Didemnins

Title: Didemnins
Literature References: Biologically active depsipeptides extracted from a Caribbean tunicate (sea squirt) family Didemnidae, genus Trididemnum. First marine natural product to enter clinical trials as antineoplastic. The three components, didemnins A, B and C are weakly basic compds with antiviral, antitumor activity. Didemnin A is the most abundant, whereas didemnin B is generally the most active. Isoln and bioactivity: K. L. Rinehart, Jr. et al., Science 212, 933 (1981). Extraction and purification: K. L. Rinehart, Jr., EP 48149; idem, US 4493796 (1982, 1985 both to Univ. Illinois). Structure determn: K. L. Rinehart, Jr. et al., J. Am. Chem. Soc. 103, 1857 (1981). Revised structure and total synthesis: K. L. Rinehart, Jr. et al., ibid. 109, 6846 (1987). See also: U. Schmidt et al., Tetrahedron Lett. 29, 3057 (1988); eidem, ibid. 4407. Crystal structure of B: M. B. Hossain et al., Proc. Natl. Acad. Sci. USA 85, 4118 (1988). Efficient total synthesis of A and B: Y. Hamada et al., J. Am. Chem. Soc. 111, 669 (1989). Mechanism of action study: L. H. Li et al., Cancer Lett. 23, 279 (1984). In vitro and in vivo immunosuppressive activity of B: D. W. Montgomery, C. F. Zukowski, Transplantation 40, 49 (1985). HPLC determn in biological fluids: J. N. Hartshorn et al., J. Liq. Chromatogr. 9, 1489 (1986). Clinical pharmacology, pharmacokinetics: F. A. Dorr et al., Eur. J. Cancer Clin. Oncol. 24, 1699 (1988). Review of bioactivity of A and B: K. L. Rinehart, Jr. et al., Fed. Proc. 42, 87-90 (1983); of activity and toxicology of B: H. G. Chun et al., Invest. New Drugs 4, 279-284 (1986); of biological activity, structure and synthesis: W.-R. Li, M. M. Joullie, Stud. Nat. Prod. Chem. 10, 241-302 (1992).
Derivative Type: Didemnin A
CAS Registry Number: 77327-04-9
Molecular Formula: C49H78N6O12
Molecular Weight: 943.18
Percent Composition: C 62.40%, H 8.34%, N 8.91%, O 20.36%
Properties: Greenish-white solid. Sol in methanol, ethanol, dioxane, chloroform. Insol in water.
Derivative Type: Didemnin B
CAS Registry Number: 77327-05-0
Manufacturers' Codes: NSC-325319
Molecular Formula: C57H89N7O15
Molecular Weight: 1112.35
Percent Composition: C 61.55%, H 8.06%, N 8.81%, O 21.58%
Properties: Yellow-white amorphous solid. Sol in methanol, ethanol, dioxane, ethyl acetate, chloroform. Insol in water.
Derivative Type: Didemnin C
CAS Registry Number: 77327-06-1
Molecular Formula: C52H82N6O14
Molecular Weight: 1015.24
Percent Composition: C 61.52%, H 8.14%, N 8.28%, O 22.06%
Properties: Oil. Sol in methanol, ethanol, isopropanol, dioxane, ethyl acetate and chloroform. Sparingly sol in toluene. Insol in water.
Dideoxyadenosine Dienestrol Dienochlor Dienogest Diethadione

Structure of Didemnins A-C

Didemnins are cyclic depsipeptide compounds isolated from a tunicate (sea-squirt) of the genus Trididemnum (family of Didemnidæ) that were collected in the Caribbean Sea. They were first isolated in 1978 at the University of Illinois.[1]

Although more than nine didemnins (didemnins A-E, G, X and Y) have been isolated from the extract of Trididemnum solidum, didemnin B is the one that possesses the most potent biological activities.[2] It is a strong antiviral agent against both DNA and RNA viruses such as herpes simplex virus type 1, a strong immunosuppressant that shows some potential in skin graft [3] and is also very cytotoxic. It shows strong activity against murine leukemia cells. Large amounts of didemnin B were chemically synthesized and it was advanced to clinical trials by the National Cancer Institute. It has completed phase II human clinical trials against adenocarcinoma of the kidney,[4] advanced epithelial ovarian cancer,[5] and metastatic breast cancer.[6] Unfortunately, the compound exhibited high toxicity through a high incidence of anaphylactic reactions in patients and trials were terminated.[7]

The didemnin analog aplidine was in phase II clinical trials as of 2003.[8]