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. 2015 Oct 22;58(20):8110-27.
doi: 10.1021/acs.jmedchem.5b01180. Epub 2015 Oct 9.

Pronounced Inhibition Shift From HIV Reverse Transcriptase to Herpetic DNA Polymerases by Increasing the Flexibility of α-Carboxy Nucleoside Phosphonates

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Free PMC article

Pronounced Inhibition Shift From HIV Reverse Transcriptase to Herpetic DNA Polymerases by Increasing the Flexibility of α-Carboxy Nucleoside Phosphonates

Jubi John et al. J Med Chem. .
Free PMC article

Abstract

Alpha-carboxynucleoside phosphonates (α-CNPs) are novel viral DNA polymerase inhibitors that do not need metabolic conversion for enzyme inhibition. The prototype contains a cyclopentyl linker between nucleobase and α-carboxyphosphonate and preferentially (50- to 100-fold) inhibits HIV-1 RT compared with herpetic DNA polymerases. A synthesis methodology involving three steps has been developed for the synthesis of a series of novel α-CNPs, including a Rh(II)-catalyzed O-H insertion that connects the carboxyphosphonate group to a linker moiety and an attachment of a nucleobase to the other end of the linker by a Mitsunobu reaction followed by final deprotection. Replacing the cyclopentyl moiety in the prototype α-CNPs by a more flexible entity results in a selectivity shift of ∼ 100-fold in favor of the herpetic DNA polymerases when compared to selectivity for HIV-1 RT. The nature of the kinetic interaction of the acyclic α-CNPs against the herpetic DNA polymerases differs from the nature of the nucleobase-specific kinetic interaction of the cyclopentyl α-CNPs against HIV RT.

Figures

Fig. 1
Fig. 1
Lineweaver-Burk plots for inhibition of VZV DNA polymerase by compound 6g, thymine-α-CNP and BVDU-TP using poly dA.oligo dT as the template/primer and dTTP as the natural substrate.
Fig 2
Fig 2
Primer extension in the presence of increasing concentrations of adenine-butenyl-α-CNP (6k). (A) Dose response analysis of primer extensions with DNA polymerase RB69 gp43 (left), RB69 ABC5 (middle) and HCMV UL54 (right). (B) Sequences of primer and template used in primer extension assay.
Fig. 3
Fig. 3
Modeling of acyclic T-α-CNP (6g) in the polymerase active site of HIV-1 RT/DNA/cyclic T-α-CNP complex (PDB ID. 4R5P). The protein and DNA structures are shown in gray; active site metal ions as pink spheres with chelation indicated by dashed lines; and the acyclic T-α-CNP (6g) in green. The acyclic linker of 6h (green) does not permit favorable binding when compared to the binding of the cyclopentyl T-α-CNP (yellow) in the crystal structure: the acyclic linker develops a short contact with Y115 and forbids the thymine base to align well with the base of cyclopentyl T-α-CNP while maintaining the metal chelation.
Scheme 1
Scheme 1
Synthetic route towards modified α-CNPs (B = nucleobase) [(i) Rh(II)-catalyzed O-H insertion (ii) Mitsunobu reaction (iii) Deprotection].
Scheme 2
Scheme 2
Hydrogenation of 5c to 5e [(i) Pd/C (10%), H2 (1 atm), MeOH, rt, 2 h]
Scheme 3
Scheme 3
Synthesis of α-carboxy nucleoside phosphonate 6f with a 1,2,3-triazole heterocycle as linker moiety [(i) a. Rh2(OAc)4 Benzene, reflux; b. NaN3 acetone/H2O 60 °C, 12 h (ii) CuSO4.5H2O, Sodium ascorbate, Dioxane/H2O, rt, 16 h, 89% (iii) a. TMSBr, CH3CN, 0 °C-rt, 16 h, H2O, 1h; b. aq. NaOH, 50 °C, 12 h, charcoal column]
Scheme 4
Scheme 4
Synthesis of 2-butenyl-linked α-carboxy nucleoside phosphonate 6g [(i) Rh(II)-catalyzed O-H insertion (ii) 3g (1.0 equiv.), 4a (1.2 equiv.), PPh3 (2.1 equiv.), DIAD (2.0 equiv.), THF, −40 °C-RT, 24 h (iii) a. TMSBr, CH3CN, 0 °C-rt, 16 h, H2O, 1h; b. aq. NaOH, 50 °C, 12 h, charcoal column].
Scheme 5
Scheme 5
Synthesis of n-butyl-linked α-carboxy nucleoside phosphonate 6h [(i) Pd/C (10%), H2 (1 atm), MeOH, rt, 12 h (ii) a. TMSBr, CH3CN, 0 °C-rt, 16 h, H2O, 1h; b. aq. NaOH, 50 °C, 12 h, charcoal column].
Scheme 6
Scheme 6
Synthesis of 2-butenyl linked α-carboxy nucleoside phosphonates 6i6m with different nucleobases [(i) 3g (1.0 equiv.), 4 (1.2 equiv.), PPh3 (2.1 equiv.), DIAD (2.0 equiv.), THF, −40 °C-RT, 24 h (ii) Pd/C (10%), H2 (1 atm), MeOH, rt, 12 h (iii) a. TMSBr, CH3CN, 0 °C-rt, 16 h, H2O, 1h; b. aq. NaOH, 50 °C, 12 h, charcoal column].
Scheme 7
Scheme 7
Synthesis of α-carboxy nucleoside phosphonate 6o [(i) Rh(II)-catalyzed O-H insertion (ii) 3o (1.0 equiv.), 4a (1.2 equiv.), PPh3 (2.1 equiv.), DIAD (2.0 equiv.), THF, −40 °C-RT, 24 h (iii) a. TMSBr, CH3CN, 0 °C-rt, 16 h, H2O, 1h; b. aq. NaOH, 50 °C, 12 h, charcoal column].
Scheme 8
Scheme 8
Synthesis of carboxyphosphonate 6n [(i) Rh(II)-catalyzed O-H insertion (ii) a. TMSBr, CH3CN, 0 °C-rt, 16 h, H2O, 1h; b. aq. NaOH, 50 °C, 12 h].

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