10595-93-4Relevant articles and documents
A simple synthesis of monofluoromethylene bisphosphonic acid
Hutchinson, David W.,Thornton, David M.
, p. 93 - 100 (1988)
A simple synthesis of monofluoromethylene bisphosphonic acid has been devised, starting with an Arbusov reaction between fluorotribromomethane and triisopropyl phosphite to give diisopropyl dibromofluoromethylphosphonate.A Michaelis-Becker reaction between the latter and an excess of the sodium salt of diisopropyl phosphite yields tetraisopropyl bromofluoromethylene bisphosphonate, which is not isolated but undergoes nucleophilic debromination and protonation during the reaction and subsequent work up to produce tetraisopropyl monofluoromethylene bisphosphonate.De-esterification of the tetraester with bromotrimethylsilane followed by hydrolysis and cation exchange chromatography gives di(triethylammonium)monofluoromethylene bisphosphonate, which is converted into the free acid by further ion exchange chromatography.
1-(Fluoroalkylidene)-1,1-bisphosphonic acids are potent and selective inhibitors of the enzymatic activity of Toxoplasma gondii farnesyl pyrophosphate synthase
Szajnman, Sergio H.,Rosso, Valeria S.,Malayil, Leena,Smith, Alyssa,Moreno, Silvia N. J.,Docampo, Roberto,Rodriguez, Juan B.
, p. 1424 - 1433 (2012)
α-Fluorinated-1,1-bisphosphonic acids derived from fatty acids were designed, synthesized and biologically evaluated against Trypanosoma cruzi, the etiologic agent of Chagas disease, and against Toxoplasma gondii, the agent responsible for toxoplasmosis, and also towards the target parasitic enzymes farnesyl pyrophosphate synthase of T. cruzi (TcFPPS) and T. gondii (TgFPPS). Interestingly, 1-fluorononylidene-1,1-bisphosphonic acid (compound 43) proved to be an extremely potent inhibitor of the enzymatic activity of TgFPPS at the low nanomolar range, exhibiting an IC50 of 30 nM. This compound was two-fold more potent than risedronate (IC50 = 74 nM) that was taken as a positive control. This enzymatic activity was associated with a strong cell growth inhibition against tachyzoites of T. gondii, with an IC50 value of 2.7 μM.
Synthesis of new PMEA diphosphate mimics
Laux,Perigaud,Imbach,Gosselin
, p. 1003 - 1004 (1999)
We synthesized and characterized new diphosphate mimics of the acyclic nucleotide phosphonate PMEA [Adefovir, 9-(2-phosphonylmethoxyethyl)adenine].
(R)-β,γ-fluoromethylene-dGTP-DNA ternary complex with DNA polymerase β
McKenna, Charles E.,Kashemirov, Boris A.,Upton, Thomas G.,Batra, Vinod K.,Goodman, Myron F.,Pedersen, Lars C.,Beard, William A.,Wilson, Samuel H.
, p. 15412 - 15413 (2007)
β,γ-Fluoromethylene analogues of nucleotides are generally considered to be useful mimics of the natural substrates for DNA polymerases, but direct structural evidence defining their active site interactions has not been available. In addition, the effect of introducing a new chiral center (the CHF carbon) has been unexplored. We report here structural studies of the diastereomeric β,γ-CHF analogues (R, 3; S, 4) of dGTP interacting with the active site of DNA pol β, a repair enzyme that plays an important role in base excision repair (BER) and oncogenesis. The conjugation of dGMP 5′-morpholidate with a tetrabutylammonium salt of (fluoromethylene)bisphosphonic acid (6b, prepared like its difluoro analogue 7b via fluorination of tetraisopropyl methylenebisphosphonate carbanion with Selectfluor) gives a 1:1 mixture of 3 and 4 (by 19F NMR, pH 10). The β,γ-CF2 (2) and β,γ-CH2 (1) dGTP analogues were also synthesized. Crystallization from a solution containing 3 + 4 together with a preformed DNA pol β complex of a 16-mer template DNA and a one-nucleotide gapped primer produced crystals containing the (R)-analogue 3, as shown by the X-ray structure (2.1 A), which revealed a 3.0 A (bonding) distance between a guanidine N of Arg 183 and the CHF fluorine atom. Ligand docking simulations of 3 vs 4 using Autodock 3.0 predicted that both 3 and 4 can adopt an overall orientation closely overlaying that of dGTP itself in the active site; however, a polar C-F··Arg183 bonding interaction is favored only with 3. A similar orientation of one fluorine atom in 2 is observed. The results suggest that introduction of a single fluorine atom at the bridging carbon atom of a β,γ-methylene-dNTP analogue may enable a new, stereospecific interaction within the pre-organized active site complex. Copyright
The effect of bisphosphonate acidity on the activity of a thymidylyltransferase
Beaton, Stephen A.,Jiang, Patricia M.,Melong, Jonathan C.,Loranger, Matthew W.,Mohamady, Samy,Veinot, Thomas I.,Jakeman, David L.
, p. 5473 - 5480 (2013)
Thymidylyltransferases (thymidine diphospho pyrophosphorylases) are nucleotidylyltransferases that play key roles in the biosynthesis of carbohydrate components within bacterial cell walls and in the biosynthesis of glycosylated natural products. They catalyze the formation of sugar nucleotides concomitant with the release of pyrophosphate. Protein engineering of thymidylyltransferases has been an approach for the production of a variety of non-physiological sugar nucleotides. In this work, we have explored chemical approaches towards modifying the activity of the thymidylyltransferase (Cps2L) cloned from S. pneumoniae, through the use of chemically synthesized 'activated' nucleoside triphosphates with enhanced leaving groups, or by switching the metal ion co-factor specificity. Within a series of phosphonate-containing nucleoside triphosphate analogues, thymidylyltransferase activity is enhanced based on the acidity of the leaving group and a Br?nsted-type analysis indicated that leaving group departure is rate limiting. We have also determined IC50 values for a series of bisphosphonates as inhibitors of thymidylyltransferases. No correlation between the acidity of the inhibitors (pKa) and the magnitude of enzyme inhibition was found. The Royal Society of Chemistry.
Synthesis of a potent inhibitor of HIV reverse transcriptase
Hamilton, Chris J.,Roberts, Stanley M.,Shipitsin, Alexander
, p. 1087 - 1088 (1998)
The newly synthesised P(β),-P(γ)-difluoromethylenebisphosphonate analogue 2 of nor-carbovir triphosphate is a potent inhibitor of HIV reverse transcriptase; it also exhibits a greatly enhanced stability to dephosphorylation, in foetal blood serum, relative to AZTTP and other nucleoside triphosphates.
An improved method for the synthesis of nucleoside triphosphate analogues
Mohamady, Samy,Jakeman, David L.
, p. 10588 - 10591 (2005)
Nucleoside monophosphates, when activated by trifluoroacetic anhydride and N-methylimidazole, efficiently couple with a variety of electron-deficient diphosphonates in a reproducible and efficient manner (72% isolated yield). Unlike traditional methods for the preparation of nucleoside 5′-β,γ-methylenetriphosphate analogues, there is no requirement for predrying, or conversion to specific salt forms, of commercially available nucleoside monophosphate starting materials.
Bisphosphonate-Generated ATP-Analogs Inhibit Cell Signaling Pathways
Malwal, Satish R.,O'Dowd, Bing,Feng, Xinxin,Turhanen, Petri,Shin, Christopher,Yao, Jiaqi,Kim, Boo Kyung,Baig, Noman,Zhou, Tianhui,Bansal, Sandhya,Khade, Rahul L.,Zhang, Yong,Oldfield, Eric
supporting information, p. 7568 - 7578 (2018/05/31)
Bisphosphonates are a major class of drugs used to treat osteoporosis, Paget's disease, and cancer. They have been proposed to act by inhibiting one or more targets including protein prenylation, the epidermal growth factor receptor, or the adenine nucleotide translocase. Inhibition of the latter is due to formation in cells of analogs of ATP: the isopentenyl ester of ATP (ApppI) or an AppXp-type analog of ATP, such as AMP-clodronate (AppCCl2p). We screened both ApppI as well as AppCCl2p against a panel of 369 kinases finding potent inhibition of some tyrosine kinases by AppCCl2p, attributable to formation of a strong hydrogen bond between tyrosine and the terminal phosphonate. We then synthesized bisphosphonate preprodrugs that are converted in cells to other ATP-analogs, finding low nM kinase inhibitors that inhibited cell signaling pathways. These results help clarify our understanding of the mechanisms of action of bisphosphonates, potentially opening up new routes to the development of bone resorption, anticancer, and anti-inflammatory drug leads.
Synthesis and polymerase incorporation of β,γ-modified α-L-threofuranosyl thymine triphosphate mimics
Chen, Zhe,Meek, Kirsten N.,Rangel, Alexandra E.,Heemstra, Jennifer M.
, p. 3958 - 3962 (2016/08/01)
Three β,γ-modified α-L-threofuranosyl nucleoside triphosphates were synthesized. The β,γ-modified tTTPs undergo a single incorporation event with HIV RT but undergo multiple incorporations to form full-length product with engineered thermophilic polymeras
5′-β,γ-CHF-ATP Diastereomers: Synthesis and Fluorine-Mediated Selective Binding by c-Src Protein Kinase
Hwang, Candy S.,Kung, Alvin,Kashemirov, Boris A.,Zhang, Chao,McKenna, Charles E.
supporting information, p. 1624 - 1627 (2015/04/14)
The first preparation of the individual β,γ-CHF-ATP stereoisomers 12a and 12b is reported. Configurationally differing solely by the orientation of the C-F fluorine, 12a and 12b have discrete 31P (202 MHz, pH 10.9, ΔδPα 6 Hz, ΔδPβ 4 Hz) and 19F NMR (470 MHz, pH 9.8, ΔδF 25 Hz) spectral signatures and exhibit a 6-fold difference in IC50 values for c-Src kinase, attributed to a unique interaction of the (S)-fluorine of bound 12b with R388 in the active site.
