Total Synthesis And Activity Evaluation Of Marine Alkaloid Aaptamine Derivatives

Sponge is one of the sources of new drug creation and a treasure trove of new chemical molecular entities.Secondly,there are many kinds of raw metabolites and the chemical structure is extremely rich.About one-third of the new marine natural products found are derived from sponges.Aaptamines are a class of alkaloids unique to sponges that have a unique benzo[1,6]naphthyridine skeleton.These compounds have good biological activity,especially in anti-tumor.In 2014,our group discovered a series of amino acid substituted aaptamine derivatives at the C-3 position from the South Sea sponge Aaptos aaptos,and screened them for activity.The results showed that 3-（phenethylamino）demethyl（oxy）aaptamine(hereinafter referred to as Multiple compounds including PAAP can significantly inhibit lung cancer stem cell activity.Intensive pharmacological studies have demonstrated that PAAP can target Chk1 and inhibit the ATM/Chk1/Cdc25/Cdc2 signaling pathway when used in combination with the chemotherapy drug cisplatin.It can eliminate the cell cycle arrest induced by chemotherapy drugs and increase the sensitivity of lung cancer stem cells to chemotherapy drugs.In this paper,aiming at the active natural product PAAP,starting from the commercially available 6,7-dimethoxy-isoquinoline,various methods for constructing the aaptamine three-membered ring have been tried,and three key intermediates have been selected for experimentation.Finally,through the 7-step reaction of palladium-catalyzed reduction cyclization and hydrogen bonding,such as nucleophilic addition-oxidation series,the total synthesis of natural product PAAP is achieved with a total yield of more than 20%,and structural transformation is carried out on this basis.A series of PAAP analogs were synthesized.In addition,in this thesis,the natural product aaptamine was structurally modified,and 30 C-3,C-7 aromatic substituted derivatives were synthesized based on the Suzuki reaction.Pharmacological experiments have shown that the structural modification work significantly enhances the anti-tumor activity of the compounds.Several compounds have human breast cancer MCF-7 cells,human cervical cancer Hela cells,human lung cancer H460 cells,leukemia NB4 cells and lymphoma SNK-6cells.Strong inhibition,IC₅₀values range from 0.6-10μM.