P-Tum Mimetics

Golebiowski A, Jozwik J, Klopfenstein SR, Colson AO, Grieb AL, Russell AF, Rastogi VL, Diven CP, Portlock DE, Chen JJ (2002) Solid-supported synthesis of putative peptide P-tum mimetics via Ugi reaction for diketopiperazine formation. J Comb Chem 4 584—590... 

Sanudo M, Garcia-Valverde M, Marcaccini S, Delgado JJ, Rojo J, Torroba T (2009) Synthesis of benzodiazepine P-tum mimetics by an Ugi 4CC/Staudinger/Aza-Wittig sequence. Solving the conformational behavior of the Ugi 4CC adducts. J Org Chem 74 2189-2192... 

Piscopio AD, Miller JF, Koch K (1999) Ring closing metathesis in organic synthesis evolution of a high speed, solid phase method for the preparation of P-tum mimetics. Tetrahedron 55 8189-8198... 

The scope and limitations of the solid-supported symthesis of bicyclic diketopi-perazines 165 as peptide p-tum mimetic were further investigated by Golebiowski et al. [52]. The four-component Ugi reaction of a-iV-Boc-diaminopropionic acid resin ester 160 (an amine input) and optically active a-bromoacid 163 with various isocyanides 166 and aldehydes 167 yields a series of bicyclic diketopiperazines 165 (Scheme 28). 

Two reports on the preparation of polyhydroxylated [13]thiazolo[3,2a]azepane derivatives have been published. The one reports the synthesis of the p-tum mimetic 22 from D-glucurono-3,6-lactone and L-cysteine <99TL477>, whilst the other describes, for example the preparation of 23 in 78% yield from 6-0-tosyl-23-0 isopropylidene-D-mannofuranose and 2-aminothioethanol <99S839>. 

Scheme 44 p-Tum Mimetics to Initiate Antiparallel p-Sheet Structures1 60-1621... 

Scheme 45 Preparation of an Antiparallel p-Sheet Peptide Incorporating a p-Tum Mimetic 1621...

A simple and efficient synthesis of a large library of chiral substituted heterocycles of the type 133 (Scheme 49) as p-tum mimetics containing the side chains for R2 and R3 of the parent peptide has been reported. 1661... 

In addition, there are many important nonantibiotic uses of 2-azetidinones in fields ranging from enzyme inhibition [15-21] to gene activation [22], Systems containing one carbon atom common to two rings, spirocyclic compounds, represent an important structural organization. Spirocyclic p-lactams (Fig. 3) behave as p-tum mimetics [23-26] as well as enzyme inhibitors [27, 28], they are precursors of a,a-disubstituted p-amino acids [29-32], and the spiranic p-lactam moiety is present in chartellines and chartelamides [33-38], a family of marine natural products. Synthetic studies and biosynthetic speculation inspired by an unexpected reaction on the marine alkaloid chartelline C have been described [38],... 

Dibenzofuran scaffold-based P-tum mimetic Inhibition of WW domain of PIN1, a mitosis cell cycle regulator Improved solubility and resistance to aggregation without compromising thermodynamic stability [89]... 

D-Pro-L-Pro and 2-aminocyclohexanoic acid-based P-tum mimetic Incorporated into RNase A using expressed protein ligation Semi-synthetic enzyme retains full catalytic activity and gains conformational stability [90]... 

Gardner, B., Nakanishi, H. and Kahn, M. (1993) Conformationally constrained nonpeptide P-tum mimetics of enkephalin. Tetrahedron 49 3433-3448. 

Chen, S., Chrusciel, R.A., Nakanishi, H., Raktabutr, A., Johnson, M.E., et al. (1992) Design and synthesis of a CD4 P-tum mimetic that inhibits human immunodeficiency vims envelope glycoprotein gpl20 binding and infection of human lymphocytes. Proc. Natl Acad. Sci. USA 89 5872-5876. 

Supported reagents were further applied to achieve post-cleavage purification of products obtained by solid-phase synthesis. This is illustrated by an example from Ellman s laboratory Scheme 1.6.22). The p-tum mimetic precursor 43 was released from solid support by TCEP (41) mediated cleavage of a disulfid linkage. The polymeric guanidine 44 was used to remove excess of 41 and of the phosphinoxide 42, to promote formation of the cyclic sulfide 45, and to trap the byproduct HBr from solution. 

Peptidic p-tum mimetics are generally based on cyclic backbone mimetics (e.g. replacing the turn hydrogen bond by a covalent bond) or by introducing one or several unusual amino acids, which constrain the backbone in P-tum conformations. Synthetic approaches to non-peptidic turn mimetics can be grouped into two classes 1) external P-turn mimetics, and 2) internal P-turn mimetics. ... 

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