title: Optimized synthesis and enhanced efficacy of novel triplex-forming camptothecin derivatives based on gimatecan.
abstract: 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.
authors.affiliation: CNRS UMR, Museum National d'Histoire Naturelle USM, INSERM, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Vekhoff
authors.forename: Ludovic
authors.initials: L
authors.lastname: Halby
authors.forename: Kahina
authors.initials: K
authors.lastname: Oussedik
authors.forename: Sabrina
authors.initials: S
authors.lastname: Dallavalle
authors.forename: Lucio
authors.initials: L
authors.lastname: Merlini
authors.forename: Christine
authors.initials: C
authors.lastname: Mahieu
authors.forename: Amélie
authors.initials: A
authors.lastname: Lansiaux
authors.forename: Christian
authors.initials: C
authors.lastname: Bailly
authors.forename: Alexandre
authors.initials: A
authors.lastname: Boutorine
authors.forename: Claudio
authors.initials: C
authors.lastname: Pisano
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Giannini
authors.forename: Domenico
authors.initials: D
authors.lastname: Alloatti
authors.forename: Paola B
authors.initials: PB
authors.lastname: Arimondo
mesh_terms: D002166:Camptothecin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002477:Cells / Q000378:metabolism; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D003851:Deoxyribonucleases / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D010091:Oximes / Q000737:chemistry
chemical_list: D010091:Oximes; C433984:ST 1481; C051802:triplex DNA; D004247:DNA; D003851:Deoxyribonucleases; D002166:Camptothecin