Protection of all cleavable sites of DNA with the multiple CGCG or continuous CGG sites from the restriction enzyme,indicative of simultaneous binding of small ligands |
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| Affiliation: | 1. Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan;2. Graduate School of Pharmaceutical Sciences, Nagasaki International University, 2825-7 Huis Ten Bosch Machi, Sasebo 859-3298, Japan;1. Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, 605 Fenglin Road, Nanchang, Jiangxi 330013, China;2. College of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi 330004, China;1. Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad Campus, Jawahar Nagar, Hyderabad, 500078, India;2. School of Chemistry and Molecular Biosciences and Australian Infectious Disease Research Centre, The University of Queensland, Brisbane, Australia;1. Department of Pharmacy, Health and Nutritional Sciences, DoE 2018-2022, University of Calabria, Edificio Polifunzionale, 87036 Rende (CS), Italy;2. Department of Biotechnology, Chemistry and Pharmacy, DoE 2018-2022, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy;3. Department of Life Sciences, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy;1. Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Cambridge, MA 02139, United States;2. Cardiovascular and Metabolic Diseases, Novartis Institutes for BioMedical Research, Cambridge, MA 02139, United States;3. PK Sciences, Novartis Institutes for BioMedical Research, Cambridge, MA 02139, United States |
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| Abstract: | The anthracenone ligands (1–12) with a keto-phenol and a hydroxamic acid unit were synthesized and evaluated by a restriction enzyme inhibition assay. DNA substrates composed of multiple CGCG or CGG sites are fully hydrolyzed by a restriction enzyme that is selective for each sequence. Under such conditions, the full-length DNA substrate remains only when the ligand binds to all binding sites and protects it from hydrolysis by the restriction enzymes. In the assay using AccII and the 50-mer DNA substrates containing a different number of CGCG sites at different non-binding AT base pair intervals, the more the CGCG sites, the more the full-length DNA increased. Namely, simultaneous binding of the ligand (5) to the CGCG sites increased in the order of (CGCG)5>(CGCG)2>(CGCG)1. Furthermore, the length of the spacer of the hydroxamic acid to the anthracenone skeleton played an important role in the preference for the number of the d(A/T) base pairs between the CGCG sites. The long spacer-ligand (5) showed a preference to the CGCG sites with five AT pairs, and the short spacer-ligand (10) to that with two AT pairs. The ligand (12) with the shortest spacer showed a preference in simultaneous binding to the 54-mer DNA composed of 16 continuous CGG sites in the assay using the restriction enzyme Fnu4HI that hydrolyzes the d(GCGGC)/d(CGCCG) site. Application of these ligands to biological systems including the repeat DNA sequence should be of significant interest. |
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| Keywords: | Anthracenone ligand Repeat DNA Simultaneous binding |
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