Macrocyclic analogs

Metaferia et al. reported on the synthesis and cytotoxicity of C3 -C4 linked macrocyclic taxoids in 2001. The synthetic strategy was also based on RCM. Similar to Ojima et al. s finding, these compounds (100) are less active than paclitaxel in both cytotoxicity and tubulin assays.However, after careful inspection of the bioactive conformations of taxoids with computer simulation and nuclear magnetic resonance (NMR) experiments, they designed several C-4 and C3 -Ph orf/io-position linked taxoids (101) that were highly active, several times better than paclitaxel.  

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Eli Lilly s LY-333531 (486), a new macrocyclic analog of staurosporine, was discovered to be a potent and specific inhibitor of the PKC 3-isozymes, indicating it to be a clinically useful agent for PKC-mediated human diseases, such as the vascular dysfunctions associated with diabetes mellitus (433,434) (Scheme 4.7). 

Stability Constants of Cryptates and Macrocyclic Analogs in 95% MeOH-H20 at 298 K"... 

Sedrani, R. et al., Sanglifehrin-cyclophilin interaction degradation work, synthehc macrocyclic analogs, X-ray crystal structure, and binding data, J. Am. Chem. Soc., 125, 3849, 2003. 

Comparison of the structure of [Fe([9]aneS3)2][BF4]2 with that of the PS2-donor macrocycle analog [Fe([9]anePS2)2] [BP4]2 ([9]anePS2 = 1-phenyl-l-phospha-4,7-dithiacyclo-nonane) reveal longer C-S bonds in the latter, consistent with the ready loss of ethene on heating The synthesis, structure, and detailed spectroscopic studies of [Fe([9]aneS3)2][Fe(CN)g] showed this to be a valence-trapped Turnbull s blue type Fe(II)-Fe(III) salt. ... 

With the knowledge that cyclodextrins (CDs) of appropriate dimensions and correct stoichiometries can complex Ceo and C70 fullerenes in water, Star et al. reported that common starch, of which CD is a macrocyclic analog, dispersed SWNTs in aqueous environments provided the starch molecule was activated toward complexation by wrapping itself helically around small molecules. - ... 

In the search for novel and effective therapeutics for the treatment of HCV, HCV protease inhibitors are not the only class of enzyme inhibitor to which macrocyclization strategy has been applied. Thus, macrocyclic inhibitors of the HCV NS5B polymerase have also been explored (Section 7.6.1). In addition, macrocyclic analogs of acyclic inhibitors of proteases including. Factor XIa, HIV protease, renin and beta-secretase have been investigated. Examples of each of these are briefly discussed in Section 7.6.2. 

Initial macrocyclic analogs showed enhanced potency relative to non-cyclic precursors and subsequent lead optimization of the linker, salt-bridge binder (to an acylsulfonamide), and aiyl substituents led to the identification of candidate TMC647055 (Figure 7 14) so,100,101 17-membered macrocyclic... 

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