Multicyclic peptides and methods for their preparation
The invention relates to methods for preparing a compound comprising a peptide attached to a molecular scaffold whereby multiple peptide loops are formed, to compounds that can be obtained with such methods and uses thereof.
1 . A molecular scaffold comprising:
an aromatic cyclic or heteroaromatic cyclic moiety,
two or three halides capable of participating in a thiolate nucleophilic substitution reaction, wherein each of said two or three halides capable of participating in a thiolate nucleophilic substitution reaction is attached to an activated methylene group directly attached to the same said aromatic cyclic or heteroaromatic cyclic moiety, and
two or three reactive groups capable of participating in a reaction selected from the group consisting of an oxime-ligation reaction, an alkyne-azide cycloaddition, a hydrazone ligation reaction and a ring-closing metathesis reaction, wherein each of said two or three reactive groups capable of participating in a reaction selected from the group consisting of an oxime-ligation reaction, an alkyne-azide cycloaddition, a hydrazone ligation reaction and a ring-closing metathesis reaction is directly or indirectly attached to said aromatic cyclic or heteroaromatic cyclic moiety,
whereby said molecular scaffold possesses C 2v symmetry or D 3h symmetry with the proviso that the scaffold is not 1,3,5-tris(bromomethyl)-2,4,6-tris(trimethylsilylethynyl)benzene.
2 . A molecular scaffold comprising:
an aromatic cyclic or heteroaromatic cyclic moiety, a 6-membered cycloalkyl, or a 6-membered cycloalkylene,
two halides capable of participating in a thiolate nucleophilic substitution reaction, wherein, each of said two halides capable of participating in a thiolate nucleophilic substitution reaction is attached to an activated methylene group directly attached to the same said aromatic cyclic or heteroaromatic cyclic moiety,
two reactive groups capable of participating in a reaction selected from the group consisting of an oxime-ligation reaction, an alkyne-azide cycloaddition, a hydrazone ligation reaction and a ring-closing metathesis reaction, wherein each of said two reactive groups capable of participating in a reaction selected from the group consisting of an oxime-ligation reaction, an alkyne-azide cycloaddition, a hydrazone ligation reaction and a ring-closing metathesis reaction is directly or indirectly attached to said aromatic cyclic or heteroaromatic cyclic moiety, to said 6-membered cycloalkyl, or to said 6-membered cycloalkylene, and
a freely rotatable bond located between a part of the scaffold that contains said two halides and a part of the scaffold that contains said two reactive groups,
whereby said molecular scaffold possesses C 2v symmetry with the proviso that the scaffold is not 1,3,5-tris(bromomethyl)-2,4,6-tris(trimethylsilylethynyl)benzene.
3 . The molecular scaffold according to claim 1 , wherein each of said two or three reactive groups capable of participating in the reaction selected from the group consisting of an oxime-ligation reaction, an alkyne-azide cycloaddition, a hydrazone ligation reaction and a ring-closing metathesis reaction is indirectly attached to the same said aromatic cyclic or heteroaromatic cyclic moiety via a freely rotatable bond located between a part of the scaffold containing all of said two or three reactive groups capable of participating in the reaction selected from the group consisting of an oxime-ligation reaction, an alkyne-azide cycloaddition, a hydrazone ligation reaction and a ring-closing metathesis reaction, and a part of the scaffold containing the same said aromatic cyclic or heteroaromatic cyclic moiety.
4 . The molecular scaffold according to claim 2 , wherein each of said two reactive groups capable of participating in a reaction selected from the group consisting of an oxime-ligation reaction, an alkyne-azide cycloaddition, a hydrazone ligation reaction and a ring-closing metathesis reaction is indirectly attached to the same said aromatic cyclic or heteroaromatic cyclic moiety, the same said 6-membered cycloalkyl, or the same said 6-membered cycloalkylene, and
said molecular scaffold further comprises a freely rotatable bond located between a part of the scaffold that contains said two halides, and a part of the scaffold that contains said two reactive groups capable of participating in a reaction selected from the group consisting of an oxime-ligation reaction, an alkyne-azide cycloaddition, a hydrazone ligation reaction and a ring-closing metathesis reaction.