Synthesis of Nitroxide based DNA binding Radioprotector for the Modification of Radiation Damage to DNA

Abstract

© 2024 Rezwana Nasrin ChowdhuryTreatment during cancer often involves radiation therapy which requires ionizing radiation. However, surrounding normal healthy tissue gets affected during the process which decreases the quality of life and increases the occurrence of cancer later in life. One of the primary concerns of ionizing radiation is the production of free radicals of important biological structures such as DNA, RNA, proteins etc. due to stripping of electron during the high energy radiation phenomenon. The free radicals generated during radiotherapy could directly or indirectly attack the DNA molecule and break the DNA phosphate – deoxyribose backbone with consequences leading to permanent damage to the DNA ‘code’ (ie. mutation) and even cell death resulting in adverse effects on human health. Amifostine is the only approved radioprotector that quenches free radicals produced due to oxidative DNA damage. However, DNA damage still observed which led to the approach for synthesizing new radioprotector compounds with DNA binding ability. Previously White group have successfully synthesized minor groove binding compounds bibenzimidazoles that reduces the DNA strand breakage by electron donation to damaged DNA radical cations. Although high dose requirements lead to the idea of synthesizing nitroxide radicals attached DNA minor groove binding compounds with similar electron donating mechanisms as bibenzimidazoles for the radioprotection activity. This thesis is based on the synthesis of Distamycin analogue attached with different nitroxide radicals and analysing their DNA binding and radioprotection ability. Compounds 43, 45, 46, 48, 49, 50, and 57 were synthesized successfully with various radicals and their DNA binding ability were examined using UV spectroscopy, Circular dichroism, and molecular docking methods. All the compounds showed varying degrees of DNA binding