Developing Prodrugs of antivirally active Nucleoside Triphosphates - Against all odds, it works!
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1 Developing Prodrugs of antivirally active ucleoside Triphosphates - Against all odds, it works! RSC-Meeting, London, England, April 17 th, 2015 Prof. Dr. Chris Meier, rganic Chemistry, Department of Chemistry, Faculty of Sciences, University of Hamburg, Germany
2 Antivirally active ucleosides H H H H H H H H 2 H Thymidine 3 AZT (1987) d4t (1994) ddc (1992) H 2 S H H H H 2 H 2 F S H P H 2 3TC (1995) Abacavir (1998) FTC (2006) PMPA (Tenofovir 2006) J. L. Marx, AIDS, Science 1968, 231,1504; S. A. Riddler, R. E. Anderson, J. W. Mellors, Antiviral Res. 1995, 27, ; S. M. Daluge, M. T. Martin, B. R. Sickles, D. A. Livingston, ucleosides, ucleotides ucleic Acids 2000, 19, 297; R. S. Schinazi et. al, Antimicrob. Agents Chemother. 1992, 36, 2423
3 Metabolism of ucleoside Analogues Application of the drug may be limited due to the lack of intracellular phosphorylation!!! but: the use of phosphorylated nucleosides is not possible!!!
4 Mechanism of Action of ucleoside Drugs Triphosphate of the ucleoside ucleoside Analog viral Polymerase Termination of the DA-Synthesis E. De Clercq, at. Rev. Drug Discov. 2002, 1, 13
5 ucleotide Prodrugs from the Meier Lab Synthesis (novel structure) Kinase Bypass Eur. J. rg. Chem. 2006, In preparation Angew. Chem. Int. Ed. 2008, 47, ( Top 10% papers ) ChemMedChem, 2014, 9, ( very important paper )
6 Towards TriPPPro-Prodrugs ucleoside MP DP TP Kinase Bypass Tristan Gollnest Tobias ack Chenglong Zhao
7 ucleoside Di- or Triphosphate Prodrugs? Direct delivery of triphosphate or diphosphate forms of nucleoside analogs would be desirable but is impractical because of their instability during synthesis. X. Tan, K. Chu; Advanced Drug Delivery Reviews 1999, 39,
8 MP- vs. TP-Prodrugs
9 Specific Problem with D(T)P-Prodrugs To reduce chemical lability, leave a charge at the a- and b-phosphorus atom! 1. o attack at the a- or b-phosphorus atom 2. Mono- or Diphosphate is a bad leaving group
10 cyclosal-dp-prodrugs X Y P H P H P P 3 3 AZTDP H X= H; Y= Me : 1% X= Cl; Y= H : 25% P H Properties: - Difficult purification / poor yields - AZTDP/AZTMP ratio correlates with stability - Insufficient AZTDP delivery X= H; Y= Me : 99% X= Cl; Y= H : 75% 3 AZTMP Consequence: Do not touch the Pyrophosphate!
11 Enzyme-cleavable TriPPPro-Compounds Acceptor TriPPPro-TP
12 Enzyme-cleavable TriPPPro-Compounds Acceptor Donor TriPPPro-TP
13 Enzyme-cleavable TriPPPro-Compounds Acceptor Donor TriPPPro-TP monomasked intermediate
14 TP Delivery System: TriPPPro-Compounds Acceptor Donor Features: 1. charged a and b-phosphorus atom; 2. no activation needed involving the pyrophosphate unit; 3. enzymatic activation; 4. tunable polarity and tunable stability (R)
15 Phosphoramidite Chemistry Reagents and conditions: i) triethylamine, THF, 0 C to rt, 20 h; ii) a. 5-chlorosaligenylchlorophosphite, DIPEA, CH 3 C, -20 C to rt, 3 h; b. t-buh, 0 C to rt, 30 min; iii) (H 2 P 4 )Bu 4, DMF, rt, 20 h; iv) 1 eq. DP; 1.5 eq. phosphoramidite, 1.7 eq. DCI, CH 3 C, rt, 1 min; v) 1.5 eq. t-buh, 0 C, 20 min; vi) Dowex-H 4+ ; vii) RP-18 chromatography
16 H-Phosphonate Chemistry
17 TP-Formation in aqueous PBS (ph 7.3) Chemical cleavage in PBS showed the predominant formation of TP!
18 Chem. Hydrolysis of TriPPPro-Compounds
19 PLE Cleavage of TriPPPro-d4TTP Pig liver esterase (PLE) incubation showed almost selective formation of TP
20 Primer Extension Assay of TriPPPro-dTPs Assay: HIV-RT, dtp s [2.5 µm] Conditions: 37 C, 12 min. d4t-tp (from the prodrug) dt-tp (from the prodrug) 30 nt 29 nt 28 nt 27 nt 26 nt 25 nt 30 nt 29 nt 28 nt 27 nt 26 nt 25 nt Thiago Dinis de liveira T* T*,C * Stand. Primer T*,C,G T T,C Stand. Primer T,C,G Presented at: International Conference on Antiviral Research (ICAR), Raleigh, USA, May 2014 International Round Table on ucleotides and ucleic Acids (IRT), Poznan, Poland, August 2014
21 Proof of dtp Delivery by PCR lane 1: standard lane 2: reference; all dtps present lane 3: datp, dctp, dgtp Enzyme: Fire Pol-polymerase no amplification product
22 Proof of dtp Delivery by PCR lane 1: standard lane 2: reference; all dtps present lane 3: datp, dctp, dgtp lane 4: datp, dctp, dgtp + dttp-prodrug lane 5: datp, dctp, dgtp + d4ttp-prodrug lane 6: datp, dctp, dgtp + carba-dttp-prodrug 25 mm solution of the dtp-prodrugs; Enzyme: Fire Pol-polymerase hydrolysis and delivery of dttp or T-analogue triphosphate by esterase no amplification products!!!! successful amplification or chain termination!
23 Anti-HIV Activity of d4ttp-prodrugs EC 50 (µm) CC 50 (µm) CEM/0 CEM/TK - Compound HIV-1 HIV-2 HIV-2 CEM/0 R=CH ± ± 0.16 >10 63 ± 2 R=C 4 H ± ± 0.30 >10 58 ± 3 R=C 8 H ± ± ± ± 1 R=C 11 H ± ± ± ± 0 R=C 17 H ± ± ± ± 9 d4t 0.84 ± ± ± 4.8 > 250 d4ttp-prodrugs showed very good antiviral activity in CEM cells in dependence of the length of the alkyl chain collaboration with J. Balzarini, D. Schols, Rega-Institute, Leuven
24 Symmetric TriPPPro-ucleotides Summary of the results (dependence of the alkyl chain length) Stability t 1/2 * Lipophilicity Antiviral Activity Problem: Formation of MP and DP *
25 Symmetric TriPPPro-ucleotides
26 on-symmetric TriPPPro-ucleotides modified concept: Patent filed: DE ; date:
27 Synthesis of non-symmetric TriPPPro s Tristan Gollnest
28 Selective d4tdp Formation in Cell Extracts Lina Weinschenk 0 min 1 min 4 min 15 min 60 min 120 min 420 min d4tdp retention time [min]
29 on-symmetric vs. Symmetric Compounds on-symmetric Symmetric Reference
30 In-cell Delivery of a Triphosphate! intracellular collaboration with I. Hauber, HPI, Hamburg
31 Summary Development of the first example of nucleoside triphosphate prodrugs enzymatic phosphorylation of the nucleoside analogue is needed! Chemical hydrolysis studies in PBS showed the predominant formation of TP Enzymatic hydrolysis studies using PLE showed selective formation of TP d4tdp- and d4ttp-prodrugs showed very good activity in thymidine kinasesdeficient cells
32 Acknowledgement Co-workers: Lina Weinschenk, Tristan Gollnest, Tobias ack, Thiago Dinis de liveira, Chenglong Zhao Collaboration Jan Balzarini, Domenique Schols, Rega-Institute, Leuven, Belgium Ilona Hauber, Heinrich-Pette-Institute, Hamburg
Lipophilic prodrugs of nucleoside triphosphates as biochemical probes and potential antivirals
ATICLE eceived 10 Jul 2015 Accepted 23 Sep 2015 Published 27 ct 2015 DI: 10.1038/ncomms9716 Lipophilic prodrugs of nucleoside triphosphates as biochemical probes and potential antivirals Tristan Gollnest
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