Synthesis, Biological Evaluation, and Molecular Modeling Studies of Rebeccamycin Analogues Modified in the Carbohydrate Moiety

Abstract

A new series of indolocarbazole glycosides containing disaccharides were synthesized and their in vitro antiproliferative activity was evaluated against three human cancer cell lines (A2780, H460, and GLC4). Cytotoxicity appeared to be remarkably affected by the regio- and stereochemical features of the disaccharide moiety. In vivo antitumor activity of the compounds studied, two of which having IC(50)<100 nm, was determined using ovarian cancer cell line A2780 xenografted on nude mice. One compound showed an efficacy similar to that of the reference compound edotecarin, though with a lower long-lasting activity. The topoisomerase I inhibitory properties of some compounds were also examined. Molecular dynamics simulations of the ternary topoisomerase I-DNA-ligand complexes were performed to analyze the structural features of topoisomerase I poisoning with this class of indolocarbazoles. A plausible explanation of their biological behavior was provided. These theoretical results were compared with the recently published crystal structure of an indolocarbazole monosaccharide bound to the covalent human topoisomerase I-DNA complex.

Topoisomerase 1B poisons: Over a half‐century of drug leads, clinical candidates, and serendipitous discoveries

“…In 2000, it was reported that glycosylation of indolocarbazoles in general resulted in extremely potent Top1 poisons (especially β‐linked sugars; the analogous α‐linked sugar analogs of 26 and 29 had lower potency) . The same trends (dependence on stereochemistry for activity; inactive α‐glycosides) extend to indolocarbazoles substituted with disaccharides . Amino sugars can also be effectively used .…”

“…207,208 The same trends (dependence on stereochemistry for activity; inactive α-glycosides) extend to indolocarbazoles substituted with disaccharides. 209,210 Amino sugars can also be effectively used. 211 One glucose-linked derivative, J-107088, was later renamed edotecarin (30).…”

Enzymatic synthesis of epothilone A glycosides

“…Most natural products currently used as therapeutics derive their biological functions from the sugar components present in their structure; however, alterations could broaden their pharmacological properties (Chang et al [2011]). For example, the DNA binding affinity and cytotoxicity of rebeccamycin (an antitumor drug with potential topoisomerase I poisoning effects) can be altered by variation in sugar moieties (Animati et al [2008]). Doxorubicin (similar antitumor agent with strong chemotherapeutic applications) has no antitumor activity if the sugar moiety is removed (Han et al [2011]); and tylosin and erythromycin (antibiotics) have sugar moieties that may affect their molecular mechanism of action (Langenhan et al [2005]).…”

Design, synthesis, and evaluation of small molecule glycosaminoglycan mimics

“…However, this highly conserved class of enzymes is particularly useful to gain understanding of selective binding with and inhibition of HS-binding proteins.topoisomerases would further support the argument for selective interactions between GAGs and novel GAG mimics and HS-binding proteins. Indeed, changing saccharide moieties on the topo I inhibitor rebeccamycin has been shown to affect the compound's ability to inhibit topo I 166. Molecular modeling of these compounds indicated that structural differences in the glycoside repositioned the hydroxyl groups to either minimize or maximize hydrogen-bonding interactions with topo I 166.…”

“…Indeed, changing saccharide moieties on the topo I inhibitor rebeccamycin has been shown to affect the compound's ability to inhibit topo I 166. Molecular modeling of these compounds indicated that structural differences in the glycoside repositioned the hydroxyl groups to either minimize or maximize hydrogen-bonding interactions with topo I 166. It was shown that increased hydrogen bonding contacts correlated to increased topo I inhibition, and that the rigid saccharide core was essential in optimizing the interaction between glycosidic derivatives and the topoisomerase I.…”