Natural products structure-activity-relationship studies

Chemical synthesis may be the first consideration in addressing the supply issue. However, the complexity of many marine natural products often eliminates this as an alternative. Even if synthesis is possible, a distinction must be made between academic and industrial syntheses, the latter necessarily being straightforward and low cost.2 Medicinal chemistry techniques and structure-activity relationship studies might identify analogs or the pharmacophore responsible for the activity. 

Structure/activity relationship studies on the sarcodictyin library are performed by induction of tubulin polymerization and by cytotoxicity studies with three cancer cell lines, including Taxol-resistant lines. Derivatives that induce tubulin polymerization more strongly than the natural product sarcodictyin have been determined, and can show higher cytotoxicity even as far as Taxol-resistant tumor cells are concerned. The results of the structure/... 

A mere 4 months after the discovery of platensimycin 17, Nicolaou et al. achieved the first total synthesis of the molecule in racemic form <2006AGE7086>. Although the racemic platensimycin obtained would have to be resolved to render the active version of the natural product, the synthesis established an approach for synthesizing nonnatural analogs to be used in structure-activity relationship studies in search of characteristics better than the native compound. 

Many of the same chromatographic and spectroscopic techniques were applied to the isolation and identification of natural products such as carbohydrates and glyco-lipids. The discovery, isolation, computational analysis, synthesis, and structure-activity relationship studies of antibiotics such as the aminoglycosides kanamycin and neamine are of particular note (Fig. 1.14) [157, 158],... 

Over the years, intensive studies in medicinal chemistry with regard to the structure-activity relationships of compounds being used in clinical praxis have revealed the exceptional position of heterocycles. Moreover, a multitude of bioactive natural products contain a heteroatom. Therefore, the development of reliable and efficient... 

Endothall is a structural analogue of cantharidin (Fig. 20). Its mode of action is apparently inhibition of protein phosphatase(s). A struc-ture/activity relationship study demonstrated that the presence of the oxygen bridge and the location of the two carboxylic groups play important roles in the activity of the molecules. The unusual 7-oxabicyclo[2.2.1]heptane ring of endothal is similar to that of cinmethylin, another natural product-like herbicide for which the mode of action has also eluded scientists for many years. 

Indeed, TCA (42) at a concentration of 10 Xg/mL, has been shown to elevate levels of ROS, as measured by flow cytometry. Consistent with earlier observations regarding structure-activity relationships, Me-TCA (44) showed 3-fold induction of ROS while dihydro-TCA (43) had no effect on the cellular levels of ROS.It is noteworthy that parthenolide (45), a sesquiterpene natural product structurally related to TCA, has previously been shown to increase the levels of ROS by glutathione depletion in hepatocellular carcinoma cell lines. In a separate study, parthenolide was able to inhibit DNA synthesis, cause cell cycle arrest, and induce apoptosis which are important mechanisms for controlling tumor growth. 

In summary, a stereoselective 10-step total synthetic route to the antimalarial sesquiterpene (+)-artemisinin (1) was developed. Crucial elements of the approach included diastereoselective trimethylsilylanion addition to a,p-unsaturated aldehyde 16, and a tandem Claisen ester-enolate rearrangement-dianion alkylation to afford the diastereomerically pure erythro acid 41. Finally, acid 41 was converted in a one-pot procedure involving sequential treatment with ozone followed by wet acidic silica gel to effect a complex process of dioxetane formation, ketal deprotection, and multiple cyclization to the natural product (+)-artemisinin (1). The route was designed for the late incorporation of a carbon-14 label and the production of a variety of analogues for structure-activity-relationship (SAR) studies. We were successful in preparing two millimoles of l4C-l73 which was used for conversion to I4C-arteether for metabolism75 and mode of action studies.76,77... 

Volume 29 of Studies in natural Products Chemistry contains a number of articles in frontier areas written by leading experts. The volume contains synthetic approaches, structural studies as well as structure-activity relationships to a number of classes of bioactive compounds. 

The need to maintain this data induces complex multidimensional information systems that few firms will even attempt to tackle. Clearly, this complex multidimensionality of source data exerts a profound effect on viewing and interpreting biological results correctly and efficiently. With natural products, it becomes very obvious that the traditional structure-activity relationship (SAR) rendition of results, so important to biochemists, becomes pointless due to the lack of a structure and the addition of multidimensional relationships between and within studied samples. 

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