Synthesis Of A Group Of Taurultam Derivatives And Evaluation Of Their Carbonic Anhydrase Inhibitory Properties
Project no. 249 · Status: Kapanmış · 2016
Summary
About 30 sulfonamide/sulfamide type drug which are clinically used for their diuretic and anti-glaucoma effects, show CA inhibitory effect. Though, the compact structure of these CA inhibitors show a non-selective inhibition profile due the fact that their similar interaction with aminoacid residues at the 13 catalytically active region. These limited and similar interactions resulted with a series of side effects that could be prevented by targeting only one isozyme. As a result selective inhibition of isozymes became a challenging factor in the field of CA inhibitor drug development. Among the CA izoenzymes CA IX is known to be expressed only in hipoxic tumour enviroment which makes it to be inhibited spesifically. The structure-activity relationships indicate that a primary sulphonamide group having an organic scaffold is essential for interacting with zinc ion at the active site which is resulted with a strong inhibition. Though, selective inhibition can be achieved by elongation of this scaffold by different substutions which have different physicochemical properties. This modification method is known as “Tail approach”. This is an important methodology as it gives the oppurtinity for achieving selective inhibitors for izozymes. In this study, tail approach was used to design selective CA inhibitors and taurultam was choosen as a tail for derivatizatizion of the organic scafold. Taurultam is a derivative of taurin aminoacid and metobolite of taurolidin. It was reported as an anticancer drug at low doses and this effect was considered to be the result of its tauriamide metobolite. In the light of these data, a group of taurultam derivatives and an open analog of its derivative was synthesized. The structures of the synthesized compounds were established on the basis of IR, 1H NMR, APCI-MS and ESI-MS spectra. One of the synthesized compound was choosen for its inhibitor affinity on CA II and CA IX izozymes. And also X-ray crystallographic studies were conducted for evaluating selectivity of the compound on CA IX over CA II izozyme. The data indicated that additional interactions between the drug and active site of the CA IX izozyme were responsible for compound’s selectivity. As a result, the data obtained from this work are reported for the first time with this report and the results are considered to be useful for designing new selective inhibitors for cancer-related CA IX izozyme.