Influence of the stereoisomeric position of the reactive acetate groups of the benzo[b]acronycine derivative S23906-1 on its DNA alkylation, helix-opening, cytotoxic, and antitumor activities.
S23906-1 is a benzo[b]acronycine derivative acting as a DNA-alkylating agent through covalent bonding to the exocyclic amino group of guanines and subsequent local opening of the DNA helix. This compound was selected for phase I clinical trials based on its efficient antitumor activity in experimental models and its unique mode of action. S23906-1 is the racemate of cis-1,2-diacetoxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo[b]pyrano[3,2-h]acridin-7-one. Here, we evaluated the cytotoxic and antitumor activities of the two pure cis-enantiomers and investigated the mechanism of action of both cis- and trans-racemates and their enantiomers in terms of DNA alkylation potency and locally drug-induced DNA helix opening process. Reaction with glutathione, as a detoxification process, was also studied. The trans-compounds, both as racemate or separated enantiomers, were found less potent than the corresponding cis-derivatives. Among the cis-enantiomers, the most efficient one regarding DNA alkylation bears the acetate on the reactive C1 position in the R configuration, both on purified DNA and genomic DNA extracted from cell cultures. By contrast, the most cytotoxic and tumor-active enantiomer bears the C1-acetate in the S configuration. Distinct cellular DNA-alkylation levels or covalent bonding to glutathione could not explain the differences. However, we showed that the S and R orientations of the acetate on C1 asymmetric carbon lead to different local opening of the DNA, as visualized using nuclease S1 mapping. These different interactions could lead to modulated DNA-repair, protein/DNA interaction, and apoptosis processes.
Depauw
Sabine
S
INSERM-U837, Centre de Recherches Jean-Pierre Aubert (JPARC), Team-4 "Molecular and Cellular Targeting for Cancer Treatment," Institut pour la Recherche sur le Cancer de Lille, Place de Verdun, F-59045 Lille, France.
Gaslonde
Thomas
T
Léonce
Stéphane
S
Kraus-Berthier
Laurence
L
Laine
William
W
Lenglet
Gaëlle
G
Chiaroni
Angèle
A
Pfeiffer
Bruno
B
Bailly
Christian
C
Michel
Sylvie
S
Tillequin
François
F
Pierré
Alain
A
David-Cordonnier
Marie-Hélène
MH
D000175:Acronine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000737:chemistry / Q000494:pharmacology*; D020134:Catalytic Domain; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003603:Cytotoxins / Q000737:chemistry / Q000494:pharmacology*; D018736:DNA Adducts / Q000378:metabolism; D006801:Humans; D007364:Intercalating Agents / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009374:Neoplasms, Experimental / Q000188:drug therapy; D013237:Stereoisomerism
D018906:Antineoplastic Agents, Alkylating; D003603:Cytotoxins; D018736:DNA Adducts; D007364:Intercalating Agents; C436732:S 23906-1; D000175:Acronine