The Amphidinolide Family of Natural Products and their Total Synthesis

The amphidinolides (table, structures) are a family of structurally-related cytotoxic natural products that were first isolated from various strains of the microscopic marine dinoflagellate Amphidinium sp. (25 µm in length) which was living inside the microscopic marine flatworm Amphiscolopes sp. (500 µm in length). In 1986, Kobayashi and colleagues reported finding these organisms off the coast of Okinawa, Japan. Then in 1994, a different strain of the dinoflagellate (Amphidinium clone (S1-36-5) which has now been identified as Amphidinium operculatum var. gibbosum: a heart-shaped organism 31-43 µm in length and 19-23 µm wide) was found free-swimming off the coast of the US Virgin Islands by Shimizu and colleagues. The amphidinolide class of natural products currently includes 36 macrolides (amphidinolides A - H, J - X, B3, and caribenolide I).

These compounds exhibit significant in vitro antineoplastic (anticancer) activity against murine lymphoma L1210, human epidermoid carcinoma KB, and human colon tumor cells HCT116. For example, amphidinolide K (1) is active against L1210 and KB cells (IC(50) 1.65 and 2.9 µg/mL, respectively). Amphidinolides B (2) and N (3) have exceptional biological activity against L1210 (IC(50) 0.14 and 0.05 ng/mL, respectively). Amphidinolide B (2) and caribenolide I (4) show reasonable cytotoxic activity against HCT116 (IC(50) 0.122 and 0.001 µg/mL, respectively). Furthermore, caribenolide I has displyed in vivo activity against murine tumor P388. Although extensive culturing of the dinoflagellates is currently underway at the University of Rhode Island in 15,000 liter tanks the yield of a single amphidinolide is very low. For example, culturing was previously carried out in nutrient enriched seawater (3300 liters) for 2 weeks. The dinoflagellate cells were harvested (920 grams), and after several extractions and purifications, 0.3 mg of amphidinolide K (1) was isolated. In a similar culturing experiment, 6.8 mg of amphidinolide J (5) was obtained from 4956 liters of seawater.

[amphidinolides picture]

Biosynthetic studies of amphidinolide J (5), using feeding experiments with 13C-labeled sodium acetate and methionine, indicate that the backbone of 5 was most likely derived from non-successive mixed polyketide chains formed solely from acetates. This non-successive biosynthetic route can account for the unique odd-numbered macrolide ring sizes and exo-methylenes found in several of the amphidinolides (Figure 1).

[amphidinolide J]

The members of the amphidinolide family contain a wide array of functionality. In general, each has at least one exo-methylene unit, and several have dienes, epoxides, tetrahydrofuran rings, and odd-numbered macrocyclic lactones. The diverse functionality, the stereochemical complexity, low natural abundance, and the encouraging pharmacology of the amphidinolides serves to make them attractive and challenging targets for synthesis and methodology. In addition to the numerous synthetic methodologies for synthesis of members of this natural product family that have been reported, the total synthesis of four of the amphidinolides, J, K, P and R, have been reported by Prof. Williams and colleagues (including me) at Indiana University. Prof. Fürstner's Group completed the total synthesis of amphidinolides, T1, T3, T4, T5, V and X; Ghosh and Liu completed the Total synthesis of T1 and W; and Prof. Trost and Harrington elucidated the structure of Amphidinolide A by total synthesis. Prof. Roush completed the synthesis and structural elucidation of amphidinolide E in 2007. In 2006, Prof. Nicolaou's group reported significant progress towards the synthesis of amphidinolide N and caribenolide I (the most structurally complex member of the family). To date, 14 of the 39 reported amphidinolides have been synthesized.


Amphidinolide Summary Table

Structures


By: Brian J. Myers
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Last Updated: April 19, 2008