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Information × Registration Number 0223U002149, 0117U005081 , R & D reports Title Polymer conjugates of direct and indirect telomerase inhibitors: design, synthesis and study of biological activity popup.stage_title Head Dubey Igor Ya., Доктор хімічних наук Registration Date 11-02-2023 Organization Institute of Molecular Biology and Genetics of NAS of Ukraine popup.description2 The aim of this work was design, synthesis and study of new telomerase inhibitors and their conjugates with biocompatible polymers as potential antitumor agents. Numerous new heterocyclic compounds of various classes (acridines, porphyrins, cyanines, coumarins, etc.) were obtained. Efficient telomerase inhibitors with IC50 in vitro in the range 2-5 uM were found. New classes of direct and indirect inhibitors – pyrrolopyrimidines, naphthalimides, aurones – were identified. The synergy of action of direct and indirect inhibitors was demonstrated for the first time. The conjugates of inhibitors with polyethylene glycol and dextran were obtained, including the hybrid conjugates containing 2 inhibitors of different classes. The inhibitors and conjugates with antiproliferative activity in tumor cell cultures at low micro- and nanomolar concentrations (ЕС50 0.5-1.8 uM) were found, including the dextran conjugate containing both direct and indirect inhibitors, with EC50 1.5 uM. The mechanisms of biological activity of the inhibitors, in particular, their interaction with quadruplex and duplex DNA were studied using the biophysical methods and molecular modeling. Binding constants were determined; the structures and energetic parameters of complexes were calculated. New reagents for the fluorescent labeling were developed. Using the fluorescence microscopy the efficient uptake of dextran conjugates by tumor cells was shown. New telomerase inhibitors and their conjugates could be the candidates in antitumor drugs.   Product Description popup.authors Ilchenko Mykola M. Alexeeva Inna V. Dubei Ihor Ya. Dubey Larysa V. Kostina Valentina G. Kuziv Iaroslav B Lysenko Nadia A. Negrutska Valentina V popup.nrat_date 2023-02-11 Close