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

Abstract

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-Myc oncogene promoter (Pu18 d(AG3TG4)2; G-c-Myc). The association constant for AIC:G-c-Myc complex was ~100 times and 10 times greater than the respective values for the complexes AIC:c-Myc duplex and AIC:telomeric d(TTAGGG)4 G-quadruplex. The concentrations at which AIC formed complexes with G-c-Myc were close to those that attenuated the steady-state level of the c-Myc mRNA in the human HCT116 colon carcinoma cell line. We suggest that preferential binding of AIC to G-c-Myc rather than to the c-Myc duplex might favor the quadruplex formation in the cells, thereby contributing to downregulation of the c-Myc expression by AIC.

Chemistry and Properties of Indolocarbazoles

“…160 Furthermore, it has also been established recently that compound 130 is an efficient inhibitor of the transcriptional regulators NF-κB and STAT3, with the capacity of blocking growth and maintenance of prostate cancer stem cells. 161 Additional selected reports focused on evaluation of 12-α-Larabinopyranosyl-12,13-dihydro-5H-indolo [2,3-a]pyrrolo [3,4c]carbazole-5,7(6H)-dione as a DNA intercalator with high potency against several human tumor cell lines, 162,163 and the thoroughly studied alkaloid K-252a (6), which has been demonstrated to be highly efficient against human endometrial cancer cells, whereas normal endometrial remained viable after the same treatment. 164 In a recent interesting contribution, the new antibacterial rebeccamycin derivative 140 was isolated through activityguided fractionation of the organic soluble extract from the Pseudonocardia strain BCI2, a bacterial symbiont associated with a fungus-growing ant colony (Apterostigma dentigerum).…”

“…Additional selected reports focused on evaluation of 12-α-L-arabinopyranosyl-12,13-dihydro-5 H -indolo­[2,3- a ]­pyrrolo­[3,4- c ]­carbazole-5,7­(6 H )-dione as a DNA intercalator with high potency against several human tumor cell lines, , and the thoroughly studied alkaloid K-252a ( 6 ), which has been demonstrated to be highly efficient against human endometrial cancer cells, whereas normal endometrial remained viable after the same treatment …”