title: Human polymerase alpha inhibitors for skin tumors. Part 2. Modeling, synthesis and influence on normal and transformed keratinocytes of new thymidine and purine derivatives.
abstract: Recently, the three-dimensional structure of the active site of human DNA polymerase alpha (pol alpha) was proposed based on the application of molecular modeling methods and molecular dynamic simulations. The modeled structure of the enzyme was used for docking selective inhibitors (nucleotide analogs and the non-nucleoside inhibitor aphidicolin) in its active site in order to design new drugs for actinic keratosis and squamous cell carcinoma (SCC). The resulting complexes explained the geometrical and physicochemical interactions of the inhibitors with the amino acid residues involved in binding to the catalytic site, and offered insight into the experimentally derived binding data. The proposed structures were synthesized and tested in vitro for their influence on human keratinocytes and relevant tumor cell lines. Effects were compared to aphidicolin which inhibits pol alpha in a non-competitive manner, as well as to diclofenac and 5-fluorouracil, both approved for therapy of actinic keratosis. Here we describe three new nucleoside analogs inhibiting keratinocyte proliferation by inhibiting DNA synthesis and inducing apoptosis and necrosis. Thus, the combination of modeling studies and in vitro tests should allow the derivation of new drug candidates for the therapy of skin tumors, given that the agents are not relevant substrates of nucleotide transporters expressed by skin cancer cells. Kinases for nucleoside activation were detected, too, corresponding with the observed effects of nucleoside analogs.
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie, Heinrich Heine-Universität Düsseldorf, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Höltje
authors.forename: Anja
authors.initials: A
authors.lastname: Richartz
authors.forename: Barbara
authors.initials: B
authors.lastname: Zdrazil
authors.forename: Anja
authors.initials: A
authors.lastname: Schwanke
authors.forename: Branislav
authors.initials: B
authors.lastname: Dugovic
authors.forename: Caterina
authors.initials: C
authors.lastname: Murruzzu
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Reissig
authors.forename: Hans Christian
authors.initials: HC
authors.lastname: Korting
authors.forename: Burkhard
authors.initials: B
authors.lastname: Kleuser
authors.forename: Hans-Dieter
authors.initials: HD
authors.lastname: Höltje
authors.forename: Monika
authors.initials: M
authors.lastname: Schäfer-Korting
mesh_terms: D016590:Aphidicolin / Q000737:chemistry; D017209:Apoptosis / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000201:enzymology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004256:DNA Polymerase I / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes; D055623:Keratosis, Actinic / Q000188:drug therapy* / Q000201:enzymology; D008956:Models, Chemical; D008958:Models, Molecular; D009336:Necrosis; D019384:Nucleic Acid Synthesis Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D033704:Nucleotide Transport Proteins / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D011687:Purines / Q000737:chemistry; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D013936:Thymidine / Q000737:chemistry
chemical_list: D019384:Nucleic Acid Synthesis Inhibitors; D033704:Nucleotide Transport Proteins; D011687:Purines; D016590:Aphidicolin; D004256:DNA Polymerase I; D013936:Thymidine; C030985:purine