Design, Synthesis And Bioactive Evaluation Of Pyrazolyl-Acylhydrazone Derivatives As Telomerase Inhibitors

Telomeres are specialized structures at the ends of human chromosomes and consist of protein unit and DNA component which is composed of non-coding tandem repeats of TTAGGG nucleotide DNA sequences and serve as protective "caps" at the ends of chromosomes, protecting them from DNA degradation and unwanted repair. Telomeres shorten with each successive cell division in normal human cells, whereas, in tumors, they are continuously elongated by human telomerase. Telomerase as an enzyme is responsible for the renewal of the chromosomal ends. By preventing them from shortening with each cell cycle, telomerase is able to inhibit cellular senescence and apoptosis. Thus telomerase activity was suggested as diagnostic cancer marker and prognosis factor.Pyrazole derivatives are a very encouraging class of five-element heterocyclic compounds with two consecutive nitrogens. Due to the unique structure and electron rich system, it exhibit potent and diversform substitution and metal-chelating, which contribute to its wide application in some fields, such as, medicine, agrochemical, multi-functional materials and catalysis industry. Furthermore, pyrazole derivatives have remarkable pharmacological activities as antibacterial agent, tumor necrosis inhibitor and insecticide, etc. Consequently, pyrazole framework plays an essential role and was chosen as a template for medicinal chemistry.Acylhydrazones are a class of Schiff base compounds with a common structure of-C(O)-NH-N=C-, which exhibit potent coordination in multiple forms. First of all, acylhydrazone derivatives could form complexes with metal ions. Moreover, acylhydrazone group might form hydrophobic interaction and hydrogen bond with targeting protein or DNA resulting in, probably, inhibiting cell proliferation.Given the above research and hypothesis of the pharmacological function of acylhydrazone derivatives, hydrazone group was introduced into the pyrazole motif, expecting that they might exhibit synergistic effect in anticancer activities by the inhibition against telomerase.A series of pyrazolyl-acylhydrazone derivatives (le-20e) have been designed and synthesized and their biological activities were also evaluated for telomerase inhibition and tumor cell antiproliferation. Among all the compounds,12e showed the most potent activity in vitro, which inhibited the growth of MCF-7 and B16-F10 cell lines with IC50 values of 0.57±0.03μM and 0.49±0.07 μM, respectively. Compound 12e also exhibited significant telomerase inhibitory activity (IC50=1.9±0.43μM). The result of flow cytometry (FCM) demonstrated that compound 12e induced cell apoptosis. Docking simulation was performed to insert compound 12e into the crystal structure of telomerase at ATP binding site to determine the probable binding model. Based on the preliminary results, compound 12e with potent inhibitory activity in tumor growth may be a potential anticancer agent. Based on the activity data, QSAR model was also built to study the structure-activity relationship and guide the further study.