Rebeccamycin Derivatives as Dual DNA-Damaging Agents and Potent Checkpoint Kinase 1 Inhibitors

Abstract

Rebeccamycin is an indolocarbazole class inhibitor of topoisomerase I. In the course of structure-activity relationship studies on rebeccamycin derivatives, we have synthesized analogs with the sugar moiety attached to either one or both indole nitrogens. Some analogs, especially those with substitutions at the 6Ј position of the carbohydrate moiety, exhibit potent inhibitory activity toward checkpoint kinase 1 (Chk1), a kinase that has a major role in the G 2 /M checkpoint in response to DNA damage. Some of these compounds retained a genotoxic activity either through intercalation into the DNA and/or by topoisomerase I-mediated DNA cleavage. We explored the structure-activity relationship between these compounds and their multiple targets. These rebeccamycin derivatives represent a novel class of potential antitumor agents that have a dual effect and might selectively induce the death of cancer cells.

Novel Antitumor L‐Arabinose Derivative of Indolocarbazole with High Affinity to DNA

“…5 10 5 ) m À1 for rebeccamycin R 3 -3, [10] K a = (2.64 10 4 ) m À1 for NB-506. [12,13] The indolocarbazole derivatives containing two sugar residues, AT2433-A1 and AT2433-B1, showed comparable affinity to short fragments [d(AT) 4 ) m À1 , respectively. [11,15,16] However, these high values might result from the tight binding of these ligands to the terminal stacking contacts of the short hairpins.…”

“…[7] Furthermore, in the sugar derivatives of indolocarbazoles that inhibit protein kinase C and CDKs, as well as in staurosporine, the carbohydrate residues are linked to two N atoms of indole. [1,4] The aglycon of staurosporine has been shown to interact with the AMP-binding pocket of the catalytic subunit of cAMP-dependent protein kinase. [8] These data demonstrate that the compounds of this chemical class represent a bipartite molecule in which each moiety, that is, the planar aromatic aglycon of indolocarbazole (pharmacophore) and the carbohydrate residue, can interact with the targets important for cell survival.…”

“…[1][2][3][4] The mechanisms of antitumor effects of carbohydrate derivatives of indolocarbazoles include DNA damage and inhibition of the enzymes critical for cell viability, namely, topoisomerase I (topo I) and serine/threonine protein kinases, that is, cyclin dependent kinases (CDKs) and the checkpoint kinase ChK1. [1,[5][6][7][8][9] Rebeccamycin and its analogues with N-glycoside bonds can stabilize topo I-mediated DNA single strand breaks.…”

“…[1,[5][6][7][8][9] Rebeccamycin and its analogues with N-glycoside bonds can stabilize topo I-mediated DNA single strand breaks. [4][5][6][7][10][11][12][13] The crystal structure of the complex of rebeccamycin analogue SA315F with duplex DNA and topo I revealed that SA315F intercalates into the site of a DNA break, whereas the sugar residue interacted with the enzyme in the DNA major groove. [7] Furthermore, in the sugar derivatives of indolocarbazoles that inhibit protein kinase C and CDKs, as well as in staurosporine, the carbohydrate residues are linked to two N atoms of indole.…”

Effect of topoisomerase inhibitors and DNA-binding drugs on the cell proliferation and ultrastructure of Trypanosoma cruzi

“…Drug concentrations for treatment were determined according to data presented in previous reports [28,34,[38][39][40] and were used as follows: camptothecin, To compare control and treated groups, paired t-tests were applied to results using the 95% confidence interval (GraphPad Prism version 5.00 for windows; GraphPad Software Inc., San Diego, CA).…”