Natural Products In Cancer Chemotherapy

Plants, micoorganisms, and, more recently, marine organisms of various types have traditionally represented a main source of cytotoxic anticancer agents since the beginning of chemotherapy.21 Even if the new technologies of combinatorial chemistry and high-throughput screening (HTS) represent an important step in drug discovery, the role of natural sources in providing new cytotoxics should not be disregarded for the future.22 The number of microbial species studied in this regard is still very low, and the marine ecosystem is largely unexplored.

Around half of the drugs currently in clinical use as anticancer drugs are of natural product origin, and it has been estimated that about 60% of new chemical entities (NCEs) introduced in the 1981-2002 period in this field were natural products or were derived from a natural lead compound.23 Despite this statistic, pharmaceutical companies have neglected in the recent past the development of potential natural drug candidates in favor of combinatorial chemistry and high-throughput synthesis of large compound libraries. The main reason of this reluctance to use natural products as drug candidates lies primarily in supply problems that make the development of synthetic routes necessary, which are often long and difficult to scale-up owing to their structural complexity. It is becoming increasingly apparent, however, that the unguided production of vast libraries of compounds is unlikely to result in the identification of new drugs.

In general, natural products have several functional groups which are located into a precise three-dimensional position providing specific interactions with target molecules. It is often assumed that secondary metabolites in nature organisms have been optimized through evolution to exert their still not well-defined effects. Consequently, they may be considered as highly advanced lead compounds in which further optimization of activity is difficult.24 In many cases, some parts of the complex structure of a natural product act only as a framework to position determined atoms, and more simple analogs maybe developed without considerable loss of activity. For this reason, structural modification of natural products is often directed to find the simplest portion that maintains most of the biological activity, that is, its pharmaco-phoric unit. One example of this approach is the development of the antitumor agent E7389 that arose from studies on the total synthesis of the cytotoxic marine compound halichondrin B and is currently in Phase III clinical trials. The development of synthetic strategies to obtain halichondrin B revealed that deletion of a large portion of this compound, as well as the replacement of the unstable lactone by a ketone function, did not affect its antimitotic properties.25

The notion that the use of natural product templates combined with chemical modifications leading to more selective analogs will have a better chance of success than combinatorial approaches is gaining acceptance. In other words, it is becoming more and more clear that, at least in the anticancer field, nature has already carried out the combinatorial chemistry and all we have to do is refine the structures.26 These ideas are leading to a renaissance of natural products as drug candidates.27

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