P-strand mimetics

Takahashi and co-workers [264] constructed two 48-member p-strand mimetic libraries on solid phase using a [2 -i- 3]-cycloaddition between two different Rink-amide resin-linked vinylsulfones (161) and azomethine imines. The latter were generated in situ from cyclic hydrazides (162) and various aliphatic and aromatic aldehydes (Scheme 34). The cycloaddition took place on refluxing 1,2-dichloro-ethane in a sealed tube for 48 h, followed by elimination of the p-toluenesulfonyl group with DBU. The reaction afforded a single regioisomer (164) in moderate to good yields. 

A wide array of potential pharmaceutical applications for P-strand mimetics (e.g. enzyme inhibitors, antigen... 

Ogbu, C.O., Qabar, M.N., Boatman, P.D., Urban, J., Meara, J.P., et al. (1998) Highly efficient and versatile synthesis of hbraries of constrained P-strand mimetics. Bioorg. Med Chem. Lett. 8 2321-2326. 

The synthetic scheme developed for the P-strand template (27.7) has proved to be robust and efficient. Utilizing this chemistry and the IRORI minikan system, we have produced well over 70 000 P-stfand mimetics based on this privileged chemotype (27.7). All compounds are examined for identity and purity by LC-MS, with a success rate of over 85% at a purity level of greater than 80%. ... 

Boatman, P.D., Ogbu, C.O., Eguchi, M., Kim, H.O., Nakanishi, H., etal. (1999) Secondary stmcture peptide mimetics Design, synthesis, and evaluation of 3-strand mimetic thrombin inhibitors. J. Med. Oiem. 42 1367-1375. 

In addition to incorporating the 4-(2-aminoethyl)dibenzofuran-6-propanoic acid template into small peptides where a reverse turn is desired, we have also recently incorporated this template into a mini-protein called the PIN WW domain. WW domains have a three-stranded antiparallel p-sheet structure that mediates intracellular protein-protein interactions. 31 Substitution of this 3-turn mimetic into loop 1 of the PIN WW domain leads to a folded, three-stranded, antiparallel p-sheet structure with a stability indistinguishable from that of the all a-amino acid sequence. The template-incorporated PIN WW domain (11) was synthesized by an Fmoc-based solid-phase peptide synthesis strategy (Scheme 8), utilizing N-Fmoc-protected 4-(2-aminoethyl)dibenzofuran-6-propanoic acid 10. 11 The synthesis of 10, similar to that of 8, has been published.1 1 ... 

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