A transesterification reaction is implicated in the covalent binding of benzo[b]acronycine anticancer agents with DNA and glutathion

David-Cordonnier, Marie-Hélène; Laine, William; Kouach, Mostafa; Briand, Gilbert; Vezin, Hervé; Gaslonde, Thomas; Michel, Sylvie; Thi, Huong Doan; Tillequin, François; Koch, Michel; Léonce, Stéphane; Pierre, Alain St.; Bailly, Christian

doi:10.1016/j.bmc.2003.10.056

Cited by 23 publications

(19 citation statements)

References 30 publications

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“…A similar correlation could be established for peaks c1 and d1 and peaks c2 and d2 corresponding to the (1S,2S) or (1R,2S) and either (1S,2R) or (1R,2R) enantiomers in the series bearing a C2-OH group. These data evidence the racemization of the adduct formed after the release of the reactive C1-acetate to form the reactive carbocation intermediate, as previously hypothesized (David-Cordonnier et al, 2002, 2004b. Because both cis-enantiomers react with GSH in a similar manner and give similar orientation of GSH toward the core acronycine (the sole difference being the orientation of the acetate or -OH group), we looked at inhibition of the DNA alkylation efficiency with increasing concentrations of each of the cis-enantiomers in the presence of a fixed concentration of GSH.…”

Section: Resultssupporting

confidence: 83%

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

Depauw¹,

Gaslonde²,

Léonce³

et al. 2009

Molecular Pharmacology

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S23906-1 is a benzo [b]acronycine derivative acting as a DNAalkylating 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 cisenantiomers 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.The stereoisomeric position of functional groups in bioactive molecules has been known for more than 100 years to exert an impact on the reactivity of biologically relevant compounds, including drugs. The presence of an asymmetric center in a drug requires specific studies to assess the potency of each isomer. Several cases can be encountered. 1) Both enantiomers display similar activities (qualitative and quantitative), fully justifying the clinical use of a racemate, exemplified by flecainide and fluoxetine (antiarrhythmic and antidepressant drugs, respectively) (Kroemer et al., 1989;Magyar et al., 2003). 2) The enantiomers have similar pharmacological effects but different concentration-response efficiencies, such as S-(Ϫ)-warfarin 3-to 5-fold more potent as an

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Section: Resultssupporting

confidence: 83%

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

Depauw¹,

Gaslonde²,

Léonce³

et al. 2009

Molecular Pharmacology

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“…Both distamycin derivatives and CC-1065 target guanines or adenines through covalent bonding at the N3 position and subsequently bend the DNA axis in a manner that is associated with local stabilization of the double-stranded DNA helix [ 25 ]. Both ET-743, SJG-136 and S23906-1 covalently bond DNA at the exocyclic amino-group of guanines localized in the minor groove [ 23 , 24 , 26 , 27 , 28 , 29 ]. However, those NH 2 adducts differ on the global 3D structure of the DNA helix: ET-743 and SJG-136 stabilize the DNA helix [ 23 , 30 ], whereas S23906 destabilizes the hydrogen bonds between the two DNA strands [ 30 ].…”

Section: Introductionmentioning

confidence: 99%

Protein Recognition in Drug-Induced DNA Alkylation: When the Moonlight Protein GAPDH Meets S23906-1/DNA Minor Groove Adducts

Savreux-Lenglet

Depauw

David-Cordonnier

2015

IJMS

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DNA alkylating drugs have been used in clinics for more than seventy years. The diversity of their mechanism of action (major/minor groove; mono-/bis-alkylation; intra-/inter-strand crosslinks; DNA stabilization/destabilization, etc.) has undoubtedly major consequences on the cellular response to treatment. The aim of this review is to highlight the variety of established protein recognition of DNA adducts to then particularly focus on glyceraldehyde-3-phosphate dehydrogenase (GAPDH) function in DNA adduct interaction with illustration using original experiments performed with S23906-1/DNA adduct. The introduction of this review is a state of the art of protein/DNA adducts recognition, depending on the major or minor groove orientation of the DNA bonding as well as on the molecular consequences in terms of double-stranded DNA maintenance. It reviews the implication of proteins from both DNA repair, transcription, replication and chromatin maintenance in selective DNA adduct recognition. The main section of the manuscript is focusing on the implication of the moonlighting protein GAPDH in DNA adduct recognition with the model of the peculiar DNA minor groove alkylating and destabilizing drug S23906-1. The mechanism of action of S23906-1 alkylating drug and the large variety of GAPDH cellular functions are presented prior to focus on GAPDH direct binding to S23906-1 adducts.

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“…[10][11][12] This mechanism is related to that implied in the cytotoxic and antitumor properties of the natural furanoxanthone psorospermine (5), isolated from Psorospermum febrifugum. [13][14][15] Actually, psorospermine has been shown to interact with DNA and to alkylate the N-7 of the guanine residues.…”

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confidence: 85%

Synthesis and Cytotoxic Activity of Benzo[a]pyrano[3,2-h] and [2,3-i]xanthone Analogues of Psorospermine, Acronycine, and Benzo[a]acronycine

Sittisombut¹,

Boutefnouchet²,

Van-Dufat³

et al. 2006

CHEMICAL & PHARMACEUTICAL BULLETIN

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A transesterification reaction is implicated in the covalent binding of benzo[b]acronycine anticancer agents with DNA and glutathion

Cited by 23 publications

References 30 publications

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

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

Protein Recognition in Drug-Induced DNA Alkylation: When the Moonlight Protein GAPDH Meets S23906-1/DNA Minor Groove Adducts

Synthesis and Cytotoxic Activity of Benzo[a]pyrano[3,2-h] and [2,3-i]xanthone Analogues of Psorospermine, Acronycine, and Benzo[a]acronycine

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