Pyrazine derivatives for bioconjugation
View Patent ↗Provided are compounds and compositions of general Formula IX: E1-L-Ar—X-PA, that may be utilized in bioconjugation procedures, where Ar is a chromophore and PA is a functional group capable of being attached to any bioactive molecule of interest. The present invention provides Formulas I-III that are capable of being attached to a bioactive vector for the selective delivery of said photoactive pyrazine derivatives to a desired biological target.
1. A compound of the formula: E1-L-Ar—X-PA (Formula IX), wherein:
Ar is
E1 is hydrogen;
X is selected from a single bond, —(CH 2 ) a —, —CO—, —OCO—, —HNCO—, —(CH 2 ) a CO—, —(CH 2 ) a OCO—, C5-C10 aryl, C5-C10 heteroaryl, —NR 1 CO—, —(CH 2 ) a CONR 1 —, —(CH 2 ) a SO—, —(CH 2 ) a CON(R 1 )—, —(CH 2 ) a N(R 1 )CO—, —(CH 2 ) a N(R 1 )CON(R 2 )— and —(CH 2 ) a N(R 1 )CSN(R 2 )—, —CON(R 1 )(CH 2 ) a —;
L is selected from a single bond, —HNCO—, —CONR 3 , —(CH 2 ) b —, —(CH 2 ) b CONR 3 —, —N(R 3 )CO(CH 2 ) b —, —OCO(CH 2 ) b —, —(CH 2 ) b CO 2 —, —OCONH—, —OCO 2 —, —HNCONH—, —HNCSNH—, —HNNHCO—, —OSO 2 —, —NR 3 (CH 2 ) b CONR 4 —, —CONR 3 (CH 2 ) b NR 4 CO—, —NR 3 CO(CH 2 ) b CONR 4 —, —(CH 2 ) b CON(R 3 )—, —(CH 2 ) b N(R 3 )CO—, —(CH 2 ) b N(R 3 )CON(R 4 )— and —(CH 2 ) b N(R 3 )CSN(R 4 )—;
PA is —OZ or —NR 9 Z;
Z is selected from —(CH 2 ) c CO 2 H, —(CH 2 ) c NR 9 R 10 , —(CH 2 ) c NCO, —(CH 2 ) c NCS, ——(CH 2 ) c SH, —(CH 2 ) c C≡CH, —(CH 2 ) c C≡N, —(CH 2 ) c N 3 ,
each R 1 , R 2 , R 3 , and R 4 is independently selected from hydrogen, C1-C10 alkyl, —OH, C5-C10 aryl, C1-C10 hydroxyalkyl, C1-C10 polyhydroxyalkyl, C1-C10 alkoxyl, C1-C10 alkoxyalkyl, —(CH 2 ) c CO 2 H, and —(CH 2 ) c NR 9 R 10 ;
R 5 and R 6 are each independently —(CH 2 ) f NR 16 R 17 ;
R 9 and R 10 are each independently selected from hydrogen, C1-C10 alkyl, C5-C10 aryl, and C1-C10 maleimidoalkylcarbonyl;
R 16 and R 17 are each independently hydrogen, C 1 -C 10 alkyl, C5-C10 aryl, C 1 -C 10 hydroxyalkyl, and C 1 -C 10 alkoxyalkyl;
each a is an integer independently selected from 0 to 10;
each b is an integer independently selected from 0 to 10;
each c is an integer independently selected from 0 to 10; and
each f is an integer independently selected from 0 to 10.
2. The compound of claim 1 , wherein f is 0.
3. The compound of claim 1 wherein PA is —NR 9 Z.
4. The compound of claim 3 wherein R 16 is hydrogen or C1-C10 alkyl.
5. The compound of claim 1 wherein L is —CONR 3 — and R 3 is C1-C10 alkoxyalkyl, —(CH 2 ) c CO 2 H, or —(CH 2 ) c NR 9 R 10 .
6. The compound of claim 5 wherein R 3 is C1-C10 alkoxyalkyl.
7. The compound of claim 1 wherein Z is
8. The compound of claim 1 wherein Z is
9. The compound of claim 1 wherein Z is —(CH 2 ) c CO 2 H.
10. The compound of claim 1 wherein R 3 is —(CH 2 ) c NR 9 R 10 .
11. The compound of claim 1 wherein Z is —(CH 2 ) c NR 9 R 10 .
12. The compound of claim 11 wherein R 9 and R 10 are both hydrogen.
13. The compound of claim 1 , wherein Z is selected from:
or —(CH 2 ) c NR 9 R 10 where R 9 or R 10 is C1-C10 maleimidoalkylcarbonyl.
14. The compound of claim 1 , wherein:
E1 is hydrogen;
X is —CON(R 1 )(CH 2 ) a —;
L is —CONR 3 —;
PA is —OZ or —NHZ;
Z is selected from the group consisting of —(CH 2 ) c CO 2 H, —(CH 2 ) c NR 9 R 10 , —(CH 2 ) c NCO, —(CH 2 ) c NCS, —(CH 2 ) c SH, —(CH 2 ) c C≡CH, —(CH 2 ) c C≡N, —(CH 2 ) c N 3 ,
R 3 is selected from the group consisting of hydrogen, C1-C10 alkyl, —OH, C5-C10 aryl, C1-C10 hydroxyalkyl, C1-C10 polyhydroxyalkyl, C1-C10 alkoxyl, C1-C10 alkoxyalkyl, —(CH 2 ) c CO 2 H, and —(CH 2 ) c NR 9 R 10 ;
R 5 and R 6 are each independently —(CH 2 ) f NR 16 R 17 ;
R 9 and R 10 are each independently selected from the group consisting of hydrogen, C1-C10 alkyl, C5-C10 aryl, and C1-C10 maleimidoalkylcarbonyl;
R 16 and R 17 are each independently selected from the group consisting of hydrogen, C1-C10 alkyl, C5-C10 aryl, C1-C10 hydroxyalkyl, and C1-C10 alkoxyalkyl;
each c is an integer independently selected from 0 to 10; and
f is 0.