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(Difluoromethylene)Triphosphoric Acid

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(Difluoromethylene)Triphosphoric Acid Synthesis and biological evaluation of fluorinated deoxynucleotide analogs based on bis- (difluoromethylene)triphosphoric acid G. K. Surya Prakasha,1, Mikhail Zibinskya, Thomas G. Uptona, Boris A. Kashemirova, Charles E. McKennaa, Keriann Oertella, Myron F. Goodmana, Vinod K. Batrab, Lars C. Pedersenb, William A. Beardb, David D. Shockb, Samuel H. Wilsonb, and George A. Olaha,1 aLoker Hydrocarbon Research Institute, Department of Chemistry and Department of Biology, University of Southern California, 837 Bloom Walk, Los Angeles, CA 90089-1661; and bLaboratory of Structural Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709 Contributed by George A. Olah, June 3, 2010 (sent for review April 28, 2010) It is difficult to overestimate the importance of nucleoside tri- the altered chemical properties conferred on the compound by phosphates in cellular chemistry: They are the building blocks the fluorine substituent. The van der Waals’ radius of the fluorine for DNA and RNA and important sources of energy. Modifications atom (1.47 Å) is close to the size of hydrogen (1.2 Å). Most of the of biologically important organic molecules with fluorine are of other substituent groups often used to replace hydrogen in the great interest to chemists and biologists because the size and creation of analogs are much larger. Thus fluorine is of electronegativity of the fluorine atom can be used to make defined unique value in the design of analogs, which can very closely ap- structural alterations to biologically important molecules. Although the concept of nonhydrolyzable nucleotides has been proach the natural biochemical intermediate. Good analogs of around for some time, the progress in the area of modified tripho- this kind can be useful therapeutically, but they can also be ex- sphates was limited by the lack of synthetic methods allowing to tremely valuable in defining critical sizes that contribute to — CHEMISTRY access bisCF2-substituted nucleotide analogs one of the most structural considerations in biochemically important molecules. interesting classes of nonhydrolyzable nucleotides. These com- Further, fluorinated compounds are more hydrophobic than their pounds have “correct” polarity and the smallest possible steric hydrogen counterparts and are found to provide increase in perturbation compared to natural nucleotides. No other known bioavailability. nucleotides have these advantages, making bisCF2-substituted Recently, as a result of a comprehensive effort to prepare new analogs unique. Herein, we report a concise route for the prepara- nonhydrolyzable nucleotides, we developed a synthetic method tion of hitherto unknown highly acidic and polybasic bis(difluoro- for the preparation of the hitherto unknown bis(difluoromethy- methylene)triphosphoric acid 1 using a phosphorous(III)/phos- lene)triphosphoric acid 1 (BMF4TPA, Fig. 1), a highly acidic pen- phorous(V) interconversion approach. The analog 1 compared to “ ” triphosphoric acid is enzymatically nonhydrolyzable due to substi- tabasic acid. Because of the biostericity and similar polarity of the CF2 groups to the bridging oxygen atoms (3–5), this com- tution of two bridging oxygen atoms with CF2 groups, maintaining minimal perturbations in steric bulkiness and overall polarity of the pound is a nonhydrolyzable analog of triphosphoric acid, albeit triphosphate polyanion. The fluorinated triphosphoric acid 1 was with lower pKaS (vide infra), a vital part of nucleotides containing used for the preparation of the corresponding fluorinated deoxy- both oxy- and deoxyriboses. It is important to emphasize that no nucleotides (dNTPs). One of these dNTP analogs (dT) was demon- other known (α,β),(β,γ)-bis-substituted triphosphate analog re- strated to fit into DNA polymerase beta (DNA pol β) binding pocket tains the “right” polarity and steric features of the natural tripho- by obtaining a 2.5 Å resolution crystal structure of a ternary sphate. This makes the preparation of the corresponding complex with the enzyme. Unexpected dominating effect of deoxynucleotide analogs with 1 of high scientific interest and im- triphosphate∕Mg2þ interaction over Watson–Crick hydrogen bond- portance. We report the synthesis and purification procedures for ing was found and discussed. deoxynucleotide analogs where CF2 groups are in both the (α,β)- β γ DNA polymerase beta ∣ nonhydrolyzable nucleotides ∣ fluorinated and ( , )-positions of the triphosphate group. Owing to the 1 triphosphate ∣ pentabasic acid ∣ isopolarity and bioisotericity unique properties of , these nucleotides should offer the best electronic and stereochemical mimicking of the natural deoxy- luorine is in group VII of the periodic system, and this element nucleoside triphosphates. The prepared analogs are (α,β),(β,γ)- α β β γ α β β γ Fshould be considered, according to Pauling, a “superhalogen” bisCF2 dATP, ( , ),( , )-bisCF2 dTTP, ( , ),( , )-bisCF2 dCTP, (1). Fluorine is considerably more electronegative than the other and (α,β),(β,γ)-bisCF2 dGTP. A 2.5 Å crystallographic structure halogens, and for this reason it is the only halogen that is extre- of a ternary complex of DNA pol β and (α,β),(β,γ)-bisCF2 dTTP mely unlikely to form the positive ion. The bond energy of the is also reported and discussed. C-F bond is among the highest found in natural products and is difficult to be broken enzymatically (2). Recent advances in or- ganofluorine chemistry have been responsible for the develop- Author contributions: G.K.S.P., C.E.M., M.F.G., and G.A.O. designed research; M.Z., T.G.U., ment of a large number of new compounds of importance in B.A.K., K.O., V.K.B., L.C.P., W.A.B., and D.D.S. performed research and analyzed data; G.K.S.P. and M.Z. contributed new reagents; and G.K.S.P., M.Z., K.O., V.K.B., and W.A.B. biology and medicine. The knowledge gained in the synthesis wrote the paper. of organofluorine compounds has also provided the pharmacol- The authors declare no conflict of interest. ogist with selective inhibitors of biological processes and has Data deposition: The crystal structure 10 data have been deposited in the Cambridge given the medicinal chemist the opportunity to design more active Structural Database, Cambridge Crystallographic Data Centre, Cambridge CB2 1EZ, United therapeutic agents. The use of fluoro compounds in studies of Kingdom (CSD reference no. 778743). enzyme and pharmacological mechanisms has advantages not 1To whom correspondence may be addressed: E-mail: [email protected] or [email protected]. found with many other analogs because insight into the biochemi- This article contains supporting information online at www.pnas.org/lookup/suppl/ cal phenomenon can often be gained from an understanding of doi:10.1073/pnas.1007430107/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1007430107 PNAS Early Edition ∣ 1of6 Downloaded by guest on September 24, 2021 controlled by two factors: the rate of deprotonation and steric hindrance of the base. Generally, in the case of slow deprotona- tion only a small amount of (difluoromethyl)phosphonate anion was available for reaction with phosphorous electrophile, while the major part of 4 simply remained in the reaction mixture unchanged. In such a case, the majority of the base reacted with phosphorous electrophile producing the phosphoramide. These observations suggested that a sterically hindered lithium amide base would work well in the reaction, providing relatively fast de- protonation of 4 and suppression of direct reaction of the base with phosphorous electrophile. After a brief screening of several bases, it was found that use of lithium 2,2,6,6-tetramethylpiperi- dine amide (LTMPA) as a base gave access to compound 8 in 93% yield as determined by NMR analysis. A doublet of triplet at þ6.5 ppm (2P) and a multiplet at þ54.0 ppm (1P) were observed in the 31P NMR of the crude mixture indicating the formation of 8 Fig. 1. Polarities of bridging units in tiphosphate anion and its CX2-substi- compound . The fluorine NMR spectrum showed two nonequi- tuted analogs. valent fluorine atoms as doublets of triplets at −116.8 and −118.5 ppm, respectively. Interestingly, the bulky lithium hexa- methyldisilazide (LHMDS) did not provide positive results; a Results and Discussion complex mixture was formed instead. 4 Synthesis of BMF TPA. Although the synthesis of bis(methylene)tri- In situ oxidation of compound 8 with 2.5 equivalents of meta- 3 phosphoric acid has been known for a long time (6, 7), all at- chloroperbenzoic acid (m-CPBA) in dichloromethane followed tempts at its direct preparation from dialkyl methylphosphonate by purification on silica gave access to BMF4TPA amido-ester – have failed (8). Michaelis Arbuzov-type reactions have been 9 in 75% overall isolated yield (starting from phosphonate 4). shown to be useful in the preparation of nonfluorinated analogs Treatment of compound 9 with TMSBr (10) followed by hydro- (6, 9). Although bis(difluoromethylene)triphosphoric acid 1 has a lysis gave access to the bis(difloromethylene)phosphoric acid 1, very simple structure, it remained unknown, most likely due to which was quantitatively converted to the ammonium salt by the failure of conventional approaches mentioned above. We passing through DOWEX ion-exchange resin in the ammonium 4 have now discovered that BMF TPA can be accessed starting form. The overall yield of salt 10 was 61%. directly from diethyl (difluoromethyl)phosphonate 4 (Scheme 1) As was discussed above, the introduction of fluorine atoms into employing phosphorous (III)/phosphorous(V) interconversion a molecule has an impact on the physical and chemical properties protocol. of the molecule; therefore we intended to compare bond lengths 4 Our initial approach to the synthesis of BMF TPA began with and angles of the fully fluorinated analog to those of sodium tri- the direct reaction between 2 eq. of (diethylphosphinyl)difluoro- phosphate. X-ray structure of salt 10 (Fig. 2) revealed that the methyllithium (generated by LDA) with dichlorophosphate 5 length of the P-O bridging bond in the original triphosphate 4 (Scheme 1).
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