Macrocyclization of peptidomimetics
A method of macrocyclization of peptidomimetics is described which comprises substitution of one or more of the backbone amide C═O bonds with a turn-inducing motif. The method is general with enhancements seen across a range of ring sizes (e.g. tri-, tetra-, penta- and hexapeptides). Specifically, a peptidomimetic macrocycle is described comprising a carbonyl bioisosteric turn-inducing element having the structure: wherein X is a heteroatom; and wherein R 1 to R 6 are each independently selected from alkyl, aryl, heteroaryl and H.
1. A method of synthesizing a peptidomimetic macrocycle which is a continuous loop of 11 atoms or more and which comprises a carbonyl bioisosteric turn-inducing element comprising the steps:
(a) synthesizing a linear peptidomimetic comprising the carbonyl bioisosteric turn-inducing element and
(b) performing a cyclisation reaction of the linear peptidomimetic;
wherein the turn-inducing element is:
wherein X is a secondary or tertiary amine; and wherein R 1 to R 6 are each independently selected from the group consisting of alkyl, aryl, heteroaryl and H.
2. The method according to claim 1 , wherein the cyclisation reaction is selected from the group consisting of: a head-to-tail reaction; a sidechain-to-sidechain reaction; a head-to-sidechain reaction; and a sidechain-to-tail reaction.
3. The method according to claim 2 , wherein the cyclization reaction is a sidechain-to-sidechain reaction and is achieved by an amide, ester, thioester, or disulfide bond formation.
4. The method according to claim 1 , which comprises solution-phase or solid-phase peptide synthesis.
5. The method according to claim 1 , wherein a compound of formula (III) is employed in synthesizing the linear peptidomimetic comprising the carbonyl bioisosteric turn-inducing element:
wherein X is a secondary or tertiary amine; and
wherein R 1 to R 5 are each independently selected from the group consisting of alkyl, aryl, heteroaryl and H.
6. The method according to claim 5 , wherein X is NH.
7. The method according to claim 5 , wherein the compound of formula (III) is:
wherein R b is H, alkyl, aryl, heteroaryl, or a removable protecting group.
8. The method according to claim 7 , wherein the removable protecting group is tert-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), or carboxybenzyl (Cbz).