32579-17-2Relevant articles and documents
Bisphosphonate inhibitors of squalene synthase protect cells against cholesterol-dependent cytolysins
Pospiech, Mateusz,Owens, Sian E.,Miller, David J.,Austin-Muttitt, Karl,Mullins, Jonathan G. L.,Cronin, James G.,Allemann, Rudolf K.,Sheldon, I. Martin
, (2021/06/08)
Certain species of pathogenic bacteria damage tissues by secreting cholesterol-dependent cytolysins, which form pores in the plasma membranes of animal cells. However, reducing cholesterol protects cells against these cytolysins. As the first committed st
The preparation of N-substituted aminomethylidenebisphosphonates and their tetraalkyl esters via reaction of isonitriles with trialkyl phosphites and hydrogen chloride. Part 1
Goldeman, Waldemar,Kluczyński, Artur,Soroka, Miros?aw
, p. 5290 - 5292 (2012/11/13)
The reaction of isonitriles with trialkyl phosphites in the presence of hydrogen chloride gives tetraalkyl N-substituted aminomethylidenebisphosphonates via N-methylideneaminium (isonitrilium) salts. Hydrolysis or dealkylation of these tetraalkyl esters gives N-substituted aminomethylidenebisphosphonic acids in high yields.
3-D QSAR Investigations of the Inhibition of Leishmania major Farnesyl Pyrophosphate Synthase by Bisphosphonates
Sanders, John M.,Gómez, Aurora Ortiz,Mao, Junhong,Meints, Gary A.,Van Brussel, Erin M.,Burzynska, Agnieszka,Kafarski, Pawel,González-Pacanowska, Dolores,Oldfield, Eric
, p. 5171 - 5183 (2007/10/03)
We report the activities of 62 bisphosphonatesas inhibitors of the Leishmania major mevalonate/isoprene biosynthesis pathway enzyme, farnesyl pyrophosphate synthase. The compounds investigated exhibit activities (IC 50 values) ranging from ～100 nM to ～80 μM (corresponding to Ki values as low as 10 nM). The most active compounds were found to be zoledronate (whose single-crystal X-ray structure is reported), pyridinyl-ethane-1-hydroxy-1,1-bisphosphonates or picolyl aminomethylene bisphosphonates. However, N-alicyclic amino-methylene bisphosphonates, such as incadronate (N-cycloheptyl aminomethylene bisphosphonate), as well as aliphatic aminomethylene bisphosphonates containing short (n = 4, 5) alkyl chains, were also active, with 1C50 values in the 200-1700 nM range (corresponding to Ki values of ～20-170 nM). Bisphosphonates containing longer or multiple (N,N-) alkyl substitutions were inactive, as were aromatic species lacking an o- or m-nitrogen atom in the ring, or possessing multiple halogen substitutions or a p-amino group. To put these observations on a more quantitative structural basis, we used three-dimensional quantitative structure-activity relationship techniques: comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA), to investigate which structural features correlated with high activity. Training set results (N = 62 compounds) yielded good correlations with each technique (R2 = 0.87 and 0.88, respectively), and were further validated by using a training/test set approach. Test set results (N = 24 compounds) indicated that IC50 values could be predicted within factors of 2.9 and 2.7 for the CoMFA and CoMSIA methods, respectively. The CoMSIA fields indicated that a positive charge in the bisphosphonate side chain and a hydrophobic feature contributed significantly to activity. Overall, these results are of general interest since they represent the first detailed quantitative structure-activity relationship study of the inhibition of an expressed farnesyl pyrophosphate synthase enzyme by bisphosphonate inhibitors and that the activity of these inhibitors can be predicted within about a factor of 3 by using 3D-QSAR techniques.
