78715-59-0

Basic information

• Product Name: Tetraisopropyl Difluoromethylenebisphosphonate
• Synonyms: Tetraisopropyl Difluoromethylenebisphosphonate
• CAS NO: 78715-59-0
• Molecular Formula: C₁₃H₂₈F₂O₆P₂
• Molecular Weight: 380.3021484
• Product Categories: Inhibitors;Intermediates;Phosphorylating and Phosphitylating Agents
• Mol File: 78715-59-0.mol

Chemical Properties

• Boiling Point: 376.34°C at 760 mmHg
• Flash Point: 181.404°C
• Appearance: /
• Density: 1.155g/cm³
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.419
• Solubility: Ethyl Acetate, Methanol
• CAS DataBase Reference: Tetraisopropyl Difluoromethylenebisphosphonate(CAS DataBase Reference)
• NIST Chemistry Reference: Tetraisopropyl Difluoromethylenebisphosphonate(78715-59-0)
• EPA Substance Registry System: Tetraisopropyl Difluoromethylenebisphosphonate(78715-59-0)

Safety Data

• Hazardous Substances Data: 78715-59-0(Hazardous Substances Data)

Usage

Chemical Properties

Colourless Liquid

InChI:InChI=1/C13H28F2O6P2/c1-9(2)18-22(16,19-10(3)4)13(14,15)23(17,20-11(5)6)21-12(7)8/h9-12H,1-8H3

Upstream product

• 1660-95-3 Tetraisopropyl methylenediphosphonate 
• 75-63-8 Bromotrifluoromethane 
• 27344-79-2 sodium diisopropyl phosphite 
• 75-61-6 dibromodifluoromethane 
• 65094-22-6 diethyl (bromodifluoromethyl)phosphonate 
• 65094-24-8 diisipropyl (bromodifluoromethyl)phosphonate 
• 2244-27-1 sodium dibutyl phosphite 
• 65094-23-7 di(n-butyl) bromodifluoromethylphosphonate 
• 327156-97-8 diisopropyl (methylsulfanyl)difluoromethylphosphonate 
• 124008-87-3 methylthiomethylphosphonic acid diisopropylester 
• 124008-95-3 diisopropyl methylsulfanyldichloromethylphosphonate 

Downstream Products

• 81336-71-2 difluoromethylenebisphosphonic acid bis(tri-n-butylammonium) salt 

Relevant articles and documents

Synthesis and Immunomodulatory Activity of Fluorine-Containing Bisphosphonates

Immune checkpoint blockade using anti-PD-1/PD-L1 or anti-CTLA-4 monoclonal antibodies (mAbs) has revolutionized cancer treatment. However, many types of cancer do not respond and for those that do, only a minority of patients achieve durable remissions. Therefore, oncoimmunologists are working to develop adoptive cell therapies for non-hematopoietic tumors by harnessing immune effector cells such as αβ T cells and γδ T cells. In contrast to conventional αβ T cells that recognize peptides in the context of MHC class I or II molecules, γδ T cells expressing Vγ2Vδ2 T cell receptors (also termed Vγ9Vδ2) are stimulated by isoprenoid metabolites (phosphoantigens) such as isopentenyl diphosphate in a butyrophilin-3A1-dependent manner. Vγ2Vδ2 T cells kill almost all types of tumor cells that have been treated with bisphosphonates. In this study, we synthesized a series of fluorine-containing bisphosphonates based on current drugs and found that they stimulated Vγ2Vδ2 T cell killing of tumor cells. A fluorine-containing prodrug analogue of zoledronate where phosphonate moieties were masked with pivaloyloxymethyl groups markedly enhanced Vγ2Vδ2 T-cell-mediated cytotoxicity, and also promoted the expansion of peripheral blood Vγ2Vδ2 T cells. These results demonstrate that a prodrug of a fluorine-containing zoledronate analogue can sensitize tumor cells for killing as well as expand Vγ2Vδ2 T cells for adoptive cell therapy.

Bisphosphonate-Generated ATP-Analogs Inhibit Cell Signaling Pathways

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

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

Transition state in DNA polymerase β Catalysis: Rate-Limiting chemistry altered by base-pair configuration

Kinetics studies of dNTP analogues having pyrophosphate-mimicking β,β-pCXYp leaving groups with variable X and Y substitution reveal striking differences in the chemical transition-state energy for DNA polymerase β that depend on all aspects of base-pairing configurations, including whether the incoming dNTP is a purine or pyrimidine and if base-pairings are right (T*A and G*C) or wrong (T*G and G*T). Br?nsted plots of the catalytic rate constant (log(kpol)) versus pKa4 for the leaving group exhibit linear free energy relationships (LFERs) with negative slopes ranging from -0.6 to -2.0, consistent with chemical rate-determining transition-states in which the active-site adjusts to charge-stabilization demand during chemistry depending on base-pair configuration. The Br?nsted slopes as well as the intercepts differ dramatically and provide the first direct evidence that dNTP base recognition by the enzyme-primer-template complex triggers a conformational change in the catalytic region of the active-site that significantly modifies the rate-determining chemical step.

Synthesis and biological evaluation of pyrophosphate mimics of thiamine pyrophosphate based on a triazole scaffold

Novel triazole-based pyrophosphate analogues of thiamine pyrophosphate (TPP) have been synthesised and tested for inhibition of pyruvate decarboxylase (PDC) from Zymomonas mobilis. The thiazolium ring of thiamine was replaced by a triazole in an efficient two-step procedure. Pyrophosphorylation then gave extremely potent triazole inhibitors with KI values down to 20 pM, compared to a KD value of 0.35 μM for TPP. This triazole scaffold was used for further investigation and six analogues containing mimics of the pyrophosphate group were synthesised and tested for inhibition of PDC. Several effective analogues were found with KI values down to around 1 nM.

(R)-β,γ-fluoromethylene-dGTP-DNA ternary complex with DNA polymerase β

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

Difluoromethylenediphosphonate: A convenient, scalable, and high-yielding synthesis

Since the firsf disclosure of difluoromethylenediphosphonate, 2, almost 40 years ago, interest in this compound has flourished in several research areas. In this paper, we present a convenient, high-yielding (99% overall) method for the preparation of milligram to multigram quantities of 2 (as the bis(tributylammonium salt, 2b) in a solid form that is easy to handle.

An improved method for the synthesis of nucleoside triphosphate analogues

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.

Synthesis of AZT 5′-triphosphate mimics and their inhibitory effects on HIV-1 reverse transcriptase

In search of active nucleoside 5′-triphosphate mimics, we have synthesized a series of AZT triphosphate mimics (AZT P3Ms) and evaluated their inhibitory effects on HIV-1 reverse transcriptase as well as their stability in fetal calf serum and in CEM cell

Nucleotide mimics and their prodrugs

The present invention relates to nucleoside diphosphate mimics and nucleoside triphosphate mimics, which contain diphosphate or triphosphate moiety mimics and optionally sugar-modifications and/or base-modifications. The nucleotide mimics of the present invention, in a form of a pharmaceutically acceptable salt, a pharmaceutically acceptable prodrug, or a pharmaceutical formulation, are useful as antiviral, antimicrobial, and anticancer agents. The present invention provides a method for the treatment of viral infections, microbial infections, and proliferative disorders. The present invention also relates to pharmaceutical compositions comprising the compounds of the present invention optionally in combination with other pharmaceutically active agents.