| 主权项 |
1. A compound of Formula I or a pharmaceutically acceptable salt, ester or prodrug thereof:
F1-X1-L1-X2-P1-X3-G1 (Formula I) wherein F1 is a fluorophore; preferably a fluoresceine based fluorophore; more preferably, 6-carboxy fluorescein (FAM); L1 is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, —O—, —S—, —[C(R10)(R11)]t—, —N(R10)—, —N(R10)[C(R10)(R11)], —O[C(R10)(R11)]t—, —O[C(R10)(R11)C(R10)(R11)O]u— or —S [C(R10)(R11)]t-aliphatic or substituted aliphatic; wherein t is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24; u is an integer between 1 and 500; wherein R10 and R11 is independently hydrogen, halogen, —OR20, —SR20, —NR20R21, —CF3, —CN, —NO2, —N3, —C(O)OR20, —C(O)R20, —C(O)N R20R21, acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, aliphatic, substituted aliphatic, aryl or substituted aryl; alternatively two of R10 and R11 groups together with the atoms to which they are attached and any intervening atoms may form an additional optionally substituted, 3, 4, 5, 6 or 7 membered ring; wherein each R20 and R21 is independently hydrogen, aliphatic, substituted aliphatic, aromatic or substituted aromatic; P1 is a peptide or protein that can act as a substrate to a lysine modifying enzyme, including histone deacetylase (HDAC);
P1 is preferably a one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one or twenty-two amino acid peptide containing a lysine residue wherein the side chain of the lysine residue is unsubstituted, acylated, acetylated or trifluoroacetylated, preferably comprising of natural amino acids, with optional additional substitution; more preferably, a two, three four, five or six amino acid peptide comprising natural amino acids with optional additional substitution; more preferably said two, three, four, five or six amino acid peptide is a peptide comprised of natural amino acids, containing a side-chain acetylated lysine residue (K(Ac)) or a side-chain trifluoroacetylated lysine residue (K(COCF3)) that can be deacetylated by a HDAC enzyme, or trifluoroacetyl substituted lysine residue that can act as a substrate for HDAC enzyme; more preferably, P1 is a peptide having the sequence of AA1-AA2-AA3-AA4-Lys(Ac), AA1-AA2-AA3-AA4-Lys(COCF3), or AA1-AA2-AA3-AA4-Lys wherein each AA1, AA2 and AA3 is absent or a natural or unnatural amino acid, and AA4 is a natural or unnatural amino acid;G1 is hydrophobic group;preferably, G1 is an optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl group, an alkyl group substituted with an optionally substituted aryl or heteroaryl group, an alkenyl group substituted with an optionally substituted aryl or heteroaryl group or a natural or unnatural amino acid;wherein each X1, X2, and X3 is independently a direct bond, —O—, —S—, —C(O)—, —C(O)—NR100—, —C(S)—, —C(S)—NR100—, —C(O)O—, —NR100— and —S(O)2—; wherein R100 is hydrogen, alkyl, substituted alkyl, aryl or substituted aryl. |
