(+)-Madindoline A

Madindolines are noncytotoxic indole alkaloids originally isolated from a fermentation broth of Streptomyces nitrosporeus K93-071. (+)-Madindoline A (MadA; MDL-A) and (+)-madindoline B (MadB; MDL-B) are diastereomers with MadA being the more potent compound. MadA binds competitively but noncovalently to the extracellular domain of the membrane glycoprotein gp130 and inhibits the homodimerization of the trimeric IL-6/IL-6R/gp130 or the IL-11/gp130 complex, thus inhibiting activation of the JAK/STAT signal transduction pathway. MadA inhibits IL-6 and IL-11-induced osteoclastogenesis in vitro in a dose dependent manner and postmenopausal osteoporosis in vivo, by a mechanism different from that of 17β-estradiol. IL-6 activity is known to cause various diseases such as cancer cachexia, Castleman’s disease, Crohn’s disease, rheumatoid arthritis, hypercalcemia, and multiple myeloma. Madindolines are no longer available from natural sources due to mutation of the originating bacterial strain. Thus, synthetic routes have been developed to produce madindolines. Analogs of madindolines have been synthesized as potent IL-6 inhibitors.