An Improved Route for the Synthesis of Guanine Quadruplex Ligand Phen-DC3

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%.

Key words

heterocycles - DNA - oxidation - amides - alkylation

• References and Notes

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• 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.
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