MYCOTRIENINS - A NEW CLASS OF POTENT INHIBITORS OF OSTEOCLASTIC BONE-RESORPTION

Pharmacological intervention using selective tyrosine kinase inhibitor s has been shown to be an effective approach to inhibit osteoclast fun ction. Here, we report on the structure-activity relations of benzoqui none ansamycins isolated from Streptomyces rishirensis, which form a n ew class of potent inhibitors of osteoclast-mediated bone resorption. Parathyroid hormone-stimulated bone resorption was inhibited concentra tion dependently by both mycotrienin I and mycotrienin II, showing hal f-maximal inhibition in the low nanomolar range in fetal rat long bone s in vitro. Structure-activity relation studies indicate that position 19 contained within the quinone/hydroquinone element and the double b onds in position 4, 6, and 8 are crucial for full bioactivity. In cont rast, substitutions in position 22 are well tolerated. The lack of a s imilar effect of 2,6-dimethyl-p-benzoquinone and vitamin K signifies t hat the mechanism of action is not solely due to the oxygen scavenger capacity of the quinone/hydroquinone moiety. The inhibition of osteocl astic bone resorption is in line with the diminished activity of immun opurified pp(60c-src) from bone suggesting that pp60(c-src) is a possi ble target of mycotrienins in the organ culture. Thus, mycotrienins ma y be useful as pharmacologic inhibitors of osteoclastic bone resorptio n.