammad A.</au><au>Chen, Linwei</au><au>Liu, Yuxiu</au><au>Wang, Qingmin</au><aucorp>aCollege of Pharmacy</aucorp><aucorp>Umm Al-Qura University</aucorp><aucorp>College of Chemistry</aucorp><aucorp>bState Key Laboratory of Elemento-Organic Chemistry</aucorp><aucorp>Collaborative Innovation Center of Chemical Science and Engineering (Tianjin</aucorp><aucorp>Nankai University</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Design, Synthesis, and in Vitro Biological Evaluation of 14-Hydroxytylophorine-dichloroacetate Co-drugs as Antiproliferative Agents</atitle><jtitle>Chemical & pharmaceutical bulletin</jtitle><addtitle>Chem. Pharm. Bull.</addtitle><date>2019-11-01</date><risdate>2019</risdate><volume>67</volume><issue>11</issue><spage>1208</spage><epage>1210</epage><pages>1208-1210</pages><issn>0009-2363</issn><eissn>1347-5223</eissn><abstract>Co-drug, or mutual-prodrug, is a drug design approach consisting of covalently linking two active drugs so as to improve the pharmacokinetics and/or pharmacodynamics properties of one or both drugs. Co-drug strategy has proven good success in overcoming undesirable properties such as absorption, poor bioavailability, nonspecificity, and gastrointestine tract (GIT) side effects. In this work, we successfully developed a co-drug of 14-hydroxytylophorine, a phenanthroindolizidine derivative with remarkable antiproliferative activity, and dichloroacetate, a known inhibitor of pyruvate dehydrogenase kinase. Dichloroacetate steers tumour cell metabolism from glycolysis back to glucose oxidation, which in turn reverses the Warburg effect and renders tumour cells with a proliferative disadvantage. The obtained co-drugs retained the cytotoxicity of 14-hydroxytylophorine. However, they showed similar unselectivity towards normal cells.</abstract><cop>Japan</cop><pub>The Pharmaceutical Society of Japan</pub><pmid>31495803</pmid><doi>10.1248/cpb.c19-00520</doi><tpages>3</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Antiproliferatives Bioavailability cancer Cell Line Cell Proliferation - drug effects CHO Cells co-drug Cricetulus Cytotoxicity dichloroacetate Dichloroacetic acid Dose-Response Relationship, Drug Drug Design Drug development Drug Screening Assays, Antitumor Drugs Enzyme inhibitors Glycolysis Humans Indoles - chemical synthesis Indoles - chemistry Indoles - pharmacology Kinases Metabolism Molecular Structure Oxidation Pharmacodynamics Pharmacokinetics Pharmacology Phenanthrenes - chemical synthesis Phenanthrenes - chemistry Phenanthrenes - pharmacology phenanthroindolizidine Prodrugs - chemical synthesis Prodrugs - chemistry Prodrugs - pharmacology Pyruvic acid Side effects Solubility Structure-Activity Relationship Toxicity Tumors |
| title | Design, Synthesis, and in Vitro Biological Evaluation of 14-Hydroxytylophorine-dichloroacetate Co-drugs as Antiproliferative Agents |
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