Antitumor effects of guanosine-analog phosphonates identified by molecular modelling

作者：Schwanke Anja; Murruzzu Caterina; Zdrazil Barbara; Zuhse Ralf; Natek Maja; Hoeltje Monika; Korting Hans Christian; Reissig Hans Ulrich; Hoeltje Hans Dieter; Schaefer Korting Monika

来源：International Journal of Pharmaceutics, 2010, 397(1-2): 9-18.

DOI：10.1016/j.ijpharm.2010.06.036

• Human DNA polymerase alpha
• Polymerase inhibitors
• Keratinocytes
• Tumor cell lines
• Nucleotide analogs
• Skin cancer

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 alpha (pol alpha) are developed by docking nucleoside phosphonate diphosphates into the active site of pol alpha. 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.

• 出版日期2010-9-15