北島 満里子

Mitragynine (1) is the major alkaloid in the traditional medicinal herb Mitragyna speciosa Korth. (Adkins et al. 2011 Raffa et al. 2013 Takayama 2004 Takayama et al. 2005 Watanabe et al. 1999), and has been proven to exhibit analgesic activity (Horie et al. 1995, 2005 Matsumoto et al. 1996a, b, 1997, 2005 Thongpraditchote et al. 1998 Tohda et al. 1997 Watanabe et al. 1997) mediated by opioid receptors. This natural product has been used as a seed molecule for the development of new analgesic in medicinal chemistry. This chapter covers published work on the syntheses of mitragynine derivatives, the evaluation of their analgesic activities, and the structure–activity relationship studies of mitragynine analogs.

Colchicine (1) is a well-known bioactive alkaloid that is used for the therapy of acute gout. It also acts as an antimitotic agent by binding to tubulin. However, practical anti-cancer medicines derived from colchicines have not been developed so far because of their toxicity to normal cells. In the present study, a series of novel colchicine derivatives possessing various substituents at C-4 position were prepared from colchicine (1). Among them, 4-halocolchicines 3-6 were found to exhibit more potent cytotoxicity to the tumor cells (A549, HT29, HCT116) than 1. Evaluation of the cell-growth inhibitory activities of 4-fluorocolchicine (3) and 4-chlorocolchicine (4) using mice transplanted with the HCT116 human colorectal carcinoma cell line by intraperitoneal injection demonstrated that they are capable of reducing the intrinsic toxicity of colchicine (1) and show potential for use as a clinical drug. We designed safer and more effective antitumor agents based on a tumor-activated pro-drug strategy that involved the release of free drug by the action of cathepsin B, an enzyme overexpressed in tumor cells. We prepared pro-drug 13 which consist of three parts: 4-fluorodeacetylcolchicine (12) as the active drug that would be generated by the action of cathepsin B; the lysosomally cleavable dipeptide Phe-Lys; and the self-immolative p-aminobenzyloxycarbonyl spacer between the active drug and the dipeptide. We confirmed that pro-drug 13 released the active drug 12 via the action of cathepsin B. Pro-drug 13 exhibited an approximately two-fold higher selectivity for tumor cells than normal cells. We next designed double pro-drug 21 that was activated first by nitroreductase under hypoxia, which is a common characteristic of solid tumors, to generate pro-drug 22 and then by cathepsin B to generate the active drug 23. Double pro-drug 21 was prepared by the coupling of dipeptide 36 with N-Boc colchicine derivative 37. Biological evaluation of double pro-drug 21 is currently underway.

Plants of the Kopsia genus (Apocynaceae) ranging from evergreen trees to shrubs are well known as fertile sources of structurally diversified indole alkaloids. There are 23 species belonging to this genus, which has a widespread distribution from southern China and Burma to northern Australia and Vanuatu and is most diverse in Peninsular Malaysia and Borneo. Among them, Kopsia officinalis Tsiang et P.T. Li (this species was amended to Kopsia arborea in the view of Dr. Middleton's latest revision) indigenous to Yunnan province in southwest of China has been reported for medicinal uses for the treatment of rheumatoid arthritis, dropsy, and tonsillitis. As a part of our ongoing program to search for novel and bioactive indole alkaloids, phytochemical research on this plant has led to the isolation of more than 40 alkaloids. Of these, several, such as arboloscine (10) and mersicarpine (11) are interesting for incorporating intriguing molecular skeletons. In this symposium, we present the structure elucidation of six unusual indole alkaloids, i.e.: the novel dimeric indole alkaloid kopsiyunnanine A (1), the novel rearranged oxindole alkaloid kopsiyunnanine B (2), three novel rhazinilam analogues kopsiyunnanine Cl (4), kopsiyunnanine C2 (5) and kopsiyunnanine C3 (6), and an unusual quebrachamine derivative kopsiyunnanine D (8) (Figure 1). In addition, one another novel alkaloid, named kopsiyunnanine E (9), which possesses a particular notable pentacyclic carbon skeleton incorporating a lactone ring, will be also introduced.