Discovery Of Multi-target Antitumor Lead Compounds Based On Quinoxalinone Scaffold And Novel Synthetic Methdology Research Of Bioactive Molecules

Protein tyrosine kinases (PTKs) play a pivotal role in the signal transduction pathways, and their deregulation is highly related to the oncology. Compounds that can inhibit the kinase activity of PTKs are proved to be potential chemotherapeutics in the treatment of malignant tumors. In recent years, great achievements have been made in the field of PTKs based on the fact that clusters of protein tyrosine kinases inhitors (PTKIs) have been designed and synthesized, and some of them have been approved by FDA for clinical usage. The discovery of PTKs inhibitors has established a milestone for the tumor targeted therapy. Hence, it is meaningful and urgent to develop more PTKs inhibitors with new chemical entities.DNA topoisomerase II is a kind of nuclear enzyme that modulates the topology of chromosomal DNA by inducing transient double-stranded break. This enzyme plays important parts in a number of DNA-related biological processes. Topo II is frequently overexpressed in diversified types of tumors, and has been proved as one of the ideal molecular targets for widely prescribed chemotherapy agents. A treasure of chemotherapy drugs that targeting Topo II, such as etoposide, doxorubicin and mitoxantrone, have been approved by FDA for marketing. Therefore, in addition to the PTKIs, Topo II inhibitor development is also a favorable research topic in caner therpy. Quinoxalinone is a ubiquitous and previliged scaffold of various pharmaceutical compounds. Quinoxalinone derivatives perform diverse biological activities including anti-tumor, anti-bacteria, anti-HIV, anti-diabetes, anti-inflammatory and so on. In ths case, several series of novel quinoxalinone derivatives based on the principle of bioisosterism and pharmacophore migration are designed, synthesized and evaluated hereby.Antiangiogenesis assay on HUVEC indicated that SLL-2, SLL-4, SLL-6, SLL-7exhibited remarkable activity, further evaluation on arterial ring of rat also indicated that the above four compounds performed antiangiogenesis activity. Topo-II inhibition assay also demonstrated SLL-Z-09, SLL-Z-10, SLL-Z-12performed potential Topo-II inhibition activity, particularly SLL-Z-09.The unsymmetrical substituted alkyne moiety is a ubiquitous structural motif of various bioactive natural products and synthetic pharmaceutical agents. In addition, alkyne moiety is an important intermediate widely used in the filed of synthetic chemistry. Hence, developing efficient methods to build unsymmetrical alkynes is a meaningful event. A mild procedure of Cu-catalyzed decarboxylative cross-coupling of aryl-and alkynyl-boronic acids for construction of asymmetric substituted alkynes has been developed in our group. The usage of inexpensive copper chloride as catalyst, and employing stable alkynl carboxylic acids and boronic acids as the substrates under oxidative conditions for SP-SP2coupling, making this method very easy to operate.Due to the ubiquitous existence of indole skeleton in pharmaceuticals and natural products, indole skeleton based modification has attracted enormous interest of medicinal chemists. Our group has been interested in designing and modifying indole derivatives. Herein, we describe an efficient transition metal-free approach for the synthesis of3-halogenated (3-Br,3-I) indoles using simple and readily available TBAB and KI as the halogen source respectively.