Targeting DNA bulged microenvironments with synthetic agents: lessons from a natural product.
Bulged regions of nucleic acids are important structural motifs whose function has been linked to a number of key nuclear processes. Additionally, bulged intermediates have been implicated in the etiology of several genetic diseases and as targets for viral regulation. Despite these obvious ramifications, few molecules are capable of selective binding to bulged sequences. Prompted by the remarkable affinity of a natural product metabolite, we have designed and prepared a series of readily accessible synthetic agents with selective bulge binding activity. Furthermore, by screening a library of bulge-containing oligodeoxynucelotides, correlations between structure and affinity of the agents can be drawn. In addition to potential applications in molecular biology, the availability of these spirocyclic agents now opens the door for rational drug design.
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02215, USA.
Zhen
Z
Xi
Geum-Sook
GS
Hwang
Irving H
IH
Goldberg
Jeffrey L
JL
Harris
William T
WT
Pennington
Farid S
FS
Fouad
Ghassan
G
Qabaja
Justin M
JM
Wright
Graham B
GB
Jones
D000970:Antineoplastic Agents / Q000737:chemistry; D003500:Cyclization; D004247:DNA / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D053281:Enediynes; D015723:Gene Library; D006868:Hydrolysis / Q000187:drug effects; D008024:Ligands; D009690:Nucleic Acid Conformation / Q000187:drug effects; D009838:Oligodeoxyribonucleotides / Q000737:chemistry / Q000378:metabolism; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000494:pharmacology; D013329:Structure-Activity Relationship; D009353:Zinostatin / Q000031:analogs & derivatives / Q000737:chemistry
D000970:Antineoplastic Agents; D053281:Enediynes; D008024:Ligands; D009838:Oligodeoxyribonucleotides; D013141:Spiro Compounds; C032372:neocarzinostatin chromophore; D004247:DNA; D009353:Zinostatin