Synthesis And Anti-tumor Activity Of The Marine Alkaloid Pityriacitrin And Its Derivatives,Emodin Glycoside Analogues

The thesis is composed of two parts: the first one is synthesis and anti-tumor activity of the marine alkaloid pityriacitrin and its derivatives, and the second one is synthesis and anti-tumor activity of emodin glycoside analogues.1.β-Carbolines exist widely in nature as a thoroughly investigated family of indole alkaloids. They have attracted more and more interests because of their anti-tumor activity.Pityriacitrin possesses theβ-carboline moiety to which an indole ring is attached at C-1 by carbonyl group, isolated from a marine bacterium of the genus Paracoccus (strain F-1547), and also from the yeast Malassezia furfur. Chemical synthesis of pityriacitrin has not been reported in the literature. Marine alkaloids are normally isolated in very small quantity, which hinders us to research their biological activities and further structure modification. So, it's necessary to find out chemical methods to synthesize them. Laboratory synthesis of marine alkaloids in larger quantity will allow us to perform a more complete study of their biological activities.Compared to the general two-step Pictet-Spengler reaction, the modified one-pot oxidation reaction is more efficient and convenient in preparing 1-aromatic carbonyl substitutedβ-carbolines without the need of aromatization step. Using the modified Pictet-Spengler reaction,β-carboline alkaloid pityriacitrin (9) and a series of its derivatives 10-16 have been synthesized. At the same time, another three 3-carboxy substitutedβ-carboline alkaloids 17-19 are obtained. Pityriacitrin B (17) is also synthesized for the first time as a natural compound. All compounds have been characterized by IR, NMR and mass spectrometry. They are all new compounds synthesized by chemical method for the first time.The in vitro anti-tumor activity of all the synthetic compounds is evaluated against the MCF7,MDA231,PC3 cell lines by the standard MTT assay. Pityriacitrin exhibits poor anti-tumor activity, however, some of its derivatives exhibit good anti-tumor activity against the three cell lines. 5'-methoxy substituted compound 10 (IC50 = 6.94,18.82,49.89μM) and 6-hydroxy substituted compound 13 (IC50 = 12.94,6.35,16.37μM) exhibit high anti-tumor activity. The preserved carboxy on 3 position ofβ-carboline is important to the anti-tumor activity. The 5'-methoxy and 3-carboxy substituted compound 18 exhibits the best anti-tumor activity (IC50 = 3.4,12.09,32.3μM).2. Emodin possessing planar polycyclic aromatic system has lower DNA binding affinity and lower or less insignificant cytotoxicity against cancer cells. Addition of side chains such as polymethyleneamine, sugar or heterocyclic to emodin chromophore, is usually effective to gain higher DNA binding affinity and anti-tumor activity. In order to improve its DNA binding affinity and anti-tumor activity, some new emodin glycoside derivatives are synthesized by attaching various saccharide side chains to emodin.Using the phase transfer catalysis method, 1,8-dihydroxy-3-methyl-6-[(2,3,4,6- tetra-O-acetyl-β-D-galactopyranosyl)oxy]-9,10-anthracenedione (3) and 1,8-dihydro- xy-3-methyl-6-[(2,3,4-tri-O-acetyl-β-D-xylopyranosyl)oxy]-9,10-anthracenedione (4) are synthesized. 1,8-Dihydroxy-3-methyl-6-(β-D-xylopyranosyloxy)-9,10-anthrace- nedione (5) is obtained by deprotection of compound 4. They are all synthesized by chemical method for the first time and characterized by NMR and Mass spectrometry.The in vitro anti-tumor activity is evaluated against the MDA231 cell line by the standard MTT assay. They are proven to possess moderate anti-tumor activity.