Antitumor effects of guanosine-analog phosphonates identified by molecular modelling

Author(s)
Anja Schwanke, Caterina Murruzzu, Barbara Zdrazil, Ralf Zuhse, Maja Natek, Monika Höltje, Hans Christian Korting, Hans-Ulrich Reißig, Hans-Dieter Höltje, Monika Schäfer-Korting
Abstract

Aiming to address new drug targets, molecular modelling is gaining increasing importance although the prediction capability of the in silico method is still under debate. For an improved treatment of actinic keratosis and squamous cell carcinoma, inhibitors of human DNA polymerase α (pol α) are developed by docking nucleoside phosphonate diphosphates into the active site of pol α. The most promising prodrugs OxBu and OxHex were then prepared by total synthesis and tested in the squamous cancer cell line SCC25. OxBu and OxHex proved cytotoxic and antiproliferative in the nanomolar concentration range and thus exceeded activity of aphidicolin, the relevant model compound, and 5-fluorouracil, the current standard for the therapy of actinic keratosis. Interestingly, the cytotoxicity in normal human keratinocytes with OxHex was clearly less pronounced and even not detectable with OxBu. Moreover, cytotoxicity of OxBu in particular with the colorectal carcinoma cell line HT29 even surmounted cytotoxicity in SCC25, and other tumor cell lines were influenced, too, by both agents. Taken together, OxBu and OxHex may offer a new approach to cancer therapy, given the agents are sufficiently well tolerated in vivo which is to be suspected beside their chemical structure.

Organisation(s)
External organisation(s)
Freie Universität Berlin (FU), Chiracon GmbH, Luckenwalde, Heinrich-Heine-Universität Düsseldorf, Ludwig-Maximilians-Universität München
Journal
International Journal of Pharmaceutics
Volume
397
Pages
9-18
ISSN
0378-5173
DOI
https://doi.org/10.1016/j.ijpharm.2010.06.036
Publication date
09-2010
Peer reviewed
Yes
Austrian Fields of Science 2012
301207 Pharmaceutical chemistry, 301305 Medical chemistry
Portal url
https://ucris.univie.ac.at/portal/en/publications/antitumor-effects-of-guanosineanalog-phosphonates-identified-by-molecular-modelling(6af561a6-67b7-4451-b8b8-d844fc4ff593).html