Novel Indolocarbazole Derivative 12-(α-L-arabinopyranosyl)indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7-dione Is a Preferred c-MycGuanine Quadruplex Ligand

摘要

The indolocarbazole derivative 12-(α-L-arabinopyranosyl)indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7-dione (AIC) has demonstrated a high potency (at nanomolar to submicromolar concentrations) towards the NCI panel of human tumor cell lines and transplanted tumors. Intercalation into the DNA double helix has been identified as an important prerequisite for AIC cytotoxicity. In this study, we provide evidence for preferential binding to the G-quadruplex derived from the c-Myconcogene promoter (Pu18 d(AG3TG4)2; G-c-Myc). The association constant for AIC:G-c-Myccomplex was ~100 times and 10 times greater than the respective values for the complexes AIC:c-Mycduplex and AIC:telomeric d(TTAGGG)4G-quadruplex. The concentrations at which AIC formed complexes with G-c-Mycwere close to those that attenuated the steady-state level of the c-MycmRNA in the human HCT116 colon carcinoma cell line. We suggest that preferential binding of AIC to G-c-Mycrather than to the c-Mycduplex might favor the quadruplex formation in the cells, thereby contributing to downregulation of the c-Mycexpression by AIC.