Synthesis of a bisbenzoxazole analogue of Hoechst 33258 as a Potential GC-Selective Dna Ligand

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Abstract

Using a computer modelling approach we proposed the structure of a potential GC-specific DNA ligand, which could form a complex with DNA in the minor groove similar to that formed by Hoechst 33258 at DNA AT-enriched sites. According to this model MBoz2A, a bisbenzoxazole ligand, was synthesized. The results of spectrophotometric methods supported the complex formation of the compound under study with DNA differed in the nucleotide composition.

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About the authors

A. F. Arutuynyan

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences

Email: zhuze@eimb.ru
Russian Federation, Moscow, 119991

M. S. Aksenova

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences

Email: zhuze@eimb.ru
Russian Federation, Moscow, 119991

A. A. Kostyukov

Emanuel Institute of Biochemical Physics, Russian Academy of Science

Email: zhuze@eimb.ru
Russian Federation, Moscow, 119334

A. A. Stomakhin

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences

Email: zhuze@eimb.ru
Russian Federation, Moscow, 119991

D. N. Kaluzhny

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences

Email: zhuze@eimb.ru
Russian Federation, Moscow, 119991

A. L. Zhuze

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences

Author for correspondence.
Email: zhuze@eimb.ru
Russian Federation, Moscow, 119991

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Supplementary files

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2. Fig. 1. Formation of a hydrogen bond between benzimidazole and the AT pair (a) and benzoxazole and the GC pair of DNA (b).

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3. Fig. 2. Computer model of MBoz₂A and Hoechst 33258 complexes with d(A-T)₁₀ and d(G-C)₁₀. Atoms C (ligand) – gray, C (DNA) – gold, N – blue, O – red, H – white. Predicted hydrogen bonds are marked with a thick green line.

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4. Fig. 3. Calculated energy values ​​of MBoz₂A and Hoechst 33258 complexes with d(A-T)₁₀ and d(G-C)₁₀.

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5. Fig. 4. Synthesis of MBoz₂A, a bisbenzoxazole analogue of Hoechst 33258.

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6. Fig. 5. Changes in MBoz₂A fluorescence in the water–DMSO system. a – Fluorescence spectra upon excitation at a wavelength of 280 nm; b – fluorescence excitation spectra at a wavelength of 370 nm; c – fluorescence excitation spectra at a wavelength of 530 nm; d – fluorescence decay curves recorded through a filter transmitting light longer than 305 nm upon excitation by a pulsed LED with a wavelength of 280 nm. Empty circles – water, subsequent spectra with a step of increasing the volume fraction of DMSO by 10%, full circles – 100% DMSO. Arrows indicate the change in fluorescence intensity with an increase in the proportion of DMSO in the solution. [MBoz₂A] 10 μM, fluorescence excitation slit width 5 nm, cuvette 2 × 10 mm, room temperature (~25°C).

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7. Fig. 6. Fluorescence of MBoz₂A solvate forms in the water–DMSO system depending on the volume fraction of DMSO. a – Fluorescence lifetime of solvate forms; b – contribution of solvate forms to the total fluorescence. Empty circles – solvate form with a long fluorescence lifetime (aggregate), full circles – solvate form with a short fluorescence lifetime (monomer).

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8. Fig. 7. Circular dichroism spectra of MBoz₂A upon formation of a complex with DNA of different nucleotide composition: calf thymus DNA (a), poly(dA-dT)•poly(dA-dT) (b), poly(dG-dC)•poly(dG-dC) (c). Empty circles – DNA in the absence of ligand, full circles – maximum concentration of ligand in DNA solution. Dependence of the circular dichroism signal amplitude at a wavelength of 330 nm on the concentration of MBoz₂A (d). Empty diamonds – calf thymus DNA; filled squares – poly(dA-dT)•poly(dA-dT); filled triangles – poly(dG-dC)•poly(dG-dC); [DNA] 50 µM (bp) in 10 mM Na-phosphate buffer pH 7.0, 25°C.

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9. Fig. 8. Fluorescence spectra of MBoz₂A upon formation of complex with DNA of different nucleotide composition. Calf thymus DNA (a); poly(dA-dT)•poly(dA-dT) (b); poly(dG-dC)•poly(dG-dC) (c). Empty circles – MBoz₂A in the absence of DNA, full circles – maximum DNA concentration in the ligand solution. Dependence of MBoz₂A fluorescence intensity on DNA concentration (d). Empty symbols – fluorescence at a wavelength of 370 nm; filled symbols – fluorescence at 530 nm; circles – calf thymus DNA; squares – poly (dA-dT)•poly (dA-dT); triangles – poly(dG-dC)•poly(dG-dC); [MBoz₂A] 10 µM in 10 mM Na-phosphate buffer pH 7.0, 25°C.

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