mycotrienin-i and herbimycin

Pharmacological intervention using selective tyrosine kinase inhibitors has been shown to be an effective approach to inhibit osteoclast function. Here, we report on the structure-activity relations of benzoquinone ansamycins isolated from Streptomyces rishirensis, which form a new class of potent inhibitors of osteoclast-mediated bone resorption. Parathyroid hormone-stimulated bone resorption was inhibited concentration dependently by both mycotrienin I and mycotrienin II, showing half-maximal inhibition in the low nanomolar range in fetal rat long bones in vitro. Structure-activity relation studies indicate that position 19 contained within the quinone/hydroquinone element and the double bonds in position 4, 6, and 8 are crucial for full bioactivity. In contrast, substitutions in position 22 are well tolerated. The lack of a similar effect of 2,6-dimethyl-p-benzoquinone and vitamin K signifies that the mechanism of action is not solely due to the oxygen scavenger capacity of the quinone/hydroquinone moiety. The inhibition of osteoclastic bone resorption is in line with the diminished activity of immunopurified pp60c-src from bone suggesting that pp60c-src is a possible target of mycotrienins in the organ culture. Thus, mycotrienins may be useful as pharmacologic inhibitors of osteoclastic bone resorption.

Topics: Animals; Benzoquinones; Bone and Bones; Bone Resorption; Dose-Response Relationship, Drug; Hydroquinones; Lactams, Macrocyclic; Organ Culture Techniques; Osteoclasts; Parathyroid Hormone; Protein-Tyrosine Kinases; Proto-Oncogene Proteins pp60(c-src); Quinones; Rats; Rats, Sprague-Dawley; Rifabutin; Rifamycins; Structure-Activity Relationship; Vitamin K 1