Synthesis and biological activity of isoprenoid bisphosphonates.
Bisphosphonates have been used in the clinic to treat osteoporosis and to reduce bone resorption and the accompanying pathological bone fractures that attend a number of malignancies including multiple myeloma and cancers of the prostate, breast, and lung. There is also evidence that some bisphosphonates have direct anticancer activity. Expansion of the current class of bisphosphonates may lead to compounds that more selectively and potently target these cancers through inhibition of the mevalonate pathway. To this end, a set of dialkyl bisphosphonates bearing isoprenoid chains of varying lengths has been synthesized. Some of these compounds were found to have biological activity on post-translational processing of the oncogenic small GTPases, Ras and Rap1a, in human-derived K562 leukemia cells. Most importantly, these compounds impair protein geranylgeranylation and not protein farnesylation.
Shull
Larry W
LW
Department of Chemistry, University of Iowa, Iowa City, IA 52242-1294, USA.
Wiemer
Andrew J
AJ
Hohl
Raymond J
RJ
Wiemer
David F
DF
D002460:Cell Line; D004164:Diphosphonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015394:Molecular Structure; D017368:Protein Prenylation / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013729:Terpenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D020827:rap1 GTP-Binding Proteins / Q000187:drug effects*; D018631:ras Proteins / Q000187:drug effects*
D004164:Diphosphonates; D013729:Terpenes; D020827:rap1 GTP-Binding Proteins; D018631:ras Proteins