Syntheses and Biological Activities (Topoisomerase Inhibition and Antitumor and Antimicrobial Properties) of Rebeccamycin Analogues Bearing Modified Sugar Moieties and Substituted on the Imide Nitrogen with a Methyl Group

Abstract

As a part of studies on structure-activity relationships, several potential topoisomerase I inhibitors were prepared. Different analogues of the antitumor antibiotic rebeccamycin substituted on the imide nitrogen with a methyl group were synthesized. These compounds bore either the sugar residue of rebeccamycin, with or without the chlorine atoms on the indole moieties, or modified sugar residues (galactopyranosyl, glucopyranosyl, or fucopyranosyl) linked to the aglycone via a beta- or alpha-N-glycosidic bond. Their inhibitory properties toward protein kinase C, topoisomerase I, and topoisomerase II were examined, and their DNA-binding properties were investigated. Their in vitro antitumor activities against murine B16 melanoma and P388 leukemia cells were determined. Their antimicrobial activities were tested against Gram-positive bacteria Bacillus cereus and Streptomyces chartreusis, Gram-negative bacterium Escherichia coli, and yeast Candida albicans. These compounds are inactive toward topoisomerase II but inhibit topoisomerase I. A substitution with a methyl group on the imide nitrogen led to a loss of proteine kinase C inhibition in the maleimide indolocarbazole series but did not prevent topoisomerase I inhibition. Compounds possessing a beta-N-glycosidic bond, which fully intercalated into DNA, were more efficient at inhibiting topoisomerase I than their analogues with an alpha-N-glycosidic bond; however, both were equally toxic toward P388 leukemia cells. Dechlorinated rebeccamycin possessing a methyl group on the imide nitrogen was about 10 times more efficient in terms of cytotoxicity and inhibition of topoisomerase I than the natural metabolite.

DNA Binding and Topoisomerase I Poisoning Activities of Novel Disaccharide Indolocarbazoles

“…Not surprisingly, the cationic aminosugar subunit of the AT2433 antibiotics is a positive element for DNA recognition but, unexpectedly, it is unfavorable for topoisomerase I poisoning. In the following section, these two aspects are discussed in turn because we know from our previous studies with different series of indolocarbazole glycosides that DNA interaction and topoisomerase I inhibition are two different and essentially unrelated aspects of the molecular mechanism of action of these compounds (Anizon et al, 1997;Bailly et al, 1997Bailly et al, , 1999aBailly et al, ,b, 2000. In the NB-506 series, it is clear that the drug needs not to intercalate into DNA to inhibit topoisomerase I and exert its cytotoxic activity (Bailly et al, 1999a).…”

Biosynthesis of Violacein, Structure and Function of l-Tryptophan Oxidase VioA from Chromobacterium violaceum

“…Various biological activities of violacein, including antibacterial, antiviral, as well as cytotoxic effects against several tumor cell lines, have been demonstrated (4). The related compounds rebeccamycin and staurosporine show strong antitumorigenic activity because of DNA topoisomerase or protein kinase inhibition (5,6).…”

An expeditious, highly efficient, catalyst and solvent-free synthesis of 9,10-dihydro-anthracene-9,10-α,β-succiniimide derivatives

“…Along with the photophysical and chemical properties, organic imides and diimides also play significant role in pharmacology. Imides possess wide range of biological activities such as antiinflammatory (21Á24), anticancer (25,26), antimicrobial (27), DNA binding, and apoptotic-inducing activities (28), etc. They also act as selective a1d-adrenergic receptor antagonists which modulate intercellular biochemical processes in response to changes in extracellular concentrations of the neurotransmitter norepinephrine and the circulating hormone epinephrine, leading to widespread physiological actions that make them attractive targets for *Corresponding author.…”