Design, Synthesis, Screening And Pharmacological Activity Of FGFR1Inhibitor And Anti-Inflammatory Drug Of Mono-Carbonyl Analogues Of Curcumin

Curcumin is the main active component of turmeric, having multiple pharmacological activities, such as anti-inflammation and anti-tumor effects. However, the β-diketone moiety in curcumin’s structure results in its instability, fast metabolism, poor bioavailability which limited the clinical application of curcumin. Mono-carbonyl analogues of curcumin (MCACs), replacing β-diketone moiety with a single carbonyl group, can effectively improve their stability and bioavailability, and also exhibit good pharmacological activities. Therefore, the drug research of curcumin analogues focus on the study of the MCACs. In this study, we designed, synthesized, screened FGFR1inhibitors and anti-inflammation lead compound based on MCACs, and studied the pharmacological activity and the mechanism of active compounds.1. Synthesis of the curcumin analoguesFour series of MCACs in two aspects (in the following two paragraphs) were designed and synthesized, including97new compounds. Spiro-heterocyclic "MA" was the novel molecular skeleton, and was yielded by One-pot Synthesis through1,3-dipolar cycloaddition reaction without catalyst. The synthesis of Spiro-heterocyclic "AB" and "MA" is not only high regioselectivity and stereoselectivity, but also environmentally friendly. The structures of all compounds were characterized by ESI-MS, and1H-NMR. In order to study the relationship between its structure and activity, we cultured and obtained11single crystals of the compounds, and resolved the single crystal structure by using X-ray diffraction.2. Design, pharmacological screening, and molecular mechanism study of the fibroblast growth factor receptor1(FGFR1) kinase inhibitorThe high expression of FGFR1is closely related to the tumorigenesis, and FGFR1inhibitors are found to be effective in treating these related tumors. In recent years, the new hot-spot research of kinase inhibitors was focused on the non-ATP competitive inhibitors. There are only three non-ATP-competitive FGFR inhibitors reported so far. In addition, their anti-tumor effect has not been tested in vivo yet.Using NDGA, which is a non-ATP competitive FGFR inhibitor, as a leading compound, we designed by comparative molecular field analysis (CoMFA) method, screened and obtained a series of novel non-ATP-competitive FGFR1inhibitors, which belong to MCACs. Our subsequent bioassay confirmed that the anti-tumor activity of several compounds was found to be better than that of NDGA.Among these active MCACs, Af23, Ad23, Aea4and Aea25effectively inhibited the proliferation and induced apoptosis in non-small cell lung cancer H460cells, which highly expressed FGFR1. Furthermore, these compounds exhibit significant anti-tumor activity in vivo via targeting FGFR1, and showed no significant toxicity.3. Design, anti-inflammatory screening and mechanism study of MCACSThe study on novel non-steroidal anti-inflammatory drugs has been the focus of the study of anti-inflammatory drugs. MCACs were regarded as better research prospect compounds with anti-inflammatory activity. By ligand-based drug design approach, we designed and synthesized three series of MCACs whose central linker are single-ketene, spiro-heterocyclic and piperidone, respectively. Multiple compounds exhibited good inhibitory effects against IL-6production in LPS-stimulated macrophages. The structure-activity relationship was discussed, and the quantitative structure-activity relationship (QSAR) modeling of type "L" compounds was summarized. Completely or partially through the MAPK/NF-kappaB pathway, the active compounds, including L0604, L0609, Aea37and Aea46, effectively inhibited the mRNA expression of inflammatory factor induced by LPS in the macrophages. Also, these compounds significantly protected the C57B/L6mice from LPS-induced septic death.This study provides a new structural lead for the drug design of non-ATP-competitive FGFR1inhibitors, and offers new thoughts and strategies in the research of MCACs targeting anti-tumor drugs. This work also provides a novel theoretical and experimental support for the anti-inflammatory MCACs drugs, and the ideal candidate compounds for the treatment of sepsis.