Sequence-specific camptothecins are useful tools to inhibit specifically gene expression. The camptothecins are attached to the 3' end of triplex-forming oligonucleotides (TFO), sequence-specific DNA ligands that position the camptothecin moiety exclusively in proximity to their binding site. We studied here different gimatecan derivatives or analogues, a potent lipophilic camptothecin compound in clinical trials. We optimized the synthesis procedure in order to increase the yields and the purity and obtain the conjugates on a large scale. The greatly improved synthesis is now based on the conjugation of a bromoalkyl analogue of gimatecan to the 3' phosphorothioate of the TFO. We showed that the most efficient conjugate, both in vitro and in HeLa cells, bears the TFO on position 7 of the gimatecan analogue, and it is more efficient than the previous camptothecin conjugates. In addition, the gimatecan-like moiety at the 3' end of the TFO protects from nuclease degradation.
|Titolo:||Optimized Synthesis and Enhanced Efficacy of Novel Triplex-Forming Camptothecin Derivatives Based on Gimatecan|
|Parole Chiave:||POTENT ANTITUMOR-ACTIVITY ; DNA CLEAVAGE ; TOPOISOMERASE ; OLIGONUCLEOTIDES ; REBECCAMYCIN ; TOPOTECAN ; SEQUENCE ; DESIGN|
|Settore Scientifico Disciplinare:||Settore CHIM/06 - Chimica Organica|
|Data di pubblicazione:||apr-2009|
|Digital Object Identifier (DOI):||10.1021/bc800494y|
|Appare nelle tipologie:||01 - Articolo su periodico|