Macrosphelide

Discovery, producing organism and structure (1-8)

Macrosphelides A-D, J and K were isolated from a culture broth of the fungal strain FO- 5050 and recognized as cell-adhesion inhibitors (1-5). It was reported by Numata et al that macrosphelides E-I, L were isolated from another fungal strain (6-8). The total syntheses of macrosphelides have been reported by several groups (4).

Physical data (Macrosphelide A) (1-5)

Colorless needles. C₁₆H₂₂O₈ ; mol wt 342.13. Sol. in CHCl₃, MeOH, EtOAc. Insol. in hexane.

Biological activity

1) Inhibition of cell adhesion (1,3)
Macrosphelide (MS) A showed potent inhibitory activity against cell adhesion of human leukemia cell (HL-60) to LPS-activated human umbilical vein endothelial cell (HUVEC), with an IC₅₀ value of 3.5 µM. The IC₅₀ values of macrosphelides B, C and D were 36, 67.5 and 25 µM, respectively. The IC₅₀ values of both macrosphelides J and K were greater than 100 µg/ml. Macrosphelide A and B did not show any cytocidal activities at a concentration of 100 µg/ml.

2) MSB suppressed metastasis through inhibition of adhesion of sLe_x/E-selectin molecules (9).
MSB inhibits adhesion of sialyl Lewis_x (sLe_x)-expressing HL-60 cells to LSP-activated (E-selectin-expressing) HUVECs in vitro. When MSB was administered to B16/BL6 mice at 20 mg/kg/day, lung metastatic nodules of B16/BL6 mouse melanoma cells (B16/BL6 cells) were significantly decreased (T/C = 45%). Flow cytometry analysis showed that B16/BL6 cells expressed high levels of sLe_x antigens. Under in vitro conditions, B16/BL6 cells demonstrated a greater degree of adhesion to LSP-activated HUVECs, but adhesion was significantly inhibited by MSB and sLe_x antibodies. Combined therapy of MSB and cisplatin (CDDP) induced remarkable lung metastasis inhibition without the adverse effects, of CDDP to the host.

References

1. [597] M. Hayashi et al., J. Antibiot., 48, 1435–1439 (1995)
2. [602] S. Takamatsu et al., J. Antibiot., 49, 95–98 (1996)
3. [683] S. Takamatsu et al., J. Antibiot., 50, 878–880 (1997)
4. [680] T. Sunazuka et al., J. Am. Chem. Soc., 119, 10247–10248 (1997)
5. [831] A. Fukami et al., J. Antibiot., 52, 501-504 (1999)
6. A. Numata et al., Tetrahedron Lett., 38, 8215–8218 (1997)
7. A. Numata et al., J.Chem. Soc., Perkin Trans. I., 3046–3053 (2001)
8. A. Numata et al., J. Antibiot., 55, 147–154 (2002)
9. [801] A. Fukami et al., Bioche. Biophys. Res. Comm., 291, 1065–1070 (2002)