Anti-inflammatory effects of 7-methoxycryptopleurine and structure–activity relations of phenanthroindolizidines and phenanthroquinolizidines

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Abstract

A cryptopleurine analogue, 7-methoxycryptopleurine, a phenanthroquinolizidine, was first found to exert potent anti-inflammatory activity in vitro and in vivo as well as have remarkable cytotoxic activity against cancer cells. The non-planar structure between the two major moieties, phenanthrene and indolizidine/quinolizidine, played a crucial role in the activity of phenanthroindolizidines or phenanthroquinolizidines in terms of cytotoxic effects on cancer cells and anti-inflammatory activity. We also showed that increase in planarity and rigidity of the indolizidine/quinolizidine moiety and change of the amine group into an amide by introducing a keto group to phenanthroindolizidines or phenanthroquinolizidines at the equivalent position 9 of tylophorine significantly reduced their activities. Moreover, in general, phenanthroquinolizidines are more potent than their respective phenanthroindolizines.

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Chemical synthesis

Compounds 1ad, 2ad, and 3ad were prepared as previously described [11]. The chemical syntheses of 4ad involved modified methods of Chuang et al. [11] from the Wittig reaction between phenanthrene-9-carboxaldehyde and (carboethoxymethylene)triphenylphosphorane followed by hydrolysis, azidozation, Curtius rearrangement and cyclization. Then, 2H-2-aza-triphenylen-1-one was obtained, deliquesced in DMF, and treated with NaH, followed by subsequent N-alkylation with 1-bromo-4-chlorobutane at

Anti-inflammation of cryptopleurine analogue

Compound 7-methoxycryptopleurine (2a), the quinolizidine counterpart of tylophorine (Fig. 1) was investigated for anti-inflammatory effects in terms of inhibition in (1) the protein expression of the pro-inflammatory factors iNOS and COX-2 in LPS/IFNγ-stimulated macrophages in vitro; and (2) murine paw edema induced by carrageenan in vivo.

RAW264.7 macrophages are a tumor cell line derived from ascites of a male mouse with tumor induced by Abselon Leukaemia Virus. This induction may alter the

Discussion

Phenanthroindolizidines and phenanthroquinolizidines are structurally related alkaloids and potent cytotoxic agents [4]. In contrast to the recently investigated anti-inflammation-related activities of phenanthroindolizidines, not much has been reported for phenanthroquinolines. Here, we report on the anti-inflammatory activities of a cryptopleurine analogue, revealing that the two classes of compounds, phenanthroindolizidines and phenanthroquinolines, might exhibit similar potent

Acknowledgments

We appreciate grant support by NHRI, Taiwan, ROC (BP-095-PP-04) and the National Science Council of Taiwan, ROC (95-320-B-400-010-MY3). We are thankful for the plant materials of Tylophora indica supplied by Natural Remedies Pvt. Ltd. (India) and the help from Dr. Hsin-Wei Chen and Miss Jy-Ping Tsai in the isolation of murine primary macrophages.

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