Solid-Supported Synthesis of Cryptand-like Macrobicyclic Peptides

Abstract

A straightforward method for the solid-supported synthesis of cryptand-like bicyclic peptides (1-5) on a backbone amide linker has been described. For the branching, two novel easily available building blocks, viz. N-(4-methoxytrityl)-N-(2-nitrobenzenesulfonyl)-protected N,N-bis(2-aminoethyl)-beta-alanine (6) and N-(9-fluorenylmethoxycarbonyl) protected iminodiacetic acid monoallyl ester (7), have been employed. The key steps of the synthesis are as follows: (i) stepwise coupling of one amino acid and 6 to the secondary amino group of the linker; (ii) removal of the 2-nitrobenzenesulfonyl group and SPPS by the Fmoc chemistry, using 7 as the penultimate and tert-butoxycarbonyl (Boc) protected glycine as the last amino acid; (iii) removal of the 4-methoxytrityl protection and subsequent SPPS by the Fmoc chemistry; (iv) removal of the allyl and Fmoc groups, followed by cyclization; and (v) removal of the Boc and tert-butyl groups, followed by cyclization. Final cleavage from the support and removal of benzyl-derived protecting groups gives the desired bicyclic products.

Screening Bicyclic Peptide Libraries for Protein–Protein Interaction Inhibitors: Discovery of a Tumor Necrosis Factor-α Antagonist

“…Because of their relatively large sizes and ability to make multiple points of contact with a flat surface, macrocycles effectively compete with proteins for binding to flat surfaces and yet retain many of the pharmacokinetic properties of small molecules such as membrane permeability. − Compared to protein drugs, macrocycles have greater metabolic stability, less likelihood of eliciting an immune response, and lower cost of production. To further rigidify the structures and improve the binding affinity/specificity and metabolic stability, bicyclic peptides and peptoids have also been generated. − Since rational design of macrocyclic inhibitors against PPIs is difficult, a popular approach has involved synthesizing and screening large libraries of bicyclic peptides and peptoids. To date, bicyclic peptide libraries have only been synthesized ribosomally by phage or mRNA display and are largely limited to proteinogenic amino acids (and certain unnatural α- l -amino acids) as building blocks. − …”

Synthesis, characterization and X-ray crystal structures of cyclam derivatives. Part VI. Proton binding studies of a pyridine-strapped 5,12-dioxocyclam based macrobicycle

“…[2][3][4][5] Selective molecular recognition 6,7 and signalling [8][9][10][11][12] properties are sought to provide the major impetus for further progress in this flourishing area of chemistry, while various applications in biochemistry and medicine, catalysis, or material sciences have already opened new horizons for the utilization of this class of compounds. [13][14][15][16][17] In this respect, conformationally constrained bicyclic polyamines with bridgehead nitrogen atoms have gained increasing attention over the last three decades because the additional rigidity provided by strapping the macrocyclic framework imparts intriguing anion- 18 and metal-binding properties. 19 Contemporary to the disclosure of the first cryptands by Lehn's group, 2,3 Simmons and Park showed that protonation of diazabicyclo[k,l,m]alkanes of various sizes [6 r (k,l,m) r 10] occurs outside the cavity in the initial stage, while the inversion of the ammonium nitrogen atom is in the hour time range.…”

Backbone Amide Linker in Solid-Phase Synthesis

“…Virta and Lo ¨nnberg applied the monoalkoxybenzaldehyde linker for the solid-phase synthesis of macrocyclic cryptantlike peptides and released the substrates from the resin by utilizing a mixture of HBr, AcOH, and TFA mixed with anisole as a scavenger (synthesis further discussed under section 3.2.4). 40 Brandt et al demonstrated release of a pentapeptide in good yield from a monoalkoxy BAL by a 2 h treatment with TFMSA-TFA (1:9) at room temperature. 41 In an alternative design of a slightly more acid-labile monoalkoxybenzyl BAL, Gu and Silverman introduced the alkyl spacer directly to the aromatic core of 4-methoxybenzaldehyde via carbon-carbon formation.…”