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.
Usai
Igor
I
Department of Chemistry and Pharmacy, Emil Fischer Center, Friedrich Alexander University, Schuhstrasse 19, 91052 Erlangen, Germany.
Krueger
Marcus
M
Einsiedel
Jürgen
J
Hillen
Wolfgang
W
Gmeiner
Peter
P
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