In vitro cytotoxicity of S16020-2, a new olivacine derivative

The E-ring lactone is the Achilles' heel of camptothecin derivatives: although it is considered necessary for the inhibition of the enzyme topoisomerase I (topo1), the opening of the lactone into a carboxylate abolishes the generation of topo1-mediated DNA breaks. S38809 is a novel camptothecin analog with a stable 5-membered E-ring ketone; therefore, it lacks the lactone function. DNA relaxation and cleavage assays revealed that S38809 functions as a typical topo1 poison by stimulating DNA cleavage at T2G sites. The activity was strongly dependent on the stereochemistry of the C-7 carbon atom that bears the hydroxy group. S38809 proved to be a potent cytotoxic agent, with a mean IC 50 of 5.4 nM versus 11.6 nM for topotecan and 3.3 nM for SN38 (the active metabolite of irinotecan) on a panel of 31 human tumor cell lines. The cytotoxicity of S38809 and its ability to stabilize cleavable complexes was considerably reduced in camptothecin-resistant cells that express a mutated topo1, confirming that topo1 is its primary target. Cell death induced by topo1 poisoning requires the conversion of DNA single-strand breaks into double-strand breaks that can be detected by the formation of phosphorylated histone H2AX. In HCT116 cells, topotecan, SN38, and S38809 induced histone H2AX phosphorylation in S phase of the cell cycle, with S38809 being as potent as SN38 and 5-fold more potent than topotecan. In vivo, S38809 showed a marked antitumor activity against HCT116 xenografts. These findings open a new route for improving the pharmacological properties of camptothecin derivatives.

show abstract

“…This assay has been described previously (Léonce et al, 1996). Adherent cells were seeded in 96-well microplates and incubated for 2 days.…”

Section: Methodsmentioning

confidence: 99%

Novel Stable Camptothecin Derivatives Replacing the E-Ring Lactone by a Ketone Function Are Potent Inhibitors of Topoisomerase I and Promising Antitumor Drugs

et al. 2007

View full text Add to dashboard Cite

show abstract

“…Cell proliferation was measured by the microculture tetrazolium assay essentially as described (16). Results are expressed as IC 50 , the drug concentration that reduced by 50% the absorbance at 540 nm.…”

Section: Methodsmentioning

confidence: 99%

Generation of Replication-Dependent Double-Strand Breaks by the Novel N2-G-Alkylator S23906-1

et al. 2006

View full text Add to dashboard Cite

S23906-1, a new DNA alkylating agent that reacts with the exocyclic 2-NH 2 group of guanine residues yielding monofunctional adducts, is currently under clinical evaluation in phase I trials. To investigate the mechanism of action of S23906-1, we compared parental KB-3-1 cells and KB/S23-500 cells that are 15-fold resistant to S23906-1. Cell death induced by 1 Mmol/L S23906-1 in KB-3-1 cells was associated with their irreversible arrest in the G 2 -M phases of the cell cycle followed by apoptosis, whereas a proportion of the resistant KB/S23-500 cells were able to exit from the G 2 arrest and divide, leading to a significantly lower rate of apoptosis. The attenuated apoptotic response was associated with decreased Chk2 protein phosphorylation, indicating that the DNA damage signaling pathways are more potently activated in the sensitive cells. However, similar rates of adduct formation and repair were measured in both cell lines. Exposure to S23906-1 induced a higher formation of DNA breaks, measured by the comet assay, in sensitive cells. In agreement, a histone H2AX phosphorylation assay revealed that S23906-1 induced double-strand breaks (DSB) in a dose-and timedependent manner and that these were more persistent in the parental cells. These DSBs were found mainly in S-phase cells and inhibited by aphidicolin, suggesting that they are DNA replication-mediated DSBs. These results suggest that secondary DNA lesions play an important role in the cytotoxicity of this compound and make histone H2AX phosphorylation an attractive marker for monitoring the efficacy of S23906-1.

show abstract

“…During the synthesis and evaluation of olivacine derivatives, [38] the cytotoxic compound S16020 (aka NSC 659687) was found (Figure 8), [39] which was later discovered to be a potent and selective topoisomerase II inhibitor. S16020 has since completed a Phase I clinical study, [41] and more recently has been tested on xenografts of medulloblastoma and glioblastoma, [42] where it unfortunately showed lower activity than the positive control, doxorubicin.…”

Section: Topoisomerase Inhibitorsmentioning

confidence: 99%

Heterocyclic scaffolds as promising anticancer agents against tumours of the central nervous system: Exploring the scope of indole and carbazole derivatives

Sherer

Snape

2015

European Journal of Medicinal Chemistry

135

View full text Add to dashboard Cite

HIGHLIGHTS• Brain cancer mortality rates are much higher than mortality rates for cancers of other sites. •Due to the blood brain barrier, many drugs that work on cancers of other sites do not work on brain cancers • Indoles, carbazoles and indolocarbazoles make good scaffolds for drugs to be built up around due to their rigidity, planarity and ease of synthesis. GRAPHICAL ABSTRACT ACRONYMS/INITIALISMSAML -Acute myeloid leukaemia CK2 -Casein kinase 2 CNS -Central nervous system PARP -Poly ADP ribose polymerase PDGF -Platelet-derived growth factor PKC -Protein kinase C ROS -Reactive oxygen species VEGF -Vascular endothelial growth factor ABSTRACT Tumours of the central nervous system are intrinsically more dangerous than tumours at other sites, and in particular, brain tumours are responsible for 3% of cancer deaths in the UK. Despite this, research into new therapies only receives 1% of national cancer research spend. The most common chemotherapies are temozolomide, procarbazine, carmustine, lomustine and vincristine, but because of the rapid development of chemoresistance, these drugs alone simply aren't sufficient for longterm treatment. Such poor prognosis of brain tumour patients prompted us to research new treatments for malignant glioma, and in doing so, it became apparent that aromatic heterocycles play an important part, especially the indole, carbazole and indolocarbazole scaffolds. This review highlights compounds in development for the treatment of tumours of the central nervous system which are structurally based on the indole, carbazole and indolocarbazole scaffolds, under the expectation that it will highlight new avenues for research for the development of new compounds to treat these devastating neoplasms.

show abstract

In vitro cytotoxicity of S16020-2, a new olivacine derivative

Cited by 78 publications

References 13 publications

Novel Stable Camptothecin Derivatives Replacing the E-Ring Lactone by a Ketone Function Are Potent Inhibitors of Topoisomerase I and Promising Antitumor Drugs

Novel Stable Camptothecin Derivatives Replacing the E-Ring Lactone by a Ketone Function Are Potent Inhibitors of Topoisomerase I and Promising Antitumor Drugs

Generation of Replication-Dependent Double-Strand Breaks by the Novel N2-G-Alkylator S23906-1

Heterocyclic scaffolds as promising anticancer agents against tumours of the central nervous system: Exploring the scope of indole and carbazole derivatives

Contact Info

Product

Resources

About