Structure-activity relationships natural products

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... 

The development of new synthetic methodology has successfully enabled the investigation of structure-activity relationships (SAR) of perylenequinone agents for use in photodynamic therapy. Simplified analogs, such as (M)-96, that have potency equal to the natural product hypocrellin and superior chromophores to improve photoactivation in the therapeutic window were prepared. 

Wang, W., Zhao, Z.-J., Rayburn, E. R., HiU, D. L., Wang, H., and Zhang, R. (2007). In vitro anti-cancer activity and structure-activity relationships of natural products isolated from fruits of Panax ginseng. Cancer Chemother. Pharmacol. 59,589-601. 

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. 

Salomon, A.R. Zhang, Y. Khosla, C. (2001) Structure-activity relationships within a family of selectively cytotoxic maaolide natural products. Org. Lett., 3, 57-9. 

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... 

Key Words Chemical diversity compound design diversity-oriented synthesis druglike compounds molecular properties natural products rule of five structure-activity relationship target-focused compound libraries. 

---