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Natural Product Hybrids ViewHOT metadata, TOPICS citation and similar papers at core.ac.uk brought to you by 841CORE doi:10.2533/chimia.2006.841 provided by Infoscience - École polytechniqueCHIMIA 2006 fédérale, 60, deNo. Lausanne 12 Chimia 60 (2006) 841–845 © Schweizerische Chemische Gesellschaft ISSN 0009–4293 Natural Product Hybrids Karl Gademann* Abstract: This review highlights several classes of natural product hybrids. First, structural hybrids emanating from different biosynthetic pathways exemplified by the polyketide peptide alkaloid anachelin are discussed. Another class is the so-called functional hybrids, where different functions of natural products are hybridized. The conju- gate between nostocarboline and the well-known antibacterial agent ciprofloxacin displays a very broad spectrum of activity combining photosynthesis and gyrase-inhibiting activity. Last, higher order hybrids are discussed. We present the ternary hybrid of titanium dioxide, the anachelin chromophore and poly-ethyleneglycol (PEG). This chimera allows for the functionalization of TiO2 surfaces to render those protein resistant. This article thus shows how natural products can be hybridized to generate compounds with unprecedented bioactivity thus enabling the development of novel drugs and advanced materials. Keywords: Advanced materials · Antibacterial agents · Drug discovery · Natural products · Synthesis 1. Introduction thetic organic chemistry. The goal of this 2. Anachelin – A Structural Hybrid highlight article is to demonstrate that the Natural products, i.e. chemical entities pro- biological functions of natural products Siderophores are small molecules se- duced by living organisms such as bacteria, can be expanded, combined and lever- creted by microorganisms to bind and se- fungi and plants, have historically provided aged by so-called natural product hybrids quester iron [6]. Our initial interest in these important molecular solutions to medical (sometimes also referred to as chimeras or compounds originated from the historical problems [1]. While extracts of plants have conjugates). This strategy is not limited to evolution of earth’s atmosphere. Initially, been traditionally used, the improvement natural products themselves, as also syn- the earth was thought to contain a reduc- of analytical techniques has facilitated the thetic compounds, from small molecules tive atmosphere in which the early life isolation and characterization of the active to polymers, can be hybridized to generate forms flourished [7]. Their need for iron principles, the so-called natural products. compounds with unprecedented functions. was supplemented by readily available and Improved understanding of the mode of ac- This highlight article will focus on our own soluble Fe(ii) salts [7]. Among these an- tion of such compounds combined with the work, as excellent general reviews on this cient organisms were also cyanobacteria synthesis of derivatives enables the estab- subject have been published [4]. (blue-green algae), with fossils dating their lishment of structure–activity relationships Analysis of natural products reveals an initial presence 3.5 billions years ago [8]. and thus the generation of more active, interesting pattern as many of these com- These organisms probably also developed synthetic derivatives. This general strategy pounds are composed of substructures orig- and introduced photosynthesis on this plan- remains the most promising way to gener- inating either from different biosynthetic et and were thereby directly responsible for ate potent and selective biologically active pathways or containing several biological the release of oxygen [8]. Such a very suc- compounds [2]. These statements are sup- functions. These fragments are hybridized cessful photoautotrophic strategy led how- ported by analyses of new chemical enti- by nature to generate naturally occurring ever to a change in earth’s atmosphere as ties introduced on the market in the period conjugates. Such hybrids include the well- the reductive environment slowly changed 1981 to 2002 [3]. Among these compounds known glycosylated steroids, glycosylated into an oxidative one, as it is to this day. around 40% are of natural origin or syn- or lipidated peptides, or polyketide alka- This change had dramatic consequences for thetic derivatives thereof. These numbers loids. In lipidated peptides, the lipid part is many life forms present at that time as oxy- underline the tremendous importance of responsible for anchoring these compounds gen is both a potent oxidant and cell poison. natural products in drug discovery. in biomembranes and the peptide part can Life forms surviving this disaster were soon The evolutionary wisdom enshrined in exert the main biological function [5]. faced with another challenge: Oxidation of natural products can be unlocked by syn- In this highlight article, we will discuss the soluble Fe(ii) salts to the correspond- three classes of natural product hybrids rel- ing virtually insoluble Fe(iii), species of evant to our own work. The first example which the dominant iron oxide hydrates are is a hybrid of different biosynthetic path- in general not soluble (“the world rusted”) ways (structural hybrid). The second part [7]. Iron acquisition thus became a chal- will demonstrate the hybridization of func- lenge for every organism. Although cyano- *Correspondence: Prof. Dr. K. Gademann tions thus broadening the biological activity bacteria probably caused this atmospheric Ecole Polytechnique Fédérale de Lausanne (functional hybrid). The last example will change a long time ago, there is little known Institut des sciences et ingénierie chimiques show how this concept can be expanded to so far how these organisms faced this chal- EPFL-SB-ISIC-LSYNC CH-1015 Lausanne generate ternary conjugates (higher order lenge and in particular, about complex cya- E-Mail: [email protected] hybrids). nobacterial siderophores [8–10]. HOT TOPICS 842 CHIMIA 2006, 60, No. 12 In 2000, the first complex siderophore from the cyanobacterium Anabaena cy- lindrica CCAP 1403-2a was isolated and named anachelin (1), as a mixture of two compounds [11] (Fig. 1). Later, additional isomers were reported [12]. The historical postulate outlined above that cyanobacteria were among the first organisms to encounter iron scarcity and met this challenge by use of small molecule siderophores stimulated us to initiate a research program aimed at these questions. In addition, the structure of anachelin (1) is appealing to the chemist. At least three different biosynthetic pathways are combined: The polyketide fragment, the peptide part featuring a non-standard Fig. 1. Anachelin (1), a structural natural product hybrid featuring alkaloid, d-amino acid, and the alkaloid fragment. In peptide and polyketide biosynthetic pathways addition, the origin of the salicylate part is unknown and two biosynthetic pathways are likely for its generation. Therefore, anache- lin (1) can be considered a structural natural metabolites is directed towards competing itive charge (and thus the counterion) are product hybrid based on fragments of differ- photosynthetic species. For example, pho- spatially separated. ent biogenetic origin. We have investigated tosystem II inhibitors such as fischerellin Nostocarboline (5) was found to be a the solution structure of anachelin [13], the A are thought to secure an evolutionary ad- potent inhibitor of butyrylcholinesterase, vantage by poisoning algae competing for possible biosynthesis [14] and the mode with an IC50 of 13.2 µM. This value is the same resources [19]. of action of 1 [15], and completed its total slightly lower that of galanthamine (6, 16.9 While many bioactive compounds of synthesis thereby establishing the configura- µM), which is on the market as a drug to cyanobacterial origin belong to the chemi- tion [16][17]. This research enabled also the treat Alzheimer’s disease [29]. The related cal class of modified peptides or mixed venture into surface functionalization using deschloro compound 7 has also a similar polyketide/peptide species [20], some al- these compounds, as discussed below. IC50 value. Interestingly, this compound kaloids have also been isolated and charac- is endogenous to humans, and its physi- terized from cyanobacteria. In addition to ological role is unclear [29] (Fig. 3). Some the above-mentioned fischerellin, alkaloids 3. Functional Hybrids Based on reports raise the possibility that this com- with appealing molecular structure such as Nostocarboline pound is related to 1-methyl-4-phenylpyri- welwitindoline A (2) isolated from Hapalo- dinium (TPP), a known neurotoxin. Our Cyanobacteria (often referred to as blue- siphon weilwitschi [21], and more simple data establishes that 2-methyl norhamane 7 green algae) are unicellular prokaryotic or- fragments such as the bauerines (3a-c) [22] is a butyrylcholinesterase inhibitor and this ganisms. These photoautotrophs are among or norharmane (4) [23] and harmane [24] could imply such a physiological role for the oldest life-forms still present today on were isolated (Fig. 2). this orphan ligand [25]. As a side note, there Earth and survived by populating almost In collaboration with the group of Prof. are only few human alkaloids known such every available ecological niche, from ice Dr. Friedrich Jüttner from the University as harmane and norharmane. The physi- to rocks, from the open ocean to the fur of of Zürich, we have characterized nostocar- ological role of these remains the subject polar bears. In particular in warm
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