Characterization of the Interaction of Nerve Agent Mimics with Selected Synthetic Receptors

Abstract

Qualitative NMR spectroscopic and quantitative calorimetric binding studies were performed to characterize the interaction of nontoxic mimics of the V-type nerve agent VX (O-ethyl S-[2-(diisopropylamino)ethyl] methylphosphonothioate) and the Novichok nerve agent A-234 (ethyl (1-(diethylamino)ethylidene)phosphoramidofluoridate) with a series of receptors in 100 mM aqueous phosphate buffer at pH 7.4 and 37 °C. These investigations provided information about the preferred geometry with which the nerve agent mimics are included into the receptor cavities and about the stability of the complexes formed. According to the results, the positively charged VX mimic prefers to bind to cation receptors such as sulfonated calixarenes and an acyclic cucurbituril but does not noticeably interact with cyclodextrins. While binding to the acyclic cucurbituril is stronger than that to calixarenes, the mode of inclusion into the sulfonatocalix[4]arene cavity is better suited for the development of scavengers that bind and detoxify V-type nerve agents. The neutral Novichok mimic, on the other hand, only interacts with the acyclic cucurbituril with a strength required for scavenger development. These binding studies thus provided guidelines for the further development of nerve agent scavengers.

Key words

nerve agents - sulfonatocalixarenes - cyclodextrins - acyclic cucurbiturils - binding studies

Publication History

Received: 21 July 2022

Accepted after revision: 06 September 2022

Accepted Manuscript online:
08 September 2022

Article published online:
26 October 2022

• References and Notes

• 1 Current address: Cooperative State University Karlsruhe, Erzbergerstraße 121, 76133 Karlsruhe, Germany.
• 2 Steindl D, Boehmerle W, Körner R, Praeger D, Haug M, Nee J, Schreiber A, Scheibe F, Demin K, Jacoby P, Tauber R, Hartwig S, Endres M, Eckardt K-U. Lancet 2021; 397: 249
• 3a Vale JA, Marrs TC, Maynard RL. Clin. Toxicol. 2018; 56: 1093
• 3b Carlsen L. Mol. Inf. 2019; 38: e1800106
• 4a Franca TCC, Kitagawa DAS, Cavalcante SFde A, da Silva JAV, Nepovimova E, Kuca K. Int. J. Mol. Sci. 2019; 20: 1222
• 4b Kloske M, Witkiewicz Z. Chemosphere 2019; 221: 672
• 5 Marrs TC. Toxicology of Organophosphate Nerve Agents. Marrs TC, Maynard RL, Sidell FR. Chemical Warfare Agents: Toxicology and Treatment. Chichester, UK: John Wiley & Sons; 2007: 191-221
• 6 Costanzi S, Machado J-H, Mitchell M. ACS Chem. Neurosci. 2018; 9: 873
• 7a Bhakhoa H, Rhyman L, Ramasami P. R. Soc. Open Sci. 2019; 6: 181831
• 7b Jeong K, Choi J. R. Soc. Open Sci. 2019; 6: 190414
• 7c Imrit YA, Bhakhoa H, Sergeieva T, Danés S, Savoo N, Elzagheid MI, Rhyman L, Andrada DM, Ramasami P. RSC Adv. 2020; 10: 27884
• 7d Harvey SP, McMahon LR, Berg FJ. Heliyon 2020; 6: e03153
• 7e Lee JY, Lim KC, Kim HS. Molecules 2021; 26: 1059
• 7f Otsuka M, Miyaguchi H. Chem. Phys. Lett. 2021; 785: 139116
• 7g de Koning MC, Vieira Soares C, van Grol M, Bross RPT, Maurin G. ACS Appl. Mater. Interfaces 2022; 14: 9222
• 8a Zengerle M, Brandhuber F, Schneider C, Worek F, Reiter G, Kubik S. Beilstein J. Org. Chem. 2011; 7: 1543
• 8b Brandhuber F, Zengerle M, Porwol L, Tenberken O, Thiermann H, Worek F, Kubik S, Reiter G. Toxicology 2012; 302: 163
• 8c Brandhuber F, Zengerle M, Porwol L, Bierwisch A, Koller M, Reiter G, Worek F, Kubik S. Chem. Commun. 2013; 49: 3425
• 8d Bierwisch A, Zengerle M, Thiermann H, Kubik S, Worek F. Toxicol. Lett. 2014; 224: 209
• 8e Worek F, Seeger T, Zengerle M, Kubik S, Thiermann H, Wille T. Toxicol. Lett. 2014; 226: 222
• 8f Schneider C, Bierwisch A, Koller M, Worek F, Kubik S. Angew. Chem. Int. Ed. 2016; 55: 12668
• 8g Bierwisch A, Koller M, Worek F, Kubik S. Eur. J. Org. Chem. 2016; 2016: 5831
• 8h Andrae B, Bauer D, Gaß P, Koller M, Worek F, Kubik S. Org. Biomol. Chem. 2020; 18: 5218
• 9a Sambrook MR, Notman S. Chem. Soc. Rev. 2013; 42: 9251
• 9b Finnegan TJ, Gunawardana VWL, Badjić JD. Chem. Eur. J. 2021; 27: 13280
• 10 Letort S, Balieu S, Erb W, Gouhier G, Estour F. Beilstein J. Org. Chem. 2016; 12: 204
• 11 Ede JA, Cragg PJ, Sambrook MR. Molecules 2018; 23: 207
• 12 Ajami D, Rebek Jr J. Org. Biomol. Chem. 2013; 11: 3936
• 13a Ruan Y, Dalkiliç E, Peterson PW, Pandit A, Dastan A, Brown JD, Polen SM, Hadad CM, Badjić JD. Chem. Eur. J. 2014; 20: 4251
• 13b Border SE, Pavlović RZ, Zhiquan L, Badjić JD. J. Am. Chem. Soc. 2017; 139: 18496
• 14 Liu W-E, Chen Z, Yang L-P, Au-Yeung H-Y, Jiang W. Chem. Commun. 2019; 55: 9797
• 15a Bolliger JL, Belenguer AM, Nitschke JR. Angew. Chem. Int. Ed. 2013; 52: 7958
• 15b Taylor CGP, Piper JR, Ward MD. Chem. Commun. 2016; 52: 6225
• 16a Sambrook MR, Hiscock JR, Cook A, Green CA, Holden I, Vincent JC, Gale PA. Chem. Commun. 2012; 48: 5605
• 16b Barba-Bon A, Costero AM, Parra M, Gil S, Martínez-Máñez R, Sancenón F, Gale PA, Hiscock JR. Chem. Eur. J. 2013; 19: 1586
• 16c Hiscock JR, Sambrook MR, Cranwell PB, Watts P, Vincent JC, Xuereb DJ, Wells NJ, Raja R, Gale PA. Chem. Commun. 2014; 50: 6217
• 16d Hiscock JR, Sambrook MR, Wells NJ, Gale PA. Chem. Sci. 2015; 6: 5680
• 17a van Hooidonk C, Groos CC. Recl. Trav. Chim. Pays-Bas 1970; 89: 845
• 17b van Hooidonk C, Breebaart-Hansen JCAE. Recl. Trav. Chim. Pays-Bas 1970; 89: 289
• 17c van Hooidonk C. Recl. Trav. Chim. Pays-Bas 1972; 91: 1103
• 17d Masurier N, Estour F, Froment M-T, Lefèvre B, Debouzy J-C, Brasme B, Masson P, Lafont O. Eur. J. Med. Chem. 2005; 40: 615
• 17e Wille T, Tenberken O, Reiter G, Müller S, Le Provost R, Lafont O, Estour F, Thiermann H, Worek F. Toxicology 2009; 265: 96
• 17f Müller S, Koller M, Le Provost R, Lafont O, Estour F, Wille T, Thiermann H, Worek F, Reiter G. Toxicol. Lett. 2011; 200: 53
• 17g Le Provost R, Wille T, Louise L, Masurier N, Müller S, Reiter G, Renard P-Y, Lafont O, Worek F, Estour F. Org. Biomol. Chem. 2011; 9: 3026
• 17h Letort S, Mathiron D, Grel T, Albaret C, Daulon S, Djedaïni-Pilard F, Gouhier G, Estour F. Chem. Commun. 2015; 51: 2601
• 18 Ganapati S, Isaacs L. Isr. J. Chem. 2018; 58: 250
• 19 Yang Y-C. Acc. Chem. Res. 1999; 32: 109
• 20 The synthesis of 1 was performed as described elsewhere.^8h M.p. = 114 °C; ¹H NMR (400 MHz, CDCl₃): δ = 11.69 (s, br, 1 H, NH), 3.70 – 3.59 (m, 2 H, iPrCH), 3.51 – 3.46 (m, 2 H, CH₂S), 3.08–3.03 (m, 2 H, CH₂N), 2.36 (s, 3 H, AcCH₃), 1.57 (d, J = 6.7 Hz, 6 H, iPrCH₃), 1.47 (d, J = 6.6 Hz, 6 H, iPrCH₃) ppm; ¹³C NMR (101 MHz, CDCl₃): δ = 195.7, 54.8, 46.6, 30.6, 25.9, 18.7, 17.2 ppm; MS (ESI/TOF⁺) m/z (%): 204.1 (100) [M–Cl]⁺, 401.3 (14) [M₂–CH₃CO + H–Cl]⁺, 443.3 (59) [M₂–Cl]⁺; Anal. Calcd for C₁₀H₂₂ClNOS: C, 50.09; H, 9.25; N, 5.84; S, 13.37. Found C, 49.90; H, 9.25; N, 5.82; S, 13.32.
• 21 N,N-Diethylacetimidamide was prepared as described.²² This compound (0.50 g, 4.38 mmol) was dissolved in dichloromethane (10 mL). Triethylamine (8.76 mmol, 1.21 mL) was added dropwise at 0 °C. After 15 min, benzoyl chloride (4.82 mmol, 0.56 mL) was added, and the resulting mixture was stirred at room temperature for 48 h. The solution was washed with saturated aqueous NaHCO₃ (5 mL). The solvent was evaporated, and the residue was dissolved in water (20 mL). The solution was extracted with dichloromethane (5 × 50 mL), the combined organic layers were dried over MgSO₄, and the solvent was removed. The residue was purified by column chromatography [SiO₂, n-hexane/ethyl acetate, 1: 1 (v/v)]. Yield: 0.73 g (3.33 mmol, 76%), yellow oil; ¹H NMR (400 MHz, DMSO-d ₆): δ 8.00 – 7.98 (m, 2 H, PhH^2,6), 7.51 – 7.46 (m, 1 H, PhH⁴), 7.43 – 7.39 (m, 2 H, PhH^3,5), 3.58 (q, ³ J = 7.0 Hz, 2 H, EtCH₂), 3.44 (q, ³ J = 7.1 Hz, 2 H, EtCH₂), 2.26 (s, 3 H, CH₃), 1.18 (t, ³ J = 7.0 Hz, 6 H, EtCH₃) ppm; ¹³C NMR (101 MHz, DMSO-d ₆): δ 174.0, 164.4, 137.9, 131.1, 128.8, 127.9, 42.9, 42.5, 16.7, 13.7, 12.5 ppm; MS (ESI/TOF⁺) m/z (%): 219.14 (100) [M + H]⁺; Anal. Calcd for C₁₃H₁₈ N_2O: C, 71.53; H, 8.31; N, 12.83; found C, 71.80; H, 8.52; N, 12.64.
• 22 Jalani HB, Sudarsanam V, Vasu KK. Synthesis 2012; 44: 3378
• 23 Chua S-O, Cook MJ, Katritzky AR. J. Chem. Soc., Perkin Trans. 2 1974; 546
• 24 Häfelinger G. General and Theoretical Aspects of Amidines and Imidic Acid Derivatives. Patai S. The Chemistry of Amidines and Imidates. London: John Wiley & Sons; 1975: 1-84
• 25 Rekharsky MV, Inoue Y. Chem. Rev. 1998; 98: 1875
• 26 Rubinson KA. Anal. Methods 2017; 9: 2744
• 27 Salvatierra D, Jaime C, Virgili A, Sánchez-Ferrando F. J. Org. Chem. 1996; 61: 9578
• 28 Kubik S. ChemistryOpen 2022; 11: e202200028
• 29a Biedermann F, Nau WM, Schneider H-J. Angew. Chem. Int. Ed. 2014; 53: 11158
• 29b Grimm LM, Spicher S, Tkachenko B, Schreiner PR, Grimme S, Biedermann F. Chem. Eur. J. 2022; 28: e202200529