Design, synthesis, and DNA binding properties of photoisomerizable azobenzene-distamycin conjugates: an experimental and computational study.
Here, we present the synthesis, photochemical, and DNA binding properties of three photoisomerizable azobenzene-distamycin conjugates in which two distamycin units were linked via electron-rich alkoxy or electron-withdrawing carboxamido moieties with the azobenzene core. Like parent distamycin A, these molecules also demonstrated AT-specific DNA binding. Duplex DNA binding abilities of these conjugates were found to depend upon the nature and length of the spacer, the location of protonatable residues, and the isomeric state of the conjugate. The changes in the duplex DNA binding efficiency of the individual conjugates in the dark and with their respective photoirradiated forms were examined by circular dichroism, thermal denaturation of DNA, and Hoechst displacement assay with poly[d(A-T).d(T-A)] DNA in 150 mM NaCl buffer. Computational structural analyses of the uncomplexed ligands using ab initio HF and MP2 theory and molecular docking studies involving the conjugates with duplex d[(GC(AT)10CG)]2 DNA were performed to rationalize the nature of binding of these conjugates.
Ghosh
Sumana
S
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India.
Usharani
Dandamudi
D
Paul
Ananya
A
De
Susmita
S
Jemmis
Eluvathingal D
ED
Bhattacharya
Santanu
S
D000577:Amides / Q000737:chemistry; D001391:Azo Compounds / Q000737:chemistry*; D001667:Binding, Competitive; D002942:Circular Dichroism; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D019281:Dimerization; D004214:Distamycins / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D015195:Drug Design; D004583:Electrons; D006863:Hydrogen-Ion Concentration; D007536:Isomerism; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D009691:Nucleic Acid Denaturation / Q000187:drug effects; D055668:Photochemical Processes; D011789:Quantum Theory; D013056:Spectrophotometry, Ultraviolet
D000577:Amides; D001391:Azo Compounds; D004214:Distamycins; D008024:Ligands; C030000:stallimycin; D004247:DNA; C009850:azobenzene