Leptomycin

Last updated
Leptomycin B
Leptomycin B.svg
Names
Preferred IUPAC name
(2E,5S,6R,7S,9R,10E,12E,15R,16Z,18E)-17-Ethyl-6-hydroxy-3,5,7,9,11,15-hexamethyl-19-[(2S,3S)-3-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]-8-oxononadeca-2,10,12,16,18-pentaenoic acid
Identifiers
3D model (JSmol)
ChemSpider
ECHA InfoCard 100.125.530 OOjs UI icon edit-ltr-progressive.svg
PubChem CID
UNII
  • InChI=1S/C33H48O6/c1-9-28(14-15-29-24(5)13-16-31(36)39-29)19-22(3)12-10-11-21(2)17-25(6)32(37)27(8)33(38)26(7)18-23(4)20-30(34)35/h10-11,13-17,19-20,22,24-27,29,33,38H,9,12,18H2,1-8H3,(H,34,35)/b11-10+,15-14+,21-17+,23-20+,28-19+/t22-,24+,25-,26+,27-,29+,33-/m1/s1 Yes check.svgY
    Key: YACHGFWEQXFSBS-RJXCBBHPSA-N Yes check.svgY
  • InChI=1/C33H48O6/c1-9-28(14-15-29-24(5)13-16-31(36)39-29)19-22(3)12-10-11-21(2)17-25(6)32(37)27(8)33(38)26(7)18-23(4)20-30(34)35/h10-11,13-17,19-20,22,24-27,29,33,38H,9,12,18H2,1-8H3,(H,34,35)/b11-10+,15-14+,21-17+,23-20+,28-19+/t22-,24+,25-,26+,27-,29+,33-/m1/s1
    Key: YACHGFWEQXFSBS-RJXCBBHPBE
  • OC(=O)\C=C(/C)C[C@H](C)[C@@H](O)[C@H](C)C(=O)[C@H](C)/C=C(\C)/C=C/C[C@@H](C)\C=C(/CC)\C=C\[C@@H]1OC(=O)/C=C\[C@@H]1C
Properties
C33H48O6
Molar mass 540.741 g·mol−1
Density 1.072 g/mL
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Yes check.svgY  verify  (what is  Yes check.svgYX mark.svgN ?)

Leptomycins are secondary metabolites produced by Streptomyces spp.

Contents

Leptomycin B (LMB) was originally discovered as a potent antifungal compound. [1] Leptomycin B was found to cause cell elongation of the fission yeast Schizosaccharomyces pombe . Since then this elongation effect has been used for the bioassay of leptomycin. However, recent data shows that leptomycin causes G1 cell cycle arrest in mammalian cells and is a potent anti-tumor agent against murine experimental tumors in combination therapy. [2]

Leptomycin B has been shown to be a potent and specific nuclear export inhibitor in humans [3] and the fission yeast S. pombe. [4] Leptomycin B alkylates and inhibits CRM1 (chromosomal region maintenance)/exportin 1 ( XPO1 ), a protein required for nuclear export of proteins containing a nuclear export sequence (NES), by glycosylating a cysteine residue (cysteine 529 in S. pombe). [5] In addition to antifungal and antibacterial activities, leptomycin B blocks the cell cycle and is a potent anti-tumor agent. At low nM concentrations, leptomycin B blocks the nuclear export of many proteins including HIV-1 Rev, MAPK/ERK, and NF-κB/IκB, and it inhibits the inactivation of p53. [6] Leptomycin B also inhibits the export and translation of many RNAs, including COX-2 and c-Fos mRNAs, by inhibiting the export of ribonucleoproteins.[ citation needed ]

Leptomycin A (LPA) was discovered together with LMB. LMB is twice as potent as LPA.[ clarification needed ]

See also

References

  1. ↑ Hamamoto T, Seto H, Beppu T (1983). "Leptomycins A and B, new antifungal antibiotics. II. Structure elucidation". J. Antibiot. 36 (6): 646–50. doi: 10.7164/antibiotics.36.646 . PMID   6874586.
  2. ↑ Lu, Chuanwen; Changxia Shao; Everardo Cobos; Kamaleshwar P. Singh; Weimin Gao (March 2012). "Chemotherapeutic Sensitization of Leptomycin B Resistant Lung Cancer Cells by Pretreatment with Doxorubicin". PLOS ONE. 7 (3) e32895. United States. Bibcode:2012PLoSO...732895L. doi: 10.1371/journal.pone.0032895 . ISSN   1932-6203. PMC   3296751 . PMID   22412944.
  3. ↑ Kudo N, Wolff B, Sekimoto T, et al. (August 1998). "Leptomycin B inhibition of signal-mediated nuclear export by direct binding to CRM1". Exp. Cell Res. 242 (2): 540–7. doi:10.1006/excr.1998.4136. PMID   9683540.
  4. ↑ Nishi K, Yoshida M, Fujiwara D, Nishikawa M, Horinouchi S, Beppu T (March 1994). "Leptomycin B targets a regulatory cascade of crm1, a fission yeast nuclear protein, involved in control of higher order chromosome structure and gene expression". J. Biol. Chem. 269 (9): 6320–4. doi: 10.1016/S0021-9258(17)37374-X . PMID   8119981.
  5. ↑ Kudo N, Matsumori N, Taoka H, et al. (August 1999). "Leptomycin B inactivates CRM1/exportin 1 by covalent modification at a cysteine residue in the central conserved region". Proc. Natl. Acad. Sci. U.S.A. 96 (16): 9112–7. Bibcode:1999PNAS...96.9112K. doi: 10.1073/pnas.96.16.9112 . PMC   17741 . PMID   10430904.
  6. ↑ Hietanen S, Lain S, Krausz E, Blattner C, Lane DP (2000). "Activation of p53 in cervical carcinoma cells by small molecules". Proc Natl Acad Sci U S A. 97 (15): 8501–6. Bibcode:2000PNAS...97.8501H. doi: 10.1073/pnas.97.15.8501 . PMC   26977 . PMID   10900010.

Original data copied with permission from Leptomycin B manufacturer product page (Fermentek)

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