Molecular Modes of Action of Cytotoxic Alkaloids: From DNA Intercalation, Spindle Poisoning, Topoisomerase Inhibition to Apoptosis and Multiple Drug Resistance
I. II. III. IV.
Introduction Molecular Targets of Secondary Metabolites Cytotoxicity of Alkaloids Molecular Modes of Action of Cytotoxic Alkaloids A. Interactions with DNA, RNA, andAssociated Enzymes B. Interactions with the Cytoskeleton C. Induction of Apoptosis D. Interactions with ABC Transporters and Cytochrome p450 V. Conclusions Acknowledgments References
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Plants produce a high diversity of secondary metabolites (SM), and among them, alkaloids are a most prominent class. Over 21,000 alkaloids have been identiﬁed,
Institute ofPharmacy and Molecular Biotechnology, University of Heidelberg, 69120 Heidelberg, Germany � Corresponding author. E-mail address: email@example.com (M. Wink).
The Alkaloids, Volume 64 r 2007 Elsevier Inc.
ISSN 1099-4831, DOI 10.1016/S1099-4831(07)64001-2
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which constitute the largest group among the nitrogen-containing SM (including 700non-protein amino acids, 100 amines, 60 cyanogenic glycosides, 100 gluco sinolates, and 150 alkylamides). However, the class of SM without nitrogen is even larger (more than 25,000 terpenoids, 7000 phenolics and polyphenols, 1000 polyacetylenes, fatty acids, waxes, and 200 carbohydrates) (1–4). Alkaloids are widely distributed in the plant kingdom, especially among angiosperms (more than 20% of allspecies produce alkaloids), and are less common in gymno sperms, lycopods, horsetails, mosses, and algae (3,5,6). Alkaloids also occur in bacteria, fungi, many marine animals (sponges, slugs), arthropods, amphibians, birds, and mammals (3,7–9). Alkaloids are apparently important for the ﬁtness of the organism that produces them. One of the main functions is that of chemical defence against herbivoresor predators. Some alkaloids have antibacterial, antifungal, and antiviral activities in addition. In many cases, a single alkaloid can exhibit more than one biological function. During evolution, the constitution of alkaloids has been modulated so that they usually contain more than one active functional group allowing them to interact with several molecular targets. Therefore, a pleiotropiceffect is a common theme in alkaloids and other SM (2,3,7,8,10–13). The multiple functions that alkaloids can exhibit include a few physiological tasks: sometimes, toxic alkaloids also concomitantly serve as nitrogen-storage and nitrogen-transport molecules. The ecological functions will not be reviewed in this chapter as they were discussed in previous reviews (2,7,8,10,11).
II. MOLECULAR TARGETSOF SECONDARY METABOLITES
In order to deter, repel, or inhibit the diverse range of potential enemies, ranging from arthropods, and vertebrates to bacteria, fungi, and viruses, alkaloids must be able to interfere with important cellular and molecular targets. A short over view of these potential targets is given in Figures 1 and 2. The modulation of a molecular target will negatively inﬂuence itscommunication with other compo nents of the cellular network, especially proteins (cross-talk of proteins), or elements, or signal transducers. As a consequence, the metabolism and function of cells, tissues, organs, and eventually the whole organism will be affected. Although we know the structures of many SM, our knowledge concerning their molecular mode(s) of action is largely fragmentary andincomplete. Such knowledge is, however, important in order to understand the functions of SM for the producing organism, and for the rational utilization of SM in medicine or plant protection. Whereas many SM interact with multiple targets and thus have unspeciﬁc broad activities, others are highly speciﬁc, and interact exclusively with a particular target. SM with broad activities interact...
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