Peptidomimetic primary

Bradley developed a solid-phase synthesis of peptidomimetic dendrimers using the lysine-like peptoid monomer 25 [226] which led to G1-G3 dendrimers, bearing both primary and secondary amino groups on the periphery, with promising transfection abilities and no toxicity [227] (see Fig. 25). 

The palladium-catalyzed formation of diarylamines has been used in several contexts to form molecules of biological relevance. The ability to prepare haloarenes selectively by an ortfio-metalation-halogenation sequence allows the selective delivery of an amino group to a substituted aromatic structure. Snieckus has used directed metalation to form aryl halides that were subsequently allowed to react with anilines to form diarylamines (Eq. (34)) [209]. Frost and Mendonqa have reported an iterative strategy to prepare, by the palladium-catalyzed chemistry, amides and sulfonamides that may act as peptidomimetics. Diaryl-amine units were constructed using the DPPF-ligated palladium catalysts, and the products were then acylated or sulfonated with 4-bromobenzoyl or arylsulfonyl chlorides [210]. Le-miere has coupled primary arylamines with 4-chloro-3(2H)-pyridazinones to form compounds with possible analgesic and antiinflammatory properties. 

Figure 1.16 Left Schematic presentation of the 1,3-diaminopropanone core moiety as cysteine protease-directed and active site-spanning inhibitor principle (top). Upon reaction with the enzyme nucleophile, the ketone is reversibly converted to a hemithioketal (bottom). Right Peptidomimetic cysteine protease inhibitors of subsequent generations are depicted together with their inhibitory activity and primary targets.

Figure 9.16 Structure of the primary SP peptidomimetic library Lll and of the deconvoluted hit 9.21 active on C. albicans phosphomannose isomerase (CaPMI).

Figure 9.52 Structure of the SP-encoded primary peptidomimetic library of metal complexing agents L37 and of the monomer sets M1-M4 used for its synthesis.

Coupling of the free amino derivative with Fmoc protected commercially available amino acids (alanine and phenylalanine) was accomplished via standard reaction conditions activated by DCC in anhydrous tetrahydrofiiran (THF) solution. Deprotection of synthesized peptides by treatment with aqueous methanol solution and catalytic amount of trimethylamine produced a new class of 5-thio-carbo peptides in 86% yield. This particular family of new stable peptidomimetics is conveniently protected and could be used for further additional functionalization at the primary -OH at C-6 of the thioglucose moiety. Further deprotection of the 1,2-0-isopropylidene block created another... 

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