Click-chemistry-derived tetracycline-amino acid conjugates exhibiting exceptional potency and exclusive recognition of the reverse tet repressor.
A click-chemistry-based synthesis of biologically active doxycycline-amino acid conjugates is described. Starting from 9-aminodoxycycline derivatives and complementary functionalized amino acids, ligation was accomplished by copper(I)-catalyzed azide-alkyne [3+2] cycloaddition (CuAAC). The final products were tested in a variety of TetR and revTetR systems, and the C-terminally linked phenylalanine conjugate 12 c exhibited high selectivity for revTetR over TetR. Besides the unique property of the specific effector 12 c to effectively differentiate TetR and its reverse phenotype, the test compound proved to be almost devoid of any antibacterial activity; this will be highly beneficial for future applications to control gene expression in bacterial systems.
Department of Chemistry and Pharmacy, Emil Fischer Center, Friedrich Alexander University, Schuhstrasse 19, 91052 Erlangen, Germany.
Igor
I
Usai
Marcus
M
Krueger
Jürgen
J
Einsiedel
Wolfgang
W
Hillen
Peter
P
Gmeiner
D000480:Alkynes / Q000737:chemistry; D000596:Amino Acids / Q000737:chemistry*; D001386:Azides / Q000737:chemistry; D002384:Catalysis; D003300:Copper / Q000737:chemistry; D003500:Cyclization; D004318:Doxycycline / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D024881:Drug Resistance, Bacterial; D008826:Microbial Sensitivity Tests; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D012097:Repressor Proteins / Q000378:metabolism*
C551741:9-(4-(1-(3-(2-amino-3-phenylpropionylamido)propyl)-1H-1,2,3-triazol-4-yl)butyrylamino)doxycycline; D000480:Alkynes; D000596:Amino Acids; D001386:Azides; D012097:Repressor Proteins; C034811:tetracycline resistance-encoding transposon repressor protein; D010649:Phenylalanine; D003300:Copper; D004318:Doxycycline