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DOI: 10.1055/s-0036-1591994
An Improved Route for the Synthesis of Guanine Quadruplex Ligand Phen-DC3
Funding from the Natural Sciences and Engineering Research Council (NSERC-DG, grant number 315311-2013; NSERC PGS-D), the Canada Foundation for Innovation, and Queen’s University is acknowledged.Publikationsverlauf
Received: 16. Februar 2018
Accepted after revision: 28. März 2018
Publikationsdatum:
24. April 2018 (online)
![](https://www.thieme-connect.de/media/synlett/201810/lookinside/thumbnails/st-2018-r0108-l_10-1055_s-0036-1591994-1.jpg)
Abstract
The recognition of noncanonical DNA and RNA architectures such as guanine quadruplexes by small molecule ligands has become a promising strategy for anticancer and antiviral applications in recent years, leading to an exponential increase in the number of quadruplex ligands reported in the literature. There is consequently a need for ‘benchmark’ compounds which can be used as controls to facilitate comparisons between novel and previously reported ligands. One candidate for this role is Phen-DC3, which binds with high affinity and selectivity to guanine quadruplexes. To encourage its use in this role, an alternate synthetic route for the production of Phen-DC3 that may be more appropriate for implementation on a large scale is reported. This pathway eliminates the need for several hazardous reagents and increases the overall synthetic yield from 21% to a maximum of 43%.
Supporting Information
- Supporting information for this article is available online at https://doi.org/10.1055/s-0036-1591994.
- Supporting Information
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References and Notes
- 1a Neidle S. J. Med. Chem. 2016; 59: 5987
- 1b Brooks TA. Kendrick S. Hurley L. FEBS J. 2010; 277: 3459
- 1c Müller S. Rodriguez R. Expert Rev. Clin. Pharmacol. 2014; 7: 663
- 1d Patel DJ. Phan AT. Kuryavyi V. Nucleic Acids Res. 2007; 35: 7429
- 2 Harris LM. Merrick CJ. PLoS Pathog. 2015; 11: e1004562
- 3a Huppert JL. Chem. Soc. Rev. 2008; 37: 1375
- 3b Burge S. Parkinson GN. Hazel P. Todd AK. Neidle S. Nucleic Acids Res. 2006; 34: 5402
- 4 Kim NW. Piatyszek MA. Prowse KR. Harley CB. West MD. Ho PL. C. Coviello GM. Wright WE. Weinrich SL. Shay JW. Science 1994; 266: 2011
- 5 Merle P. Evrard B. Petitjean A. Lehn J.-M. Teulade-Fichou M.-P. Chautard E. De Cian A. Guittat L. Tran PL. T. Mergny J.-L. Verrelle P. Tchirkov A. Mol. Cancer Ther. 2011; 10: 1784
- 6a Perrone R. Nadai M. Frasson I. Poe JA. Butovskaya E. Smithgall TE. Palumbo M. Palù G. Richter SN. J. Med. Chem. 2013; 56: 6521
- 6b Amrane S. Kerkour A. Bedrat A. Vialet B. Andreola M.-L. Mergny J.-L. J. Am. Chem. Soc. 2014; 136: 5249
- 6c Lista MJ. Martins RP. Billant O. Contesse M.-A. Findakly S. Pochard P. Daskalogianni C. Beauvineau C. Guetta C. Jamin C. Teulade-Fichou M.-P. Fåhraeus R. Voisset C. Blondel M. Nat. Commun. 2017; 8: 16043
- 6d Madireddy A. Purushothaman P. Loosbroock CP. Robertson ES. Schildkraut CL. Verma SC. Nucleic Acids Res. 2016; 44: 3675
- 6e Biswas B. Kandpal M. Jauhari UK. Vivekanandan P. BMC Genomics 2016; 17: 949
- 6f Fleming AM. Ding Y. Alenko A. Burrows CJ. ACS Infect. Dis. 2016; 2: 674
- 7 De Cian A. DeLemos E. Mergny J.-L. Teulade-Fichou M.-P. Monchaud D. J. Am. Chem. Soc. 2007; 129: 1856
- 8a Chung WJ. Heddi B. Hamon F. Teulade-Fichou M.-P. Phan AT. Angew. Chem. Int. Ed. 2014; 53: 999
- 8b Quadruplex graphic generated using the PyMOL Molecular Graphics System, version 1.3, Schroedinger.
- 9a De Rache A. Mergny J.-L. Biochimie 2015; 115: 194
- 9b Monchaud D. Allain C. Bertrand H. Smargiasso N. Rosu F. Gabelica V. De Cian A. Mergny J.-L. Teulade-Fichou M.-P. Biochimie 2008; 90: 1207
- 9c Bončina M. Hamon F. Islam B. Teulade-Fichou M.-P. Vesnaver G. Haider S. Lah J. Biophys. J. 2015; 108: 2903
- 9d Lacroix L. Séosse A. Mergny J.-L. Nucleic Acids Res. 2011; 39: e21
- 9e Guilbaud G. Murat P. Recolin B. Campbell BC. Maiter A. Sale JE. Balasubramanian S. Nat. Chem. 2017; 9: 1110
- 9f Gomez D. Guédin A. Mergny J.-L. Salles B. Riou J.-F. Teulade-Fichou M.-P. Calsou P. Nucleic Acids Res. 2010; 38: 7187
- 10 Larsen AF. Ulven T. Org. Lett. 2011; 13: 3546
- 11a Albrecht M. Chem. Eur J. 2000; 6: 3485
- 11b Qi H. Teesdale JJ. Pupillo RC. Rosenthal J. Bard AJ. J. Am. Chem. Soc. 2013; 135: 13558
- 11c Jun L. Zheng M. Li W. Wang H. Zhang H. Wu H. Jia Z. Zheng L. Tian J. CN 102040608, 2011
- 11d Qi D. Wang X. CN 105884683, 2014
- 12a Beer RH. Jimenez J. Drago RS. J. Org. Chem. 1993; 58: 1746
- 12b Lamarque L. Bazin H. Blanche E. WO 2010070232, 2010
- 12c Goswami S. Maity AC. Fun H.-K. Chem. Lett. 2007; 36: 552
- 12d This observation is consistent with oxygen acting as both oxidant and radical scavenger, thereby impeding progress along the chlorinating radical reaction pathway, see: Anderson AG. Tober TY. J. Org. Chem. 1980; 45: 1695
- 13 Holbrook MT. Carbon Tetrachloride . In Kirk-Othmer Encyclopedia of Chemical Technology . John Wiley and Sons; New York: 2000: 1
- 14 ExperimentalCommercially available compounds were used as received. Reagents for reactions requiring anhydrous conditions were pre-dried under vacuum and P2O5. Column chromatography was performed with Silica-P flash silica gel (40–63 μm particle size, 60 Å pore diameter). NMR data was obtained with 300 MHz, 400 MHz, and 500 MHz Bruker instruments at 25 °C. CDCl3 was neutralized before use by passing through a short column of basic alumina. Peak listings for all spectra are given in ppm and referenced against the signal of the residual solvent signal (1H NMR) or internal standard (19F NMR).
- 15 2,9-Bis(trichloromethyl)-1,10-phenanthroline (2)To a solution of 2,9-dimethyl-1,10-phenanthroline (430 mg, 2.1 mmol, 1.0 equiv) in chloroform (17 mL) under argon atmosphere at room temperature was added dropwise a solution of N-chlorosuccinimide (NCS, 2.2 g, 0.017 mol, 8.0 equiv) in chloroform (72 mL). The reaction mixture was protected from light while stirring and heating under reflux (6 h). The reaction mixture was then cooled to 4 °C and filtered. The filtrate was concentrated under reduced pressure to yield the crude product. Purification by column chromatography using gradient CHCl3/hexanes (1:1 to 2:1) afforded pure compound 2 (590 mg, 68%). CH2Cl2/hexanes was also tested as eluent but gave a slightly poorer separation by TLC. 1H NMR (400 MHz, CDCl3): δ =7.96 (s, 2 H), 8.32 (d, 3J = 8 Hz, 2 H), 8.44 (d, 3J = 8 Hz, 2 H). Rf = 0.26 (1:1 CHCl3/hexanes); mp. 227 °C (lit. 225–227°C).11c
- 16 1,10-Phenanthroline-2,9-dicarboxylic acid (3)A solution of 2 (540 mg, 1.3 mmol, 1.0 equiv) in concentrated aqueous sulfuric acid (95–98%, 17 mL) was stirred at 85 °C for 7 h. Following this, the brown solution was cooled to room temperature and poured over crushed ice. The ice was allowed to melt and the resulting white suspension filtered under vacuum, washed with water, and air-dried to afford pure compound 3 (360 mg, quant. yield). 1H NMR (300 MHz, DMSO-d 6): δ = 8.22 (s, 2 H), 8.42 (d, 3J = 8.4 Hz, 2 H), 8.74 (d, 3J = 8.4 Hz, 2 H); mp 215–216 °C (dec.).
- 17 Wehrstedt KD. Wandrey PA. Heitkamp D. J. Hazard Mater. 2005; 126: 1
- 18a Montalbetti CA. G. N. Falque V. Tetrahedron 2005; 61: 10827
- 18b Nakajima N. Ikada Y. Bioconjugate Chem. 1995; 6: 123
- 19 N,N-Bis(3-quinolinyl)-1,10-phenanthroline-2,9-dicarboxamide (4)Under anhydrous conditions, 4-dimethylaminopyridine (DMAP, 340 mg, 2.8 mmol, 2.5 equiv), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC·HCl, 640 mg, 3.4 mmol, 3.0 equiv), and 3-aminoquinoline (450 mg, 3.1 mmol, 2.8 equiv) were added as solids to a suspension of compound 3 (3.0·102 mg, 1.1 mmol, 1.0 equiv) in DMF (23 mL). The solution was placed under argon and stirred at room temperature (48 h). The resulting yellow suspension was filtered under vacuum, and the isolated precipitate washed with saturated aqueous sodium bicarbonate (30 mL), CH2Cl2 (20 mL), and diethyl ether (20 mL) to afford pure compound 4 as a pale yellow solid (490 mg, 85%). 1H NMR (300 MHz, DMSO-d6): δ = 7.68 (t, 3J = 7 Hz, 2 H), 7.75 (t, 3J = 7 Hz, 2 H), 8.09–8.13 (m, 4 H), 8.33 (s, 2 H), 8.69 (d, 3J = 8 Hz, 2 H), 8.91 (d, 3J = 8 Hz, 2 H), 9.17 (d, 4J = 2 Hz, 2 H), 9.68 (d, 4J = 2 Hz, 2 H), 11.88 (s, 2 H); mp >280 °C (lit. >260 °C).7
- 20 Alder RW. Phillips JG. E. Huang L. Huang X. Methyl Trifluoromethanesulfonate . In Encyclopedia of Reagents for Organic Synthesis . John Wiley and Sons; Hoboken, NJ: 2005: 1
- 21a Larsen AF. Nielsen MC. Ulven T. Chem. Eur. J. 2012; 18: 10892
- 21b Lefebvre J. Guetta C. Poyer F. Mahuteau-Betzer F. Teulade-Fichou M.-P. Angew. Chem. Int. Ed. 2017; 56: 11365
- 22 N,N-Bis(3-[1-methylquinolinium])-1,10-phenanthroline-2,9-dicarboxamide diiodide (5)Under anhydrous conditions and argon atmosphere, methyl iodide (0.24 mL, 4.0 mmol, 21 equiv) was added dropwise to a solution of 4 (1.0·102 mg, 0.19 mmol, 1.0 equiv) in anhydrous DMF (4.5 mL). The solution was protected from light, stirred and heated at 85 °C for 13 h. The resulting suspension was filtered, and the isolated precipitate washed with diethyl ether to afford pure product as an iodide salt (120 mg, 75%). 1H NMR (500 MHz, DMSO-d 6): δ = 4.75 (s, 6 H), 8.09 (t, 3J = 7.5 Hz, 2 H), 8.26 (t, 3J = 7.5 Hz, 2 H), 8.40 (s, 2 H), 8.54–8.57 (2 d, 4 H), 8.33 (s, 2 H), 8.77 (d, 3J = 8.4 Hz, 2 H), 8.99 (d, 3J = 8.4 Hz, 2 H), 9.93 (s, 2 H), 10.33 (s, 2 H), 12.17 (s, 2 H).
- 23 Dorazco-González A. Höpfl H. Medrano F. Yatsimirsky AK. J. Org. Chem. 2010; 75: 2259
- 24 Phen-DC3 Method 1A solution of silver(I) triflate (13 mg, 5.1·10–5 mol, 2.2 equiv) in methanol (0.60 mL) was added to a solution of 5 (19 mg, 2.4·10–5 mol, 1.0 equiv) in acetonitrile (13 mL) and methanol (24 mL). Immediate precipitation of a yellow solid was observed. The suspension was protected from light and left to stir at room temperature (30 min), then filtered, and the filtrate concentrated under reduced pressure to afford Phen-DC3 as a pale yellow powder (20 mg, 99%).Method 2To a solution of 5 (28 mg, 3.5·10–5 mol, 1.0 equiv) in acetonitrile (10 mL) and methanol (18 mL) was added a solution of calcium(II) triflate (71 mg, 0.21 mmol, 6.0 equiv) in the same mix of acetonitrile/methanol (1.5 mL). The solution was protected from light and stirred at room temperature (40 min), then concentrated to dryness. MilliQ water (7 mL) was added, and the suspension filtered and washed with diethyl ether to obtain Phen-DC3 as a yellow powder (25 mg, 84%). Anal Calcd (%) for C36H26N6F6O8S2·2 H2O: C, 48.87; H, 3.42; N, 9.50. Found: C, 49.23; H, 3.72; N, 9.57. Quantification by 19F NMR spectroscopy using a known volume of standard (trifluorotoluene) also confirmed that two equivalents of triflate were present in the product of each method.19F NMR (500 MHz, DMSO-d 6 + trifluorotoluene): δ = –80.3.
- 25a Kim S. Choi JE. Choi J. Chung K.-H. Park K. Yi J. Ruy D.-Y. Toxicol. In Vitro 2009; 23: 1076
- 25b Zhou X.-H. Kong D.-M. Shen H.-X. Anal. Chem. 2010; 82: 789
- 26 Adapted fromGries W.-K. Günther E. Hünig S. Liebigs Ann. Chem. 1991; 1021