title: Mycotrienins. A new class of potent inhibitors of osteoclastic bone resorption.
abstract: 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.
authors.affiliation: Department of Bone & Joints, Sandoz Pharma Limited, Basel, Switzerland.
authors.forename: D
authors.initials: D
authors.lastname: Feuerbach
authors.forename: R
authors.initials: R
authors.lastname: Waelchli
authors.forename: T
authors.initials: T
authors.lastname: Fehr
authors.forename: J H
authors.initials: JH
authors.lastname: Feyen
mesh_terms: D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology* / Q000633:toxicity; D001862:Bone Resorption / Q000139:chemically induced*; D001842:Bone and Bones / Q000187:drug effects* / Q000196:embryology; D004305:Dose-Response Relationship, Drug; D006873:Hydroquinones / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D047029:Lactams, Macrocyclic; D009924:Organ Culture Techniques; D010010:Osteoclasts / Q000187:drug effects; D010281:Parathyroid Hormone / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000187:drug effects; D011809:Quinones / Q000494:pharmacology / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D017828:Rifabutin / Q000031:analogs & derivatives*; D012294:Rifamycins; D013329:Structure-Activity Relationship; D010837:Vitamin K 1 / Q000494:pharmacology
chemical_list: D016227:Benzoquinones; D006873:Hydroquinones; D047029:Lactams, Macrocyclic; D010281:Parathyroid Hormone; D011809:Quinones; D012294:Rifamycins; D017828:Rifabutin; C020754:herbimycin; C036970:mycotrienin I; C036971:mycotrienin II; D010837:Vitamin K 1; D011505:Protein-Tyrosine Kinases; D016392:Proto-Oncogene Proteins pp60(c-src)