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Diazonamide A

Pepe.king.prawn/Diazonamide A
Names
IUPAC name
Butanamide, N-​[(1R,​7S,​10S,​27aS)​-​16,​18-​dichloro-​7,​8,​9,​10-​tetrahydro-​10-​(1-​methylethyl)​-​8-​oxo-​6H,​19H-​14,​17-​epoxy-​3,​5-​etheno-​1,​23,​27-​(iminomethyno)​-​13,​11-​nitrilo-​1H-​furo[3',​4':10,​11]​[1,​4]​oxaazacyclododecino[​12,​11-​g]​pyrrolo[2,​3,​4-​rs]​[4]​benzazacyclopentadec​in-​7-​yl]​-​2-​hydroxy-​3-​methyl-​, (2S)​-
Other names
(-)-diazonamide A
Identifiers
Properties
C40H34Cl2N6O6
Molar mass 765.64
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Tracking categories (test):

Diazonamide A is a chlorinated peptide natural product isolated from the marine invertebrate Diazona chinensis. It attracted attention as a result of errors in its initial structure assignment.[1] The unprecedented structure and potent cytotoxicity of diazonamide A have prompted several total syntheses enabling elucidation of its true structure and further investigation into its potential use as an antineoplastic drug.


First total synthesis.[2]

Reassignment of structure by Harran et al (2001)[3]

Nicolaou 2002. [4]

Nicolaou 2003. [5]

Nicolaou 2004. [6]

Synthesis Harran et al[7]


AB-5, a C25 and C27 deschloro analogue of diazonamide A, shows high potency (IC50 < 10 nM) in vitro against numerous human cancer cell lines. Its cytotoxicity was found comparable to taxane or vinca alkaloid antimitotic drugs. AB-5 showed promising pharmacokinetic performance in vivo, and no overt toxicity was observed when administered intravenously to mice at 20 mg/kg.[8]


[9]

History

[edit]
Structure of diazonamide A initially assigned by Fenical, Clardy and co-workers[10]

The isolation and structure of diazonamide A was reported in 1991 by William Fenical, Jon Clardy and co-workers.[10] It was isolated from Diazona chinensis, an ascidian, collected in the Philippines along the northwest coast of Siquijor. Diazonamide A was found to be a potent (IC50 < 15 ng/mL) cytotoxic agent when tested against HCT-116 human colon carcinoma and B-16 murine melanoma cell lines. The structural connectivity could not be completely assigned by correlation spectroscopy, and thus the structures of diazonamide A and B were inferred from an single crystal x-ray structure of a derivative of diazonamide B. The original structural assignments are shown at the left.[10] In 2001, Harran and co-workers completed a total synthesis of the originally proposed structure, which proved to be unstable,[2] prompting reassignment of the structure.[3]








Synthesis

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Biology

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See also

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References

[edit]
  1. ^ Nicolaou, K. C.; Snyder, S. A. (February 2005). "Chasing molecules that were never there: Misassigned natural products and the role of chemical synthesis in modern structure elucidation". Angew. Chem.-Int. Edit. 44 (15): 1012–1044. doi:10.1002/anie.200460864. PMID 15688428.{{cite journal}}: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)
  2. ^ a b Li, J.; Jeong, S.; Esser, L.; Harran, P. G. (December 2001). "Total synthesis of nominal diazonamides - Part 1: Convergent preparation of the structure proposed for (-)-diazonamide A". Angew. Chem.-Int. Edit. 40 (24): 4765–4770. doi:10.1002/1521-3773(20011217)40:24<4765::AID-ANIE4765>3.0.CO;2-1. PMID 1240441.{{cite journal}}: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)
  3. ^ a b Li, J.; Burgett, A.W.G.; Esser, L.; Amezcua, C.; Harran, P.G. (December 2001). "Total synthesis of nominal diazonamides - Part 2: On the true structure and origin of natural isolates". Angew. Chem.-Int. Edit. 40 (24): 4770–4773. doi:10.1002/1521-3773(20011217)40:24<4770::aid-anie4770>3.0.co;2-t. PMID 12404412.{{cite journal}}: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)
  4. ^ Nicolaou, K.C.; Bella, M.; Chen, D.Y.-K.; Huang, X.; Ling, T.; Snyder, S.A. (September 2002). "Total Synthesis of Diazonamide A". Angew. Chem.-Int. Edit. 41 (18): 1521–3773. doi:10.1002/1521-3773(20020916)41:18<3495::AID-ANIE3495>3.0.CO;2-7. PMID 12298077.{{cite journal}}: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)
  5. ^ Nicolaou, K. C.; Rao, P. B.; Hao, J. L.; Reddy, M. V.; Rassias, G.; Huang, X. H.; Chen, D. Y. K.; Snyder, S. A. (April 2003). "The second total synthesis of diazonamide A". Angew. Chem.-Int. Edit. 52 (15): 1753–1758. doi:10.1002/anie.200351112. PMID 12707898.{{cite journal}}: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)
  6. ^ Nicolaou, K.C.; Chen, D.Y.-K.; Huang, X.; Ling, T.; Bella, M.; Snyder, S.A. (2004). "Chemistry and biology of diazonamide A: First total synthesis and confirmation of the true structure". J. Am. Chem. Soc. 126 (40): 12888–12896. doi:10.1021/ja040092i. PMID 15469286.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  7. ^ Burgett, A. W. G.; Li, Q. Y.; Wei, Q.; Harran, P. G. (September 2003). "A concise and flexible total synthesis of (-)-diazonamide A". Angew. Chem.-Int. Edit. 42 (40): 4961–4966. doi:10.1002/anie.200352577. PMID 14579451.{{cite journal}}: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)
  8. ^ Williams, N. S.; Burgett, A. W. G.; Atkins, A. S.; Wang, X. D.; Harran, P. G.; McKnight, S. L. (February 2007). "Therapeutic anticancer efficacy of a synthetic diazonamide analog in the absence of overt toxicity". Proc. Natl. Acad. Sci. U.S.A. 104 (7): 2074–2079. doi:10.1073/pnas.0611340104. PMC 1794345. PMID 17287337.{{cite journal}}: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)
  9. ^ {{cite journal}}: Empty citation (help)
  10. ^ a b c Lindquist, N.; Fenical, W.; Van Duyne, G. D.; Clardy, J. (March 1991). "Isolation and structure determination of diazonamides A and B, unusual cytotoxic metabolites from the marine ascidian Diazona chinensis". J. Am. Chem. Soc. 113 (6): 2303–2304. doi:10.1021/ja00006a060.{{cite journal}}: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)




Category:Medicinal chemistry Category:Alkaloids Category:Antineoplastic drugs

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