Prodrugs of Pyrazolo[3,4‑d]pyrimidines: From Library Synthesis to Evaluation as Potential Anticancer Agents in an Orthotopic Glioblastoma Model
Pyrazolo[3,4-d]pyrimidines are potent protein kinase inhibitors with promising antitumor activity but suboptimal aqueous solubility, consequently worth being further optimized. Herein, we present the one-pot two-step procedure for the synthesis of a set of pyrazolo[3,4-d]pyrimidine prodrugs (1a−...
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| Veröffentlicht in: | Journal of medicinal chemistry 2017-07, Vol.60 (14), p.6305-6320 |
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| creator | Vignaroli, Giulia Iovenitti, Giulia Zamperini, Claudio Coniglio, Federica Calandro, Pierpaolo Molinari, Alessio Fallacara, Anna Lucia Sartucci, Andrea Calgani, Alessia Colecchia, David Mancini, Andrea Festuccia, Claudio Dreassi, Elena Valoti, Massimo Musumeci, Francesca Chiariello, Mario Angelucci, Adriano Botta, Maurizio Schenone, Silvia |
| description | Pyrazolo[3,4-d]pyrimidines are potent protein kinase inhibitors with promising antitumor activity but suboptimal aqueous solubility, consequently worth being further optimized. Herein, we present the one-pot two-step procedure for the synthesis of a set of pyrazolo[3,4-d]pyrimidine prodrugs (1a−8a and 9a−e) with higher aqueous solubility and enhanced pharmacokinetic and therapeutic properties. ADME studies demonstrated for the most promising prodrugs a better aqueous solubility, a favorable hydrolysis in human and murine serum, and an increased ability to cross cell membranes with respect to the parental drugs, explaining their better 24 h in vitro cytotoxicity against human glioblastoma U87 cell line. Finally, the 4–4a couple of drug/prodrug was also evaluated in vivo, revealing a profitable pharmacokinetic profile of the prodrug associated with a good efficacy. The application of the prodrug approach demonstrated to be a successful strategy for improving aqueous solubility of the parental drugs, determining a positive impact also in their biological efficacy. |
| doi_str_mv | 10.1021/acs.jmedchem.7b00637 |
| format | Article |
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Herein, we present the one-pot two-step procedure for the synthesis of a set of pyrazolo[3,4-d]pyrimidine prodrugs (1a−8a and 9a−e) with higher aqueous solubility and enhanced pharmacokinetic and therapeutic properties. ADME studies demonstrated for the most promising prodrugs a better aqueous solubility, a favorable hydrolysis in human and murine serum, and an increased ability to cross cell membranes with respect to the parental drugs, explaining their better 24 h in vitro cytotoxicity against human glioblastoma U87 cell line. Finally, the 4–4a couple of drug/prodrug was also evaluated in vivo, revealing a profitable pharmacokinetic profile of the prodrug associated with a good efficacy. The application of the prodrug approach demonstrated to be a successful strategy for improving aqueous solubility of the parental drugs, determining a positive impact also in their biological efficacy.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.7b00637</identifier><identifier>PMID: 28650650</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Animals ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacokinetics ; Antineoplastic Agents - pharmacology ; Blood-Brain Barrier - metabolism ; Brain Neoplasms - drug therapy ; Cell Line, Tumor ; Drug Screening Assays, Antitumor ; Glioblastoma - drug therapy ; Humans ; Male ; Membranes, Artificial ; Mice, Inbred C57BL ; Mice, Nude ; Microsomes, Liver - metabolism ; Prodrugs - chemical synthesis ; Prodrugs - chemistry ; Prodrugs - pharmacology ; Protein Kinase Inhibitors - chemistry ; Protein Kinase Inhibitors - pharmacokinetics ; Protein Kinase Inhibitors - pharmacology ; Pyrazoles - chemical synthesis ; Pyrazoles - chemistry ; Pyrazoles - pharmacokinetics ; Pyrazoles - pharmacology ; Pyrimidines - chemical synthesis ; Pyrimidines - chemistry ; Pyrimidines - pharmacokinetics ; Pyrimidines - pharmacology ; Small Molecule Libraries - chemical synthesis ; Small Molecule Libraries - chemistry ; Small Molecule Libraries - pharmacology ; Solubility ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 2017-07, Vol.60 (14), p.6305-6320</ispartof><rights>Copyright © 2017 American Chemical Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a394t-a674affa113e1daeace15c0a61eb4d5c57ee949a1cb162bf7be2632f19f2dd7d3</citedby><cites>FETCH-LOGICAL-a394t-a674affa113e1daeace15c0a61eb4d5c57ee949a1cb162bf7be2632f19f2dd7d3</cites><orcidid>0000-0001-8987-940X ; 0000-0001-8434-5177 ; 0000-0003-0456-6995</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.7b00637$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.jmedchem.7b00637$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,780,784,2765,27076,27924,27925,56738,56788</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28650650$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Vignaroli, Giulia</creatorcontrib><creatorcontrib>Iovenitti, Giulia</creatorcontrib><creatorcontrib>Zamperini, Claudio</creatorcontrib><creatorcontrib>Coniglio, Federica</creatorcontrib><creatorcontrib>Calandro, Pierpaolo</creatorcontrib><creatorcontrib>Molinari, Alessio</creatorcontrib><creatorcontrib>Fallacara, Anna Lucia</creatorcontrib><creatorcontrib>Sartucci, Andrea</creatorcontrib><creatorcontrib>Calgani, Alessia</creatorcontrib><creatorcontrib>Colecchia, David</creatorcontrib><creatorcontrib>Mancini, Andrea</creatorcontrib><creatorcontrib>Festuccia, Claudio</creatorcontrib><creatorcontrib>Dreassi, Elena</creatorcontrib><creatorcontrib>Valoti, Massimo</creatorcontrib><creatorcontrib>Musumeci, Francesca</creatorcontrib><creatorcontrib>Chiariello, Mario</creatorcontrib><creatorcontrib>Angelucci, Adriano</creatorcontrib><creatorcontrib>Botta, Maurizio</creatorcontrib><creatorcontrib>Schenone, Silvia</creatorcontrib><title>Prodrugs of Pyrazolo[3,4‑d]pyrimidines: From Library Synthesis to Evaluation as Potential Anticancer Agents in an Orthotopic Glioblastoma Model</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Pyrazolo[3,4-d]pyrimidines are potent protein kinase inhibitors with promising antitumor activity but suboptimal aqueous solubility, consequently worth being further optimized. Herein, we present the one-pot two-step procedure for the synthesis of a set of pyrazolo[3,4-d]pyrimidine prodrugs (1a−8a and 9a−e) with higher aqueous solubility and enhanced pharmacokinetic and therapeutic properties. ADME studies demonstrated for the most promising prodrugs a better aqueous solubility, a favorable hydrolysis in human and murine serum, and an increased ability to cross cell membranes with respect to the parental drugs, explaining their better 24 h in vitro cytotoxicity against human glioblastoma U87 cell line. Finally, the 4–4a couple of drug/prodrug was also evaluated in vivo, revealing a profitable pharmacokinetic profile of the prodrug associated with a good efficacy. The application of the prodrug approach demonstrated to be a successful strategy for improving aqueous solubility of the parental drugs, determining a positive impact also in their biological efficacy.</description><subject>Animals</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacokinetics</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Blood-Brain Barrier - metabolism</subject><subject>Brain Neoplasms - drug therapy</subject><subject>Cell Line, Tumor</subject><subject>Drug Screening Assays, Antitumor</subject><subject>Glioblastoma - drug therapy</subject><subject>Humans</subject><subject>Male</subject><subject>Membranes, Artificial</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Nude</subject><subject>Microsomes, Liver - metabolism</subject><subject>Prodrugs - chemical synthesis</subject><subject>Prodrugs - chemistry</subject><subject>Prodrugs - pharmacology</subject><subject>Protein Kinase Inhibitors - chemistry</subject><subject>Protein Kinase Inhibitors - pharmacokinetics</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Pyrazoles - chemical synthesis</subject><subject>Pyrazoles - chemistry</subject><subject>Pyrazoles - pharmacokinetics</subject><subject>Pyrazoles - pharmacology</subject><subject>Pyrimidines - chemical synthesis</subject><subject>Pyrimidines - chemistry</subject><subject>Pyrimidines - pharmacokinetics</subject><subject>Pyrimidines - pharmacology</subject><subject>Small Molecule Libraries - chemical synthesis</subject><subject>Small Molecule Libraries - chemistry</subject><subject>Small Molecule Libraries - pharmacology</subject><subject>Solubility</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kc9q3DAQxkVJaLZp36AUHXOoN_pnO85tCUla2JKFtqdSzFgaZxVkayPJhe2pr5BXzJNU6W5yLAwMjH7fDPo-Qt5zNudM8FPQcX43oNFrHOZ1x1gl61dkxkvBCnXG1AGZMSZEISohj8ibGO8YY5IL-ZocibOqZLlm5GEVvAnTbaS-p6ttgN_e-R_yo3r882B-brbBDtbYEeM5vQp-oEvbBQhb-nU7pjVGG2ny9PIXuAmS9SOFSFc-4ZgsOLrITcOoMdDFbZ5FajMx0puQ1j75jdX02lnfOYjJD0C_eIPuLTnswUV8t-_H5PvV5beLT8Xy5vrzxWJZgGxUKqCqFfQ9cC6RG0DQyEvNoOLYKVPqskZsVANcd7wSXV93KCopet70wpjayGNystu7Cf5-wpjawUaNzsGIfootb7h68qnmGVU7VAcfY8C-3WRfsg0tZ-1TGG0Oo30Oo92HkWUf9hemLr-9iJ7dzwDbAf_kfgpj_vD_d_4FBs-eCg</recordid><startdate>20170727</startdate><enddate>20170727</enddate><creator>Vignaroli, Giulia</creator><creator>Iovenitti, Giulia</creator><creator>Zamperini, Claudio</creator><creator>Coniglio, Federica</creator><creator>Calandro, Pierpaolo</creator><creator>Molinari, Alessio</creator><creator>Fallacara, Anna Lucia</creator><creator>Sartucci, Andrea</creator><creator>Calgani, Alessia</creator><creator>Colecchia, David</creator><creator>Mancini, Andrea</creator><creator>Festuccia, Claudio</creator><creator>Dreassi, Elena</creator><creator>Valoti, Massimo</creator><creator>Musumeci, Francesca</creator><creator>Chiariello, Mario</creator><creator>Angelucci, Adriano</creator><creator>Botta, Maurizio</creator><creator>Schenone, Silvia</creator><general>American Chemical Society</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>7X8</scope><orcidid>https://orcid.org/0000-0001-8987-940X</orcidid><orcidid>https://orcid.org/0000-0001-8434-5177</orcidid><orcidid>https://orcid.org/0000-0003-0456-6995</orcidid></search><sort><creationdate>20170727</creationdate><title>Prodrugs of Pyrazolo[3,4‑d]pyrimidines: From Library Synthesis to Evaluation as Potential Anticancer Agents in an Orthotopic Glioblastoma Model</title><author>Vignaroli, Giulia ; Iovenitti, Giulia ; Zamperini, Claudio ; Coniglio, Federica ; Calandro, Pierpaolo ; Molinari, Alessio ; Fallacara, Anna Lucia ; Sartucci, Andrea ; Calgani, Alessia ; Colecchia, David ; Mancini, Andrea ; Festuccia, Claudio ; Dreassi, Elena ; Valoti, Massimo ; Musumeci, Francesca ; Chiariello, Mario ; Angelucci, Adriano ; Botta, Maurizio ; Schenone, Silvia</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a394t-a674affa113e1daeace15c0a61eb4d5c57ee949a1cb162bf7be2632f19f2dd7d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Animals</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacokinetics</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Blood-Brain Barrier - metabolism</topic><topic>Brain Neoplasms - drug therapy</topic><topic>Cell Line, Tumor</topic><topic>Drug Screening Assays, Antitumor</topic><topic>Glioblastoma - drug therapy</topic><topic>Humans</topic><topic>Male</topic><topic>Membranes, Artificial</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Nude</topic><topic>Microsomes, Liver - metabolism</topic><topic>Prodrugs - chemical synthesis</topic><topic>Prodrugs - chemistry</topic><topic>Prodrugs - pharmacology</topic><topic>Protein Kinase Inhibitors - chemistry</topic><topic>Protein Kinase Inhibitors - pharmacokinetics</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Pyrazoles - chemical synthesis</topic><topic>Pyrazoles - chemistry</topic><topic>Pyrazoles - pharmacokinetics</topic><topic>Pyrazoles - pharmacology</topic><topic>Pyrimidines - chemical synthesis</topic><topic>Pyrimidines - chemistry</topic><topic>Pyrimidines - pharmacokinetics</topic><topic>Pyrimidines - pharmacology</topic><topic>Small Molecule Libraries - chemical synthesis</topic><topic>Small Molecule Libraries - chemistry</topic><topic>Small Molecule Libraries - pharmacology</topic><topic>Solubility</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Vignaroli, Giulia</creatorcontrib><creatorcontrib>Iovenitti, Giulia</creatorcontrib><creatorcontrib>Zamperini, Claudio</creatorcontrib><creatorcontrib>Coniglio, Federica</creatorcontrib><creatorcontrib>Calandro, Pierpaolo</creatorcontrib><creatorcontrib>Molinari, Alessio</creatorcontrib><creatorcontrib>Fallacara, Anna Lucia</creatorcontrib><creatorcontrib>Sartucci, Andrea</creatorcontrib><creatorcontrib>Calgani, Alessia</creatorcontrib><creatorcontrib>Colecchia, David</creatorcontrib><creatorcontrib>Mancini, Andrea</creatorcontrib><creatorcontrib>Festuccia, Claudio</creatorcontrib><creatorcontrib>Dreassi, Elena</creatorcontrib><creatorcontrib>Valoti, Massimo</creatorcontrib><creatorcontrib>Musumeci, Francesca</creatorcontrib><creatorcontrib>Chiariello, Mario</creatorcontrib><creatorcontrib>Angelucci, Adriano</creatorcontrib><creatorcontrib>Botta, Maurizio</creatorcontrib><creatorcontrib>Schenone, Silvia</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Vignaroli, Giulia</au><au>Iovenitti, Giulia</au><au>Zamperini, Claudio</au><au>Coniglio, Federica</au><au>Calandro, Pierpaolo</au><au>Molinari, Alessio</au><au>Fallacara, Anna Lucia</au><au>Sartucci, Andrea</au><au>Calgani, Alessia</au><au>Colecchia, David</au><au>Mancini, Andrea</au><au>Festuccia, Claudio</au><au>Dreassi, Elena</au><au>Valoti, Massimo</au><au>Musumeci, Francesca</au><au>Chiariello, Mario</au><au>Angelucci, Adriano</au><au>Botta, Maurizio</au><au>Schenone, Silvia</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Prodrugs of Pyrazolo[3,4‑d]pyrimidines: From Library Synthesis to Evaluation as Potential Anticancer Agents in an Orthotopic Glioblastoma Model</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2017-07-27</date><risdate>2017</risdate><volume>60</volume><issue>14</issue><spage>6305</spage><epage>6320</epage><pages>6305-6320</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>Pyrazolo[3,4-d]pyrimidines are potent protein kinase inhibitors with promising antitumor activity but suboptimal aqueous solubility, consequently worth being further optimized. Herein, we present the one-pot two-step procedure for the synthesis of a set of pyrazolo[3,4-d]pyrimidine prodrugs (1a−8a and 9a−e) with higher aqueous solubility and enhanced pharmacokinetic and therapeutic properties. ADME studies demonstrated for the most promising prodrugs a better aqueous solubility, a favorable hydrolysis in human and murine serum, and an increased ability to cross cell membranes with respect to the parental drugs, explaining their better 24 h in vitro cytotoxicity against human glioblastoma U87 cell line. Finally, the 4–4a couple of drug/prodrug was also evaluated in vivo, revealing a profitable pharmacokinetic profile of the prodrug associated with a good efficacy. The application of the prodrug approach demonstrated to be a successful strategy for improving aqueous solubility of the parental drugs, determining a positive impact also in their biological efficacy.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>28650650</pmid><doi>10.1021/acs.jmedchem.7b00637</doi><tpages>16</tpages><orcidid>https://orcid.org/0000-0001-8987-940X</orcidid><orcidid>https://orcid.org/0000-0001-8434-5177</orcidid><orcidid>https://orcid.org/0000-0003-0456-6995</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Journal of medicinal chemistry, 2017-07, Vol.60 (14), p.6305-6320 |
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| source | MEDLINE; American Chemical Society Journals |
| subjects | Animals Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacokinetics Antineoplastic Agents - pharmacology Blood-Brain Barrier - metabolism Brain Neoplasms - drug therapy Cell Line, Tumor Drug Screening Assays, Antitumor Glioblastoma - drug therapy Humans Male Membranes, Artificial Mice, Inbred C57BL Mice, Nude Microsomes, Liver - metabolism Prodrugs - chemical synthesis Prodrugs - chemistry Prodrugs - pharmacology Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacokinetics Protein Kinase Inhibitors - pharmacology Pyrazoles - chemical synthesis Pyrazoles - chemistry Pyrazoles - pharmacokinetics Pyrazoles - pharmacology Pyrimidines - chemical synthesis Pyrimidines - chemistry Pyrimidines - pharmacokinetics Pyrimidines - pharmacology Small Molecule Libraries - chemical synthesis Small Molecule Libraries - chemistry Small Molecule Libraries - pharmacology Solubility Structure-Activity Relationship |
| title | Prodrugs of Pyrazolo[3,4‑d]pyrimidines: From Library Synthesis to Evaluation as Potential Anticancer Agents in an Orthotopic Glioblastoma Model |
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