Madindoline

Discovery, producing organism and structure (1,2)

Madindolines were isolated from a culture broth of the actinomycete strain K93-0711 and found to be selective growth inhibitors of IL-6-dependent cells (MH-60) (1). Madindoline B (3aR, 8aS, 2’S) is a stereoisomer of madindoline A (3aR, 8aS, 2’R) (2,3). The total syntheses of madindolines have been reported by two groups 1) First total synthesis (3) and 2) Second total synthesis (4).

Physical data (Madindoline A) (2)

Light yellow needles. C₂₂H₂₇NO₄ ; mol wt 370.20. Sol. in MeOH, EtOH, CHCl₃. Insol. in hexane.

Biological activity (1)

1) Growth inhibition of the IL-6-dependent MH60 cells
Madindolines A and B (MDL-A, B) showed potent growth inhibitory activity against IL-6 dependent MH60 cells with IC50 values of 8 and 30 µM, respectively. Madindolines did not show antimicrobial or cytocidal activity at 1000 µg/ml and 100µg/ml, respectively.

2) Selectivity of madindoline A
Selectivity against some cytokines was examined in cytokine-dependent or -sensitive cell lines. MDL-A inhibited growth of IL-6 dependent MH60 cells at 68 µM, but did not influence other cytokine activity.

3) Inhibitory mechanism of madindoline A (5)
IL-6 has three topological binding sites (sites I, II, and III), and gp130 has two binding sites (sites 1 and 2); IL-6 first binds to the IL-6 receptor (IL-6R) at site I, IL-6 then binds to site I of the first gp130 at site II, forming a trimeric IL-6/IL-6R/gp130 complex. The trimeric complex then induces homodimerization of gp130 and forms a hexameric complex, activating the JAK/STAT signal transduction cascade. MDL-A binds to gp130 and inhibits actions of IL-6 without inhibiting formation of the trimeric complex. Therefore, the MDL-A mechanism of action involves binding to gp130 site 2, the site for IL-6 site III, and inhibiting gp130 homodimerization, resulting in inhibition of IL-6 activity.

References

1. [647] M. Hayashi et al., J. Antibiot., 49, 1091–1095 (1996)
2. [688] S. Takamatsu et al., J. Antibiot., 50, 1069–1072 (1997)
3. [745] T. Sunazuka et al., J. Am. Chem. Soc., 122, 2122-2123 (2000)
4. [799] T. Hirose et al., Organic Letters 4, 501-503 (2002)
5. [813] M. Hayashi et al., Proc. Natl. Acad. Sci. USA, 99, 14728-14733 (2002)