Lavendamycin

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Lavendamycin
Names
Preferred IUPAC name
1-(7-Amino-5,8-dioxo-5,8-dihydroquinolin-2-yl)-4-methyl-9H-pyrido[3,4-b]indole-3-carboxylic acid
Identifiers
3D model (JSmol)
ChemSpider
UNII
  • InChI=1S/C22H14N4O4/c1-9-16-10-4-2-3-5-13(10)24-20(16)19(26-17(9)22(29)30)14-7-6-11-15(27)8-12(23)21(28)18(11)25-14/h2-8,24H,23H2,1H3,(H,29,30)
    Key: IGQJRDIREIWBQP-UHFFFAOYSA-N
  • InChI=1/C22H14N4O4/c1-9-16-10-4-2-3-5-13(10)24-20(16)19(26-17(9)22(29)30)14-7-6-11-15(27)8-12(23)21(28)18(11)25-14/h2-8,24H,23H2,1H3,(H,29,30)
    Key: IGQJRDIREIWBQP-UHFFFAOYAD
  • Cc1c2c3ccccc3[nH]c2c(nc1C(=O)O)c4ccc5c(n4)C(=O)C(=CC5=O)N
Properties
C22H14N4O4
Molar mass 398.378 g·mol−1
Appearance Dark red crystals[1]
Melting point >300 °C[1]
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Lavendamycin is a naturally occurring chemical compound discovered in fermentation broth of the soil bacterium Streptomyces lavendulae.[2] Lavendamycin has antibiotic properties and anti-proliferative effects against several cancer cell lines. The use of lavendamycin as a cytotoxic agent in cancer therapy failed due to poor water solubility and non-specific cytotoxicity. The study of lavendamycin-based analogs designed to overcome these liabilities has been an area of research.[3]

Discovery[edit]

Lavendamycin was first discovered in 1981 by Doyle et al., who isolated it from Streptomyces lavendulae.[3] As the compound failed to crystallize, a direct characterization of the molecular structure with X-ray crystallography was not possible. Careful analysis using NMR, IR, and UV-VIS spectroscopy and mass spectrometry allowed the assignment of the pentacyclic structure consisting of a β-carboline unit and a quinolinequinone unit.[citation needed]

Total syntheses[edit]

The attractive biological properties and complex structure of lavendamycin have made it the target of a large number of total syntheses.[4] Within a few years after the structural elucidation by Doyle et al., the research groups of Kende,[5] Hibino,[6] Rao,[7] and Boger[8] had already developed total syntheses for the compound independently of one another. The discovery that analogs of lavendamycin are potent inhibitors of HIV reverse transcriptase led to further attempts in the 90s to develop efficient routes to lavendamycin.[9][10][11][12] However, large numbers of steps, low overall yields (0.5–2%) or poorly available starting materials make these syntheses unattractive for further systematic development of lavendamycin and its analogs. Notably, total syntheses by Behforouz[13] and Nissen[14] offer flexible construction of the lavendamycin scaffold at high yields.

References[edit]

  1. ^ a b "Lavendamycin". Römpp's Chemistry Lexicon (in German).
  2. ^ Balitz, D. M.; Bush, J. A.; Bradner, W. T.; Doyle, T. W.; O'Herron, F. A.; Nettleton, D. E. (1982). "Isolation of lavendamycin, a new antibiotic from Streptomyces lavendulae". The Journal of Antibiotics. 35 (3): 259–65. doi:10.7164/antibiotics.35.259. PMID 7076573.
  3. ^ a b Hassani, M.; Cai, W.; Koelsch, K. H.; Holley, D. C.; Rose, A. S.; Olang, F.; Lineswala, J. P.; Holloway, W. G.; Gerdes, J. M.; Behforouz, M.; Beall, H. D. (2008). "Lavendamycin antitumor agents: Structure-based design, synthesis, and NAD(P)H:quinone oxidoreductase 1 (NQO1) model validation with molecular docking and biological studies". Journal of Medicinal Chemistry. 51 (11): 3104–15. doi:10.1021/jm701066a. PMID 18457384.
  4. ^ Bringmann, Gerhard; Reichert, Yanina; Kane, Vinayak V. (2004). "The total synthesis of streptonigrin and related antitumor antibiotic natural products". Tetrahedron. 60 (16): 3539–3574. doi:10.1016/j.tet.2004.02.060.
  5. ^ Kende, Andrew S.; Ebetino, Frank H. (1984). "The regiospecific total synthesis of lavendamycin methyl ester". Tetrahedron Letters. 25 (9): 923–926. doi:10.1016/S0040-4039(01)80063-0.
  6. ^ Hibino, Satoshi; Okazaki, Miko; Sato, Kohichi; Morita, Itsuko; Ichikawa, Masataka (1983). "Synthetic Approach to the Antitumor Antibiotic Lavendamycin: a Synthesis of Demethallavendamycin Methyl Ester". Heterocycles. 20 (10): 1957. doi:10.3987/R-1983-10-1957 (inactive 2024-02-09). ISSN 0385-5414.{{cite journal}}: CS1 maint: DOI inactive as of February 2024 (link)
  7. ^ Rao, A.V.Rama; Chavan, Subhash P.; Sivadasan, Latha (1986). "Synthesis of lavendamycin". Tetrahedron. 42 (18): 5065–5071. doi:10.1016/S0040-4020(01)88058-3.
  8. ^ Boger, Dale L.; Duff, Steven R.; Panek, James S.; Yasuda, Masami (1985). "Total synthesis of lavendamycin methyl ester". The Journal of Organic Chemistry. 50 (26): 5790–5795. doi:10.1021/jo00350a070. ISSN 0022-3263.
  9. ^ Ciufolini, Marco A.; Bishop, Michael J. (1993). "Studies towards streptonigrinoids: formal synthesis of lavendamycin methyl ester". Journal of the Chemical Society, Chemical Communications (18): 1463–1464. doi:10.1039/c39930001463. ISSN 0022-4936.
  10. ^ Molina, Pedro; Fresneda, Pilar M.; Cánovas, Mercedes (1992). "Iminophosphorane-mediated synthesis of 1-substituted-β-carbolines: investigative studies on the preparation of alkaloids lavendamycin and eudistomins framework". Tetrahedron Letters. 33 (20): 2891–2894. doi:10.1016/S0040-4039(00)78888-5.
  11. ^ Molina, Pedro; Murcia, Fernando; Fresneda, Pilar M. (1994). "A straightforward and practical formal synthesis of lavendamycin ethyl ester". Tetrahedron Letters. 35 (9): 1453–1456. doi:10.1016/S0040-4039(00)76244-7.
  12. ^ Rocca, Patrick; Marsais, Francis; Godard, Alain; Quéguiner, Guy (1993). "A new approach to the synthesis of lavendamycin analogues". Tetrahedron Letters. 34 (18): 2937–2940. doi:10.1016/S0040-4039(00)60486-0.
  13. ^ Behforouz, Mohammad; Gu, Zhengxiang; Cai, Wen; Horn, Mark A.; Ahmadian, Mohammad (1993). "A highly concise synthesis of lavendamycin methyl ester". The Journal of Organic Chemistry. 58 (25): 7089–7091. doi:10.1021/jo00077a032. ISSN 0022-3263.
  14. ^ Nissen, Felix; Detert, Heiner (2011). "Total Synthesis of Lavendamycin by a [2+2+2] Cycloaddition". European Journal of Organic Chemistry. 2011 (15): 2845–2853. doi:10.1002/ejoc.201100131.
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