Design and synthesis of WR-1065 zn²+-cyclen complex

WR-1065 is active metabolite of amifostine that activate p53 protein to bind with consensus DNA. However, individual with replacement of cysteine with serine has reduces in p53 binding activity to target DNA. Additional of Zn2+ ions have significant role in regulation of p53 protein binding to specific target DNA while a novel prototype of Zn2+-cyclen derivatives had widely being used in DNA recognition. The aim of this study were to design and synthesis WR-I 065 Zn2+-cyclen complex as a new chemical entity and further complexation of Zn2+ ions with WR-I 065 cyclen complex. The consequences objective was to study the DNA binding properties of WR-1065 Zn2+-cyclen complex by using natural calf-thymus DNA. The methodologies involved seven-step synthesis ofWR-1065 appended with Zn2+-cyclen complex with bromoethane as a ligand that linked through SN2 mechanism. First, 1, 4, 7, I 0-tetraazacyclododecane or free cyclen was protected with (Boe )20 with ratio of free cyclen/(Boc)20 at 1:2.8. The major product form is 3-Boc cyclen. Second step was reaction with bromoethane to form 3-Boc cylen appended bromoethane. This compound was then undergo bromination step by N-bromosuccinimide (NBS) through free radical mechanism. The product of bromination was then linked with WR-I 065 through bromine atom substitution. The intermediates of all compounds were characterized by thin layer chromatography (TLC) and further confirmation by NMR spectroscopy (1 H). The half part of synthesis of WR-I 065 appended Zn2+-cyclen complex through SN2 mechanism shows positive result. However, the result for bromination step with NBS led to low percentage yield. Thus, the final product could not be synthesized due to scarce of material; hence DNA binding property of final product cannot be identified.