Synthesis, in Vitro Evaluation, and Antileishmanial Activity of Water-Soluble Prodrugs of Buparvaquone

dc.contributorAalto-yliopistofi
dc.contributorAalto Universityen
dc.contributor.authorMäntylä, Anttien_US
dc.contributor.authorGarnier, Tracyen_US
dc.contributor.authorRautio, Jarkkoen_US
dc.contributor.authorNevalainen, Tapioen_US
dc.contributor.authorVepsäläinen, Joukoen_US
dc.contributor.authorKoskinen, Arien_US
dc.contributor.authorCroft, Simon L.en_US
dc.contributor.authorJärvinen, Tomien_US
dc.contributor.departmentDepartment of Chemistryen
dc.date.accessioned2016-09-23T09:20:42Z
dc.date.issued2004en_US
dc.description.abstractWater-soluble phosphate prodrugs of buparvaquone (1), containing a hydroxynaphthoquinone structure, were synthesized and evaluated in vitro for improved topical and oral drug delivery against cutaneous and visceral leishmaniasis. The successfull prodrug synthesis involved a strong base; e.g., sodium hydride. Buparvaquone-3-phosphate (4a) and 3-phosphonooxymethylbuparvaquone (4b) prodrugs possessed significantly higher aqueous solubilities (>3.5 mg/mL) than the parent drug (e0.03 íg/mL) over a pH range of 3.0-7.4. Moreover, 4a and 4b maintained adequate lipophilicity as indicated by distribution coefficients (log D) between 0.5 and 3.0 over this pH range. Both 4a and 4b were also shown to be substrates for alkaline phosphatase in vitro and thus are promising bioreversible prodrugs for the improved topical and oral bioavailability of 1. Buparvaquone and its prodrugs showed nanomolar or lowmicromolar ED50 activity values against species that cause cutaneous leishmaniasis, e.g., L. major, L. amazonensis, L. aethiopica, L. mexicana, and L. panamensis and also L. donovani, which is the causative agent of visceral leishmaniasis. From these results, the human skin permeation of the prodrugs 4a and 4b were studied in vitro. While no buparvaquone permeated across post mortem skin in vitro during 72 h of experiments, both prodrugs 4a and 4b permeated readily through the skin. In addition, 4b easily released the parent drug in human skin homogenate and, therefore, is a promising prodrug candidate to deliver buparvaquone through the skin for the treatment of cutaneous leishmaniasis.en
dc.description.versionPeer revieweden
dc.format.extent188-195
dc.format.mimetypeapplication/pdfen_US
dc.identifier.citationMäntylä, A, Garnier, T, Rautio, J, Nevalainen, T, Vepsäläinen, J, Koskinen, A, Croft, S L & Järvinen, T 2004, ' Synthesis, in Vitro Evaluation, and Antileishmanial Activity of Water-Soluble Prodrugs of Buparvaquone ', Journal of Medicinal Chemistry, no. 47, pp. 188-195 . https://doi.org/10.1021/jm030868aen
dc.identifier.doi10.1021/jm030868aen_US
dc.identifier.otherPURE UUID: 0ef7a283-a6be-4cb7-b4d3-5bc5c6b05af5en_US
dc.identifier.otherPURE ITEMURL: https://research.aalto.fi/en/publications/0ef7a283-a6be-4cb7-b4d3-5bc5c6b05af5en_US
dc.identifier.otherPURE FILEURL: https://research.aalto.fi/files/7159586/ms099.pdfen_US
dc.identifier.urihttps://aaltodoc.aalto.fi/handle/123456789/22396
dc.identifier.urnURN:NBN:fi:aalto-201609234399
dc.language.isoenen
dc.relation.ispartofseriesJournal of Medical Chemistryen
dc.relation.ispartofseriesissue 47en
dc.rightsopenAccessen
dc.subject.keywordbuparvaquoneen_US
dc.subject.keywordorganic chemistryen_US
dc.subject.keywordsynthesisen_US
dc.subject.keywordwater-solubleen_US
dc.titleSynthesis, in Vitro Evaluation, and Antileishmanial Activity of Water-Soluble Prodrugs of Buparvaquoneen
dc.typeA1 Alkuperäisartikkeli tieteellisessä aikakauslehdessäfi
dc.type.versionacceptedVersion

Files