Design, Synthesis And Anti-tumor Activity Study Of Podophyllotoxin Derivatives And Total Synthesis Of A 4,5-Dioxoaporphine Alkaloid-Artabotrine

An important approach for the discovery of antitumor drugs is the synthesis and structure modifications of active natural products. Podophyllotoxins and isoquinoline alkaloids, wide-spreaded in plants, are two kinds of antitumor natural products. In this thesis, the studies were carried out on them and consisted of two parts.The first part is the design, synthesis, anti-tumor activity and SAR studies of podophyllotoxin derivatives, including two classes, four series of new compounds. One class of compounds is composed of three series of novel compounds as hybrids of podophyllotoxin with different types of isoquinolines. These three series of compounds we designed were 1-phenyl-3,4-di-hydroisoquinolines, 1-phenylisoquinolines and N-benzoyl-1-phenyl-1,2,3,4-tetra-hydroisoquinolines with different substitutes on B and E rings. The other class of compounds is 4-deoxyisopodophyllotoxins with unsaturated aliphatic side chains on the E-ring or with the D-ring opened.In vitro biological evaluation indicated that some of the synthetic compounds existed remarkable cytotoxicities with IC50 Values on selected tumor cell lines at 10^-6 mol/L scale. With the cytotoxicitic results, SAR studies of three series of hybrids were performed, and a 3D-QSAR model was built by the preliminary CoMFA molecular-modelling study, which could be a guide for further drug design.The second part is the total synthesis of a novel cytotoxic 4,5-dioxoaporphine alkaloid, artabotrine (6.1), and one of its analogue N-methoxycepharadione B (6.2). The syntheses started from guaiacol, which was commercially available. By Suzuki cross-coupling reaction, the key intermediates biphenylacetamide were obtained. Following with the condition of (COCl)₂/SnCl₄, the target compounds were facilely achieved by one-pot sequential C/B ring formation. This pathway simplifies the synthesis of 4,5-dioxoaporphines, which is significant for future research of this kind of alkaloids.Moreover, the two targets were subjected to the screening of cytotoxicity in vitro. Artabotrine did not exhibit potent activity, while its analogue 6.2 was cytotoxic to Hela cells and could be a lead compound for further study.