{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T18:05:51Z","timestamp":1791050751709,"version":"4.1.0"},"reference-count":52,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2012,8,6]],"date-time":"2012-08-06T00:00:00Z","timestamp":1344211200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemMedChem"],"published-print":{"date-parts":[[2012,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>A new type of double prodrug of the antiviral family of bicyclic nucleoside analogues (BCNA) bearing cyclization self\u2010cleavage spacers between the Val\u2010Pro dipeptide sequence as well as the parent compound were synthesized and evaluated with regard to activation by the DPPIV\/CD26 enzyme and for their stability in human and bovine serum. In buffer solution, carbamate and ester prodrugs were found to be chemically stable. Most prodrugs containing a dipeptidyl linker efficiently converted into the BCNA parent drug. In contrast, the Val\u2010Pro alkyldiamino prodrugs converted predominantly into their alkyldiamino prodrug intermediates in the presence of CD26 and human serum. A marked increase in water solubility was observed for all prodrugs. In contrast to the parent compound, a tetrapeptide prodrug containing the Val\u2010Val dipeptide as a self\u2010cleavage spacer released substantial amounts of the BCNA parent drug at the basolateral side of Caco\u20102 cell cultures and exhibited 15\u2010 to 20\u2010fold increased bioavailability in mice relative to the poorly bioavailable parent compound.<\/jats:p>","DOI":"10.1002\/cmdc.201200295","type":"journal-article","created":{"date-parts":[[2012,8,6]],"date-time":"2012-08-06T10:13:33Z","timestamp":1344248013000},"page":"1612-1622","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Dipeptidyl Peptidase IV\u2010Activated Prodrugs of Anti\u2010Varicella Zoster Virus Bicyclic Nucleoside Analogues Containing Different Self\u2010Cleavage Spacer Systems"],"prefix":"10.1002","volume":"7","author":[{"given":"Alberto","family":"Diez\u2010Torrubia","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Cabrera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid","family":"De\u2005Meester","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda\u2010Jos\u00e9","family":"Camarasa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Balzarini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonsoles","family":"Vel\u00e1zquez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2012,8,6]]},"reference":[{"key":"e_1_2_6_1_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.133.3.1250"},{"key":"e_1_2_6_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0167-5699(99)01486-3"},{"key":"e_1_2_6_3_2","doi-asserted-by":"publisher","DOI":"10.1080\/713609354"},{"key":"e_1_2_6_4_2","doi-asserted-by":"publisher","DOI":"10.3109\/10409239309082572"},{"key":"e_1_2_6_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0167-0115(99)00089-0"},{"key":"e_1_2_6_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0074-7696(04)35004-7"},{"key":"e_1_2_6_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2004.02.017"},{"key":"e_1_2_6_8_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm0606490"},{"key":"e_1_2_6_9_2","unstructured":"\u00a0"},{"key":"e_1_2_6_10_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.89.10.4392"},{"key":"e_1_2_6_11_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm00093a002"},{"key":"e_1_2_6_12_2","doi-asserted-by":"publisher","DOI":"10.2174\/1568026043388600"},{"key":"e_1_2_6_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2007.06.009"},{"key":"e_1_2_6_14_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm901590f"},{"key":"e_1_2_6_15_2","unstructured":"\u00a0"},{"key":"e_1_2_6_16_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm101624e"},{"key":"e_1_2_6_17_2","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.201100504"},{"key":"e_1_2_6_18_2","unstructured":"\u00a0"},{"key":"e_1_2_6_19_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm990346o"},{"key":"e_1_2_6_20_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm000210m"},{"key":"e_1_2_6_21_2","unstructured":"\u00a0"},{"key":"e_1_2_6_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0925-4439(02)00091-1"},{"key":"e_1_2_6_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2006.04.001"},{"key":"e_1_2_6_24_2","unstructured":"For reviews of cyclization\u2010activated prodrugs see:"},{"key":"e_1_2_6_25_2","doi-asserted-by":"publisher","DOI":"10.3390\/12112484"},{"key":"e_1_2_6_26_2","volume-title":"Prodrugs: Challenges and Rewards, Part\u20051\u20132","year":"2007"},{"key":"e_1_2_6_27_2","unstructured":"For examples of prodrugs bearing these types of diamine cyclization spacers see:"},{"key":"e_1_2_6_28_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm0009078"},{"key":"e_1_2_6_29_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm00163a016"},{"key":"e_1_2_6_30_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm001033s"},{"key":"e_1_2_6_31_2","unstructured":"Dipeptides have been widely used as drug carriers for cyclization\u2010activated prodrugs; for example see:"},{"key":"e_1_2_6_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2005.01.065"},{"key":"e_1_2_6_33_2","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.200800012"},{"key":"e_1_2_6_34_2","unstructured":"For other examples of dipeptide\u2010based prodrugs see:"},{"key":"e_1_2_6_35_2","doi-asserted-by":"publisher","DOI":"10.1021\/mp800008c"},{"key":"e_1_2_6_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpharm.2006.11.058"},{"key":"e_1_2_6_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpharm.2008.05.024"},{"key":"e_1_2_6_38_2","unstructured":"Two\u2010step prodrugs have also been proposed involving an initial enzymatic step leading to a dipeptide\u2010based prodrug intermediate; for example see:"},{"key":"e_1_2_6_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-894X(02)00433-X"},{"key":"e_1_2_6_40_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm020139f"},{"key":"e_1_2_6_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2007.01.066"},{"key":"e_1_2_6_42_2","unstructured":"\u00a0"},{"key":"e_1_2_6_43_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja972051a"},{"key":"e_1_2_6_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0040-4020(01)86305-5"},{"key":"e_1_2_6_45_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2836(76)80019-8"},{"key":"e_1_2_6_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2008.08.009"},{"key":"e_1_2_6_47_2","unstructured":"\u00a0"},{"key":"e_1_2_6_48_2","doi-asserted-by":"publisher","DOI":"10.1021\/jo01265a071"},{"key":"e_1_2_6_49_2","doi-asserted-by":"publisher","DOI":"10.1002\/jps.2600700510"},{"key":"e_1_2_6_50_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm101356p"},{"key":"e_1_2_6_51_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkm376"},{"key":"e_1_2_6_52_2","doi-asserted-by":"publisher","DOI":"10.1016\/0022-1759(95)00239-1"}],"container-title":["ChemMedChem"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fcmdc.201200295","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cmdc.201200295","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T10:27:39Z","timestamp":1760264859000},"score":1,"resource":{"primary":{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/10.1002\/cmdc.201200295"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,8,6]]},"references-count":52,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2012,9]]}},"alternative-id":["10.1002\/cmdc.201200295"],"URL":"https:\/\/doi.org\/10.1002\/cmdc.201200295","archive":["Portico"],"relation":{},"ISSN":["1860-7179","1860-7187"],"issn-type":[{"value":"1860-7179","type":"print"},{"value":"1860-7187","type":"electronic"}],"subject":[],"published":{"date-parts":[[2012,8,6]]},"assertion":[{"value":"2012-06-13","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2012-08-06","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}