Natural products targets from

Figure 19. Natural product targets from the early 2(lf century.

Thus, a synthetic source of promising allelochemicals is essential if we are to comprehensively study the agent s mode of activity and establish its basic structure-activity profile. The proposed work addresses this need. We will synthesize alleopathic natural products isolated from the sunflower (the heliannuols), and structurally related compounds, in optically pure form based on biomimetic phenol-epoxide cyclizations. The bioactivity of the targets and intermediates will be evaluated through laboratory tests on plant germination and growth. Bioassays will be performed on the synthetic intermediates to allow for the development of a preliminary structure-activity profile for these novel natural herbicides. 

DHAP-dependent aldolases have also been used as key step in the synthesis of several complex natural products starting from achiral precursors. Thus, the sex pheromone (+)-exo-brevicomin can be synthesized in a multi-step route starting with the stereospecific aldol addition between DHAP and 5-oxohexanal or its 5-dithiane-protected analog catalyzed by FBPA from rabbit muscle ( RAMA ) as the key step by which the absolute configuration of the target is estabUshed (Scheme 4.16) [40]. 

Wong CC, Cheng KW, He Y-Y, Chen F (2008) Unraveling the molecular targets of natural products Insights from genomic and proteomic analyses. Proteomics Clin Appl 2 338-354... 

The unique structure and extraordinary bioactivity of manzamine alkaloids have attracted great interest from synthetic chemists as one of the most challenging natural product targets for total synthesis. Great efforts have been made to achieve total synthesis of manzamine A and related alkaloids. Methodological studies towards the synthesis of manzamine structural units have also been reported [31-33]. 

Figure 1 Example of workflow in natural product isolation from a complex biological matrix using high-performance liquid chromatography for the target compound purification and identification. With successive application of several chromatographic modes of different selectivity (i.e., hydrophobicity/hydrophilicity, charge, molecular size) the chromatographic separation can become multidimensional.

However, despite encouraging results, Phase I clinical trials were suspended due to pneumotoxicity at high doses.It is not yet known whether toxicity arose from DDM itself or from metabolic products. Work toward nontoxic and active DDM analogues is, nevertheless, stiU ongoing. However, the ability to make a natural product at this level of complexity indicates that the total synthesis of complex, challenging natural product targets can be achieved to deliver sufficient material for clinical studies with the aid of modem synthetic chemistry. 

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