| Oxoaporphines alkaloids is a kind of isoquinoline alkaloids with striking structural diversities as well as significant biological activities.Oxoaporphines are present in minor amounts inplants although it can be found in several families of plants,such as Magnoliaceae,Tetrandraceae,Euphoraceae,Camphor,Raniaceae,Lychee,Aristolochia,Berberaceae,Papaver,Ranunculaceae,Rutaceae and so on.The wide range of pharmacological properties exhibited by 7H-dibenzo[de,g]quinolin-7-one alkaloids have attracted the chemists’ attention,since the first isolation of liriodenine from Atherospermamoschatum.Over the past several decades,some methodologies have allowed access to dibenzo[de,g]quinolin-7-one alkaloids.Unfortunately,some disadvantages such as the low yield,the long synthetic steps,and the severe reaction conditions,limited their applications.Herein,a new synthetic route has been redesigned in this thesis.Oxoaporphines alkaloids were effectively synthesized in one pot from 8-bromoisoquinoline or 8-isoquinolinyl-boronic acid.In thesis,twenty oxoaporphines alkaloids and its five new rare earth complexes were synthesized,and their antitumor activity were investigated.The main contents are as follows:(1)The research progresses of the metal-based anticancer drugs and their clinical applications and pharmacological activity have been reviewed.What’s more,the classify of aporphine alkaloids and oxoaporphine alkaloids also have been introduce including the biological activities such as anti-tumor,antioxidant,antibacterial and antiviral activities.Several synthetic approaches for the production of oxoaporphine cores have been summarized in this thesis.The following methodologies have allowed access to 7H-dibenzo[de,g]quinolin-7-one alkaloids:(a)Coupling of rings A/D:using the Pschorr cyclization of 1-(2-amionbenzoyl)isoquinoline,and other methods are photocyclization or Bu3SnH-induced aryl radical cyclization.(b)Ring closure between rings B and D:intramolecular Friedel-Crafts acylation of 8-phenyl-3,4-dihydroisoquinolines in polyphosphoric acid has been utilized.(c)A convergentmethod involving the intermolecular[4+2]cyclo addition ofprotected 1-methylene-isoquinoline with benzyne or(methoxyimino)phenanthren-9-one with dimethyl acetylene dicaboxylate(DMAD)to provide the tetracyclic skeleton.(d)Using the heck coupling also can give the 7H-dibenzo[de,g]quinolin-7-one alkaloids skeleton.(2)In this thesis,we development of an novel efficient one pot method for the preparation of oxoaporphine structures.Based on Suzuki coupling and oxidativecross-dehydrogenative-coupling,we finally succeed to get the 7H-dibenzo[de,g]quinolin-7-one alkaloids skeleton.Twenty kinds of oxoaporphine alkaloids and five rare earth complexes were synthesized by the novel one pot method.Among of them,there are 16 new oxoaporphines and five new rare earth complexes which have not been reported.The structures are as follows:9-methyl-7H-dibenzo[de,g]quinolin-7-one 9-hydroxy-7H-dibenzo[de,g]quinolin-7-one 10-methyl-7H-dibenzo[de,g]quinolin-7-one 10-fluoro-7H-dibenzo[de,g]quinolin-7-one 10-methoxy-7H-dibenzo[de,g]quinolin-7-one 9-chloro-7H-dibenzo[de,g]quinolin-7-one 9-(benzyloxy)-7H-dibenzo[de,g]quinolin-7-one 9-methoxy-7H-dibenzo[de,g]quinolin-7-one 10-chloro-7H-dibenzo[de,g]quinolin-7-one 9-(benzyloxy)-3-methoxy-7H-dibenzo[de,g]quinolin-7-one 8-fluoro-7H-dibenzo[de,g]quinolin-7-one 2,3-dimethoxy-7H-dibenzo[de,g]quinolin-7-one 3-methoxy-7H-dibenzo[de,g]quinolin-7-one 9-(benzyloxy)-2,3-dimethoxy-7H-dibenzo[de,g]quinolin-7-one 9-hydroxy-2,3-dimethoxy-7H-dibenzo[de,g]quinolin-7-one 9-hydroxy-3-methoxy-7H-dibenzo[de,g]quinolin-7-one[La(C16H9NO)3(NO3)3][Sm(C16H9NO)2(NO3)3][Ce(C16H9NO)2(NO3)3][Eu(C16H9NO)2(NO3)3][Pr(C16H9NO)2(NO3)3]The structures of all the complexes were determined by 1HNMR,ESI-MS spectrometry and single crystal X-ray diffraction analysis.(3)By MTT assay,we conducted the preliminary screening of antitumor activities in vitro of these 20 compounds and 5 rare earth complexes against 5 kinds of tumor cell lines(MGC-803,T-24,SK-OV-3,HepG2,Hela)and human normal liver cell line HL-7702,WI-38.The results showed that compounds 4,4B,4G,4L,4Q,4R,4S and 4X had exhibited good activities on the tumor cell lines.The compounds 4B、4Q and 4R shows higher activity on human gastric carcinoma cell(MGC-803)cell lines with IC50 of 10.0±1.2 μm,9.2±0.8 μm and 7.3±0.7μm,respectively.The 5 kinds of complexes on five kinds the tumor cell lines exhibited good activity.The compounds 4,4G,4R,4S and 4X shows higher activity on human bladder transitional carcinoma cells(T-24)cell lines with IC50 of 9.5 ± 0.25 μm,8.6±0.7 μm,6.5 ±0.5 μm,7.3±1.7 μm and 7.3±1.6 μm,respectively.The IC50 of compound 4L to human hepatocellular carcinoma cell line is 7.3+0.5 μm.The IC50 of compound 4R to SK-OV-3cellline IC50 is 10.4±1.3 μm.The Complexs 4-Pr,4-La,4-Sm on human gastric carcinoma cell(MGC-803)cell lines exhibited good activity with IC50 of 4.2±0.2 μm,3.2±1.3 μm,1.0±0.8μm.Flow cytometry was used to detect the effects of compounds 4 and 4B on the cell cycle of corresponding tumor cell lines.The results showed that complexe 4 caused T-24 tumor cells arrest in G2/M phased and can induce the early apoptosis;the compound 4B make T-24 tumor cells arrest in G2/M phased and can induce the early apoptosis.Moreover,compounds 4 and 4B were carried on a further xenograft mouse models.The results showed that tumor growth inhibition rate of compound 4 is 41.3%and displayed weaker antitumor activity than cisplatin(55.9%);The tumor growth inhibition rate compounds 4B is 41.1%and weaker than cisplatin(49.1%).But,we also found that 4B exhibit lower toxic effects comparable to cisplatin. |
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