Biological Targets of Antitumor Indolocarbazoles Bearing a Sugar Moiety

Abstract

Natural and synthetic indolocarbazole compounds have triggered considerable interest since the discovery in 1986 of the inhibitory properties of staurosporine toward protein kinase C (PKC). Later, it has been shown that indolocarbazole compounds may inhibit various kinases, such as cyclin dependent-kinases and/or topoisomerase I, someones behave only as DNA intercalators. In this review are presented various indolocarbazole compounds bearing a sugar moiety and their biological targets. The relevance of these targets to develop indolocarbazole compounds as potential antitumor agents is discussed.

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

“…Topoisomerase I-mediated DNA cleavage by UCN-01 was also studied under the same conditions. The results concerning topoisomerase I-mediated DNA cleavage, binding to DNA, and antiproliferative activities by compounds 1 to 10 and 18 have been reported previously Prudhomme, 2004a), as well as those for compounds 11 to 15 and 17 , 16 (Moreau et al, 1999b), 19 (Marminon et al, 2003a), 20 and 21 (Facompré et al, 2002). The antiproliferative activities of compounds 20 to 30 have been reported previously .…”

“…The similarities between the structures of the indocarbazole synthon that inhibits either protein kinases or topoisomerases led us to explore in detail whether derivatives of indolocarbazoles might retain both activities (Prudhomme, 2004a). We have synthesized a large number of rebeccamycin derivatives, substituted on the imide nitrogen or at 3,9 positions of the indole moieties, or on the sugar moiety ( Fig.…”

Marine Natural Products as Models to Circumvent Multidrug Resistance

“…The mechanisms of their antitumor effects include topoisomerase I poisoning, inhibition of PKC, PKA, pyruvate dehydrogenase kinase (PDK)/cyclin B, and cyclin-dependent kinase 5 (CDK5)/p5 [144,145]. The naturally occurring arcyriaflavin (63) and indolcarbazole K252c or staurosporin aglycone (64, Figure 12) showed the most potent effects in BCRP inhibition in the BCRP-transferred HEK-293 cell line, with low toxicity in BCRP-transfected cells, and reduced the relative resistance of ABCG2-transfected cells SN-38 [29,146].…”

 

“…This bisindole compounds have been isolated from the shawls, sponges, plant leaves, roots, bark, flowers, algae, fungi and mycotic fungi, [3] most commonly isolated from actinomycetes, [3] a class of bacteria known for production of secondary metabolites. [4] In recent years, most scientists are interested in the use of bisindoles as drug molecules. They are committed to synthesizing bisindole derivatives, testing drug properties, and separating new molecules.…”

“…They are committed to synthesizing bisindole derivatives, testing drug properties, and separating new molecules. [3,4] In this review, we discussed the bioactivities and biosynthetic pathways of bisindole compounds.…”