I. Study on Synthesis and Biological Activities of Stevioside Analogues; II. Study on Cytotoxicity of Cantharidinimide Derivatives

• Main Authors: Lun-Huei Lin, 林倫輝
• Other Authors: Pen-Yuan Lin
• Format: Others
• Language: zh-TW
• Published: 2004
• Online Access: http://ndltd.ncl.edu.tw/handle/71057927346630345599

博士 === 臺北醫學大學 === 藥學系 === 92 === I.The medicinal preparations based on the modification natural compounds frequently exceeded the native substances in the activity. In this connection investigation into the chemistry and pharmacological properties of bioactive natural substances has become an important direction in the modern bioorganic and medicinal chemistry. The renewed interest in Stevioside reflects the general trends observed in medicine were remedies of the natural origin are finding an increasing application. Stevioside 3, an ent-kaurene glycoside extracted from Stevia rebaudiana Bertoni (Compositae), is used not only as a food additive for sweetening purposes but for anti-hypertensive, anti-hyperglycemia, anti-inflammatory and suppressed the tumor-promoting effects. Thus, stevioside analogues would be of interest to exploit its potential activities and to establish structure activity relationships. Twenty-two novel steviolbioside analogues and their related steviol and isosteviol dimers are prepared using aliphatic alkylamines and alkyldiamines by the activated esters method (PyBOP coupling). The structures of these compounds were established using spectroscopic analysis including IR, 1H NMR, 13C NMR, FABMS, and LC/MS/MS(ESI). The results obtained, however, strongly confirm the influence of amine nucleophilicity, basicity, the steric hiderance and reaction termerature somewhat influenced the formation of steviolbioside carboxamides. Glycoside sugars did not seem to perturb the coupling reactions of carboxamides. The cytotoxicities of all of the synthesized compounds to cancer cell lines and human embryo lung cells are examined. These results suggest that the cytotoxic effect on cancer cells involves many different structural domains of the compounds. The antibacterial activities of these synthesized compounds were also detected using modified microplate antibiotic susceptibility testing method (MMAST) with both gram-positive and gram-negative bacteria. The results indicated that compound 2t is more-potent antibacterial effect than penicillin G on Bacillus subtilis (BCRC 10029). Prior to this study, the available information on dimerization and glycodic moiety of SAR indicated that molecular recognition involved specific receptor interactions. We propose that the various chain lengths can change the binding of ligands to their respective receptors and thereby improve biological activities. II.Cantharidin is found in Mylabris caraganae and various other insects and has an extremely high potency with antitumor properties, causes leukocytosis and inhibition of protein phosphatase activity. However, it is rarely employed to the therapeutic treatment owing to the irritation and vesication side effects and as toxic properties. In our previous studies, a series of N-thiazolyl and thiadiazolyl cantharidinimides were prepared starting from cantharidin with various amines in triethylamine by heating to ca. 200 oC, and the analogues with better solubility showed cytotoxicity against human hepatocellular carcinoma cell lines, which encouraged us to prepare cantharidinimide derivatives. This present study, the aliphartic cantharidinimide 3a—3c is synthesized and the cytotoxicity of aliphartic, aryl, and pyridyl of twenty-one derivatives and cantharidin is investigated against Hep G2 and HL-60 cell lines. Cytotoxicity tests shows that Cantharidin 1 is more toxic and exhibits greater cytotoxicity, while synthesized cantharidinimides is less toxic but also exhibits inhibitory effects. It can be suspected that the decrease with the inductive electron negative effect of the N-substituted group will decrease the yield and increase the cytotoxicity. The results suggest that the presence of a nitropyridyl or nitrophenyl moiety display strong inhibitory effects on both cell lines as did cantharidin.