Synthesis, characterisation and theoretical studies on 2,6-BIS (1,4,7,10- tetraazacyclododecane propylamine) pyridine for DNA binding agent

The aim of the study was to synthesize a ligand of 2,6-Bis(l,4,7,10- tetraazacyclododecane propyl amine) pyridine that can form complex with Zn2+ ion which can be potentially used as anti-helminthic. Synthesizing of this compound involved seven steps of chemical reactions. First step is the dehydrochlorination of cyclen tetrahydrochloride salt to yield cyclen. Second step involved the protection of three nitrogen in the cyclen using Boe, leaving one nitrogen without protection. The product of this reaction was 3Boc-cyclen. Third step was the bromination of methoxypropylamine to yield bromopropylamine. Next step was the reaction of bromopropylamine with 3Boc-cyclen to yield 3Boc-cyclen propylamine which was the arm for the proposed molecule. Then, it would be reacted with the 2,6- pyridinediarnine to form 2,6-pyridinediamine di-3Boc-cyclen propylamine. The sixth step was the removal of all the Boe from the cyclen to yield 2,6-Bis(1,4,7,10- tetraazacyclododecane propyl amine) pyridine. The product was then complexed with Zn2+ ion. However during the fourth step which is the reaction of bromopropylamine with 3Boc-cyclen to yield 3Boc-cyclenpropylamine, only a small amount of cyclen arms were successfully produced which hindered further steps of synthesizing this proposed molecule. In order to understand more on the physical properties of the proposed molecule, the theoretical studies had also been performed using quantum mechanical software package of Gaussian09 at the theoretical level of DFT B3LYP 6-31G(d,p). One of the importance uses of these parameters are to evaluate the interaction energy between the proposed compound with selected transition metal (M2+) ions such as Fe2+, Co2+, Ni2+, Cu2+, Zn2+, Pd2+ and pf+. Results showed that only Zn2+, Ni2+, Pd2+ and Pt2+ could form stable metal complexes with the proposed ligand where the interaction energy in decreasing order are Ni2+ ( 795.7 kJ/mol) > Pt2+ ( 720.7 kJ/mol) > Pd2+ (473.6 kJ/mol) > Zn2+ (398.8 kJ/mol). It is worth to mention that the L\E gap also is of the same order as the interaction energy: Ni2+ (1.63 eV) < Pt2+ (1.77 eV) < Pd2+ (1.98 eV) < Zn2+ (2.15 eV). Measurement on the distance between the two metal ions revealed that there were not very much different in size and in the order of 14 A: 14.59 A (Zn2+), 14.32 A (Ni2+), 14.24 A (Pd2+) and 14.32 A (Pt2+). Due to Zn2+ is needed as an active ingredient in anti-helminthic, the complex of this metal ion was further tested with four types of nucleotides which are thymidine, guanidine, adenosine and cytidine. Results showed that only thyrnidine could form a stable complex with the proposed metal complex with the interaction energy of 797.2 kJ/mol and the distance (Zn2+ to N of cyclen) of 2.24 A. The distance between the two Zn2+ ions is also reduced from 14.59 A to 11.90 A. Based on the global softness values of the metal complexes between 0.93 (Zn2+) and 1.23 (Ni2+), it is believed that these metal complexes of 2, 6-Bis(1,4,7,10- tetraazacyclododecane propyl amine)pyridine with Zn2+, Ni2+, Pd2+ and Pt2+ are compatible to human body and therefore can be used as a groove binder to DNA nucleotides specifically to thymidine.