Pentapeptides, structure-activity analysis

Sansalvamide A is an antineoplastic macrocyclic depsipeptide isolated from the marine fungus Fusarium by William Fenical in 1999. Studies have shown potent cytotoxicity against NCI s 60 cell line panel for the natural product and ten-fold inhibition over the depsipeptide for the pentapeptide derivative. A library of over 100 derivatives of the compound have been synthesized and the Structural Activity Relationships (SARs) show promising bio-potency against pancreatic, colon, breast, prostate and melanoma cancer cell-lines. Six derivatives show over 100-fold differential selectivity for cancer cell lines over normal cell lines and are over 100 times more active against pancreatic cancer cell lines than compounds used clinically to treat these cancers (e.g., 5-FU). Through use of inhibition assays and analysis of trends emerge that can be used to modify the scaffold to produce more potent compounds. 

In EpiD, formation of the enethiol product has been confirmed by direct mass spectrometric and NMR analysis.A crystal structure of an EpiD mutant with a pentapeptide substrate analogue bound " and the biochemical characterization of various site-directed mutants subsequently indicated the crucial involvement of a histidine residue in the oxidation of the substrate thiol. Similar mutagenesis studies on the PPCDC activity of the E. coli CoaBC protein confirmed that this enzyme had a similar requirement, but also fingered a cysteine residue to be important in the subsequent reduction reaction. Subsequently, the AtHAL3a protein of A. thaliana was found to have PPCDC activity, and the corresponding mutants of the monofunctional protein further supported these conclusions. A crystal structure of the A. thaliana protein in which this... 

---