Design And Synthesis Of A New Series Of Pyrazolopyridine Compounds With Potent Anti-tumor Activities

This thesis consists of the design and synthesis of a new series of Pyrazolopyridine compounds with potent anti-tumor activities.Pyrazolopyridine derivative is an important class of fused heterocyclic. Pyrazolopyridines have attracted considerable attention due to their widespread biological activities and their structure similarity with indole and aza-indole. These compounds have good results in the cure of Gram's negative and positive bacteria, tumors and cancer, asthma, neurological diseases, bone osteoporosis, and senile dementia. Pyrazolopyridines mainly include Pyrazolo[3,4-b]pyridines, Pyrazolo[1,5-a] pyridines, Pyrazolo[4,3-c]pyridines and other series.But pyrazolo[1,5-a]pyridines have attracted more attention than other series. The synthesis methods of pyrazolo[1,5-a]pyridines include:a, by the method of N-amino pyridinium; b, by the method of N-aminopyridines with alkynes; c, by the method of Lithium 5-Lithiomethyl-3-methylpyrazole-1-carboxylate and its Reaction with a-Oxoketene Dithioacetals, d, by the method of an unusual intramolecular condensation of a,β-unsaturated esters with aldehydes. And their biological activities include:a, as inhibitor of herpes; b, as Dopamine receptor antagonists; c, as potent p38 kinase inhibitors; d, as Adenosine Al Receptor Antagonist. However, few reports exist in the literature regarding the anticancer activity of pyrazolo[1,5-a] pyridines, which prompted us to explore the antitumor activity of pyrazolo[1,5-a]pyridine scaffold.Survey of literature revealed that isoxazole and isoxazole derivatives are also one important class of heterocyclic compounds. They are not only important intermediate synthon in organic synthesis, but also the potent compounds with the broad spectrum pharmacological activity and biological activity. Their pharmacological activities include analgesics, anti-inflammatory, anti-TB, anticonvulsant, anti-bacterial, anti-neurological excitement and treatment of Alzheimer's disease and so on. Because isoxazole heterocyclic compounds containing nitrogen compounds are also hot spots of biological activities research, the chemists and pharmaceutical scientists are interesting in the isoxazole heterocyclic compounds. Recently many scientists introduce isoxazole ring into the target compounds to improve the antitumor activity of compounds and have received good results.Therefore we are interested in the incorporation of isoxazole core into pyrazolo[1,5-a]pyridine scaffold to improve the biological activity. Thus, ethyl 3-[5-(aminomethyl)isoxazol-3-yl]-2-phenyl H-pyrazolo[1,5-a]pyridine-5-carboxylates were designed and synthesized. In continuation of our previous work,11 final compounds (lla-llk) were synthesized in 8 steps from acetophenone. The structures of all the final compounds and the important intermediate compounds have been confirmed by 1HNMR,13CNMR, IR and LC-MS analysis.Then, the new pyrazolo[1,5-a]pyridine derivatives were evaluated in vitro against the cell proliferation of several human tumor cell lines. The human tumor cells included human pancreatic cancer SW-1990 cells, human bladder cancer T-24 cells, human breast cancer MCF-7 cells, human lung cancer A-549 cells. The compounds (10, 11c, 11e) exhibit potent activities against human pancreatic cancer SW-1990 cells, human bladder cancer T-24 cells, human breast cancer MCF-7 cells, human lung cancer A-549 cells. Compound 11d exhibits excellent special activities against human lung cancer A-549 cells and human breast cancer MCF-7 cells.