Structure-activity relationship by NMR

If the assignment is available or can be made in reasonable time (and preferably, but not necessarily, if the protein structure is approximately known), the location of the binding site may be easily derived. This method is currently implemented in the so-called SAR (Structure-Activity Relationship) by NMR technique [13]. 

In addition to extending the utility of analytical NMR, these developments have had a direct impact on screening methodologies, where NMR spectroscopy may now be used directly as a rapid and sensitive method for the characterization of binding affinities of mixtures of compounds in combinatorial libraries.3,9 11 A powerful screening method based on observation of NMR signals from a protein target has been developed by researchers at Abbott laboratories.12 Termed SAR (structure-activity relationship) by NMR, this technique has proved to be extremely valuable for the identification of novel lead compounds. 

Sirockin, F., Sich, C., Improta, S., Schaefer, M., Saudek, V., Froloff, N., Karplus, M., and Dejaegere, A. (2002) Structure activity relationship by NMR and by computer a comparative study. Journal of the American Chemical Society, 124, 11073-11084. 

Researchers at Abbott Laboratories used a different approach for discovering high-affinity protein ligands, the structure-activity relationships by nuclear magnetic resonance ( SAR by NMR ) (71). In this method, the relatively large site is divided into two smaller half-sites that are targeted individually by small... 

Abstract Protoberberine alkaloids and related compounds represent an important class of molecules and have attracted recent attention for their various pharmacological activities. This chapter deals with the physicochemical properties of several isoquinoline alkaloids (berberine, palmatine and coralyne) and many of their derivatives under various environmental conditions. The interaction of these compounds with polymorphic DNA structures (B-form, Z-form, H -form, protonated form, triple helical form and quadruplex form) and polymorphic RNA structures (A-form, protonated form, triple helical form and quadruplex form) reported by several research groups, employing various analytical techniques such as spectrophotometry, spectrofluorimetry, circular dichro-ism, NMR spectroscopy, viscometry as well as molecular modelling and thermodynamic analysis to elucidate their mode and mechanism of action for structure-activity relationships, are also presented. 

In summary, we have shown that stable cationic charge centers can significantly enhance the reactivities of adjacent electrophilic centers. Most of the studied systems involve reactive dicationic electrophiles. A number of the reactive dications have been directly observed by low temperature NMR. Along with their clear structural similarities to superelectrophiles, these dicationic systems are likewise capable of reacting with very weak nucleophiles. Utilization of these reactive intermediates has led to the development of several new synthetic methodologies, while studies of their reactivities have revealed interesting structure-activity relationships. Based on the results from our work and that of others, it seems likely that similar modes of activation will be discovered in biochemical systems (perhaps in biocatalytic roles) in the years to come. 

From interesting new ligands, a substructure or similarity search will reveal compounds that can be tested by the same NMR methods, so that some knowledge about the structure-activity relationship is built up. This can lead to optimization of the ligand and to increased binding affinity, although improvement by more than an order of magnitude... 

More recendy the cis and trans isomers of the mosquito repellent CIC-4, a mixture of citronella isomers, have been separated by preparative hplc and bioassayed for effectiveness (23). Chiral-phase capillary gas chromatography and mosquito repellent activity of some oxazolidine derivatives of (+)-and (— )-citronellal have been studied to find structure—activity relationships (24). Several 2-alkyl- -acetyloxalidines have been synthesized and tested against mosquitoes, with further efforts using nmr to determine the rotational isomers of the more active N-acetyl-2,2-dimethyloxazolidine (25). 

NMR ( H, 13C), mass spectrometry, infrared (IR), and ultraviolet (UV) were used, especially NMR, in studying the complexation interactions of artemisinins with agents, such as /3-cyclodextrin <2004JPS2076> and micellar dispersions of octanoyl-6-O-ascorbic acid <2002JPS2265>. Furthermore, the structure-activity relationship of solution structures of deoxoartemisinin 10a and carboxypropyldeoxoartemisinin 10b, as antitumor compounds, was studied by H and 13C NMR <2000BBR359>. 

---