Akuammiline alkaloids

Minfiensine (99) [43] exemplifies a variety of indole alkaloids containing the novel l,2,3,4-tetrahydro-9a,4a-(iminoethano)-9/7-carbazole ring skeleton. These include minfiensine (99), vincorine (100) [44], corymine (101) [45], and echitamine (102) [46] (Fig. 4). They exhibit a number of impressive biological activities, including significant anticancer activity [47]. Since the first characterization of the first akuammiline alkaloid member echitamine (102), more than 80 years ago, only a few successful syntheses of this challenging tetracyclic system have been reported. 

Recent Reports on the Isolation and Biological Activity of Members of the Akuammiline Alkaloid Family... 

Studies Concerning Akuammiline Alkaloids Containing the N4—C2 Scaffold Connectivity... 

The akuammiline alkaloids, a family of nitrogen-based natural products comprised of complex scaffolds, found in many plants of the Apocyna-... 

The chapter that follows will supplement the above referenced work in order to provide a timely update on the field through 2014. Included here will be a brief overview, followed by a report on the new alkaloids, and the akuammiline alkaloid bioactivities that have been reported since the Ramirez review. We will then turn to a comprehensive summary of the early efforts toward total syntheses and the reports on completed total syntheses that have been published in recent years. 

There are now numerous scaffolds that comprise the akuammiline alkaloid family. Illustrated below are representative examples of the various architectures that can arise from the akuammiline and echitamine cores (Figure 2). 

RECENT REPORTS ON THE ISOLATION AND BIOLOGICAL ACTIVITY OF MEMBERS OF THE AKUAMMILINE ALKALOID FAMILY... 

There have been numerous reports on the isolation of novel akuammiline alkaloids in the years since publication of the 2003 Ramirez review. 

For example, the akuammiline alkaloids have been reported to have anticancer activity. AspidophyUine A (8), 2(S)-10-methoxycathafbhne (69), 10-demethoxyvincorine (70), 11-methoxyvincorine (71), and 11-deme-thoxyquatemine (74) have aU been shown to reverse drug-resistance in drug-resistant KB ceUs. N-Methyl aspidodasycarpine (55) displayed moderate cytotoxicity against PC-3 prostate cancer cells. Scholarisin I... 

Table 1 New akuammiline alkaloids reported since 2003-Isolated akuammiline alkaloid...

Isolated akuammiline alkaloid Plant source/References... 

Members of the akuammiline alkaloid family also hold promise for treatment of pain and inflammation. Scholarisin I (60) and scholarisin VI (65) were claimed as selective inhibitors of COX-2, while pseudoakuammigine (13) has been reported to have in vivo anti-inflammatory and analgesic activity in rats observed via the carrageenan-induced paw edema and tail flick models respectively. " Picrinine (5) has also been su ested to have antiinflammatory and analgesic activity in mice based on results from various in vivo assays, while (Z)-alstoscholarine (29) was disclosed to be an inhibitor of nuclear factor-KB. ... 

The second portion of this section will then address the akuammiline alkaloids containing an N4—C3 connectivity (Figure 4). 

An additional six steps consisting of deprotections, oxidations, and meth-ylations completed the first total synthesis of an akuammiline alkaloid, ( )-vincorine (18). This racemic synthesis took a total of 31 steps and proceeded with a 1% overall yield. 

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