Optimized synthesis and enhanced efficacy of novel triplex-forming camptothecin derivatives based on gimatecan.
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.
Vekhoff
Pierre
P
CNRS UMR, Museum National d'Histoire Naturelle USM, INSERM, Paris, France.
Halby
Ludovic
L
Oussedik
Kahina
K
Dallavalle
Sabrina
S
Merlini
Lucio
L
Mahieu
Christine
C
Lansiaux
Amélie
A
Bailly
Christian
C
Boutorine
Alexandre
A
Pisano
Claudio
C
Giannini
Giuseppe
G
Alloatti
Domenico
D
Arimondo
Paola B
PB
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
D010091:Oximes; C433984:ST 1481; C051802:triplex DNA; D004247:DNA; D003851:Deoxyribonucleases; D002166:Camptothecin