Efficient solid-phase synthesis of a library of distamycin analogs containing novel biaryl motifs on SynPhase Lanterns.
Distamycin is a naturally occurring antibiotic that binds to AT-rich sequences in the minor groove of DNA in a noncovalent manner. It continues to be of interest as a "building block" for more-complex small-molecule ligands capable of targeting specific DNA sequences for gene regulation purposes (i.e., transcription factor inhibitors). We report here a convenient and efficient synthesis of a library of 72 novel analogs (3a-f) of the parent distamycin on SynPhase Lanterns. To investigate structure-activity relationships including DNA-binding affinity and sequence-selectivity, two previously unexplored points of diversification have been introduced into the distamycin structure by replacing one of its pyrrole rings with novel biaryl motifs. The key aspects of the synthetic approach include the development of an efficient protocol for preparation of the heterocyclic polyamide chain, optimization of the Suzuki-Miyaura cross-coupling reaction and application of a split-and-mix technique based on radiofrequency encoding. In addition, a series of biaryl carboxamide derivatives (4a-f) has been synthesized utilizing the title library diversity reagents.
Brucoli
Federico
F
Gene Targeted Drug Design Research Group, Department of Pharmaceutical and Biological Chemistry, The School of Pharmacy, University of London, 29-39 Brunswick Square, London, UK.
Howard
Philip W
PW
Thurston
David E
DE
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020650:Combinatorial Chemistry Techniques / Q000191:economics / Q000379:methods*; D004247:DNA / Q000378:metabolism; D004214:Distamycins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000998:Antiviral Agents; D004214:Distamycins; C030000:stallimycin; D004247:DNA