In Vitro Cytotoxicity of the Protoberberine-Type Alkaloids

Abstract

In vitro cytotoxic activities of 24 quaternary protoberberine alkaloids related to berberine have been evaluated using a human cancer cell line panel coupled with a drug sensitivity database. Extending the alkyl chain at position 8 or 13 strongly influenced the cytotoxic activity, that is, relative lipophilicity as well as the size of the substituent affects cytotoxicity. The highest level of activity was observed in 8- or 13-hexyl-substituted derivatives of berberine. Structure-activity relationships are described.

Human topoisomerase I poisoning: docking protoberberines into a structure-based binding site model

“…Specifically, intercalative mode A with +1 scissile strand thymine yielded the structure with the lowest energy and hence we selected this binding mode for further investigation. This result is in line with experimental evidence that the binding of the protoberberine alkaloids to contiguous A-T seqences is much favoured over binding to G-C or mixed sequences [6,33].…”

“…First, in contrast to the camptothecins, which are inactivated by lactone hydrolysis at physiological pH [19], the protoberberines are chemically stable. Second, the protoberberines induce a unique pattern of DNA cleavage sites relative to camptothecins [6,33,39], indicating that they may target the human genome differently and hence potentially exhibit a different spectrum of anticancer activity from the camptothecins [40,41]. However, the most severe factor which markedly limit the clinical use of the camptothecins is their toxicity profile; these compounds present a narrow therapeutic index, with a small difference between the dose required for an antitumour effect and that responsible for unacceptable toxicity; in addition, toxicity is observed earlier than the therapeutic effect [42].…”

“…[5][6][7]). The overall biological profile of protoberberines [7] is very similar to camptothecin and its derivatives, some of which are currently in clinical use for the treatment of a variety of solid cancers [8].…”

Antimicrobial activity of Mahonia aquifolium crude extract and its major isolated alkaloids

“…Berberine seems to be active against a number of pathogenic and potentially pathogenic microorganisms, including bacteria, fungi, protozoa and viruses, as indicated by several in vitro studies (Kaneda et al, 1998;Lampert and Shaffner, 1995). As to the molecular basis of the biological activity of isoquinoline alkaloids, berberine has been reported to be able to interact with DNA by intercalation with AT base pair preferences (Iwasa et al, 2001). This binding affinity may cause inhibition of replicational and/or transcriptional activity of the target cells.…”

Anti-Helicobacter pylori Activity and Structure-Activity Relationships of Berberine Derivatives

“…Although berberine was known to inhibit the growth of H. pylori, 6 its derivatives have not thoroughly been investigated yet. We have previously discussed the antimicrobial, 7 antimalarial, 8 and anticancer activities 9 of the synthetic protoberberine-type alkaloids. In the present study, we prepared berberine derivatives in order to evaluate their inhibitory activity against H. pylori and urease, which play important roles in pathogenesis of gastric ulcers.…”