- Email: [email protected]
Detoxification of Toxic Gases of VX and Sarin
CHAPTER SIXTEEN
Detoxification of Toxic Gases of VX and Sarin Contents 16.1 Introduction to VX 16.2 Introduction to Sarin 16.3 How VX Works as Toxic Materials in the Human Body 16.4 Detoxification of VX References
197 198 199 200 202
16.1 INTRODUCTION TO VX In 2017, Jong-nam Kim was said to have been assassinated using O-ethyl S-[2-(diisopropylamino)ethyl] methylphosphonothioate (VX) in front of security cameras at the airport. He was half-brother to Jong-un Kim, the Chairman of the Workers’ Party of Korea (WPK) and supreme leader of the Democratic People’s Republic of Korea (DPRK). This episode may remind Japanese people of when the Japanese cult Aum Shinrikyo killed one person and injured two more using VX in 1994–1995; they were the first victims of VX. V-type nerve agents (structural formulas of VX-families are shown in Fig. 16.1.1) are toxic organophosphonates (OPs), and used as chemical weapons. The materials that have phosphono-thioester bonds with the amino group in the side chain are harmful, being VX. VX is a tasteless and odorless liquid with an amber-like color. It destroys the nervous system of the body. As little as ten milligrams is fatal for a human through skin contact. Therefore, detoxifying VX in vitro (out of the body) as well as in vivo (in the body) is very important. In 2018, Sergei Skripal, who was a retired Russian military intelligence officer, and his daughter, Yuliya were poisoned on March 4 in Salisbury, England. U.K. Prime Minister Theresa May said, “It is now clear that Biochemistry for Materials Science https://doi.org/10.1016/B978-0-12-817054-0.00016-3
© 2019 Elsevier Inc. All rights reserved.
197
198
Biochemistry for Materials Science
(A)
(B)
(C)
(D)
(E)
(F)
(G)
(H)
(I)
Fig. 16.1.1 Structural formulas of V-type nerve agents. (A) VX, (B) VM, (C) CVX, (D) n-propyl VX, (E) VR, (F) VE. A family of “Novichok” poisons. (G) A-230. (H) A-232. (I) A-234.
Mr. Skripal and his daughter were poisoned with a military-grade nerve agent of a type developed by Russia.” VR-family nerve agents such as A-230, A-232, and A-234, which are called “Novichok” poisons (see Fig. 16.1.1G–I) could have been used (Peplow, 2018).
16.2 INTRODUCTION TO SARIN Sarin is a colorless, odorless, and venomous liquid, which is used as a chemical weapon, because it is one of the strongest nerve agents. Sarin is an organophosphorus compound expressed as [(CH3)2CHO]CH3P(O)F, of which the IUPAC name is Propan-2-yl-methylphosphonofluoridate (see Fig. 16.2.1). Sarin has history regarding the politics of America. In 2003, the Iraq War started with the invasion of the US-led troops ordered by their President,
Detoxification of Toxic Gases of VX and Sarin
199
Fig. 16.2.1 Sarin.
George Bush. The reason for the invasion was that Iraq was believed to possess chemical weapons of mass destruction including sarin, and to use them in the military. In April 2017, the U.S. President, Donald Trump, ordered the strikes by cruise missiles on Syria due to believed suspicious use of sarin. In 1995, the Japanese cult Aum Shinrikyo caused the Tokyo subway sarin attack, in which 12 persons were killed, 50 were severely injured, and about 5000 more were injured.
16.3 HOW VX WORKS AS TOXIC MATERIALS IN THE HUMAN BODY How VX works is schematically shown in Fig. 16.3.1. This figure shows the nerve terminal when VX does not exist. The nerve signal is transmitted from the terminal of the presynaptic cell to the target cell. There are synaptic vesicules at the terminal of the cell, in which acetylcholine (ACh) is accumulated (shown as dots in Fig. 16.3.1A-1). When the nerve signal comes, the synaptic vesicules are opened, and ACh is released. ACh attaches at the ion channel of the target cell, and opens the ion channels. This allows Na+ ions to enter the target cell (Fig. 16.3.1A-2). This changes the membrane potential of the target cell, resulting in transmitting signals from the terminal cell to the target cell. After a few tens of milliseconds, acetylcholinesterase (AChE), which exists ubiquitously at the synapse, attaches to the ACh (Fig. 16.3.1A-3). Finally, both ACh and AChE are released from the ion channel, resulting in the ion channel closing (Fig. 16.3.1A-4). The used ACh is scavenged and returned into the terminal of the cell, and ACh and AChE are prepared to be reused. When VX (diamonds) exists, VX reacts with acetylcholinesterase (AChE) (Fig. 16.3.1B-30 ). In this form, AChE cannot react with ACh, which is attached to the ion channel. As result, the ion channel is kept open, and the signal cannot be transmitted properly at the synapse. Ultimately, this causes death.
200
Biochemistry for Materials Science
(3) (2)
(1) Terminal of cell
(4)
Na+
Na+
Target cell
Without VX Acetylcholine (ACh)
VX
Acetylcholinesterase (AChE)
(A)
(3¢) (4)
(B)
With VX
Fig. 16.3.1 Nerve terminal and function of acetylcholine (ACh). (A) Without VX and (B) with VX.
Sarin works similarly to VX, as it also reacts with AChE, so that ACh is not decomposed. Thus, the ion channel is kept open and the signal cannot be transmitted properly at the synapse any more.
16.4 DETOXIFICATION OF VX Schneider et al. (2016) succeeded in detoxifying VX using sulfonatocalix[4]arenes which are strong cation binders in water. These calixarenes were decorated with a substituent containing a hydroxamic acid, which is known to detoxify organophosphonates (OPs) (e.g. Perret et al., 2006; Guo and Liu, 2014; Hof, 2016). The compounds shown in Fig. 16.4.1A (X ¼ N) and Fig. 16.4.1B (X ¼ CH) have highly promising
201
Detoxification of Toxic Gases of VX and Sarin
Fig. 16.4.1 Sulfonatocalix[4]arenes. (A) X ¼ N. (B) X ¼ CH.
properties under 37°C and pH 7.40 (Schneider et al., 2016). Their study showed that both compounds effectively detoxified VX (Fig. 16.1.1A) as well as V-type nerve agents (Fig. 16.1.1B–F). The compound of Fig. 16.4.1A detoxified 78% of VX within the first hour under 37°C and pH 7.40 at the same amount, and 94% under two equivalent of VX. The compound of Fig. 16.4.1B detoxified similarly to that of Fig. 16.4.1A. However, the residual VX reached plateaus of 5% and 20% after 24 h with one equivalent of the compounds of Fig. 16.4.1A and B, respectively. As a result, the calixarenes mediate the selective cleavage of the PdS bond of VX, and efficiently suppress the formation of the toxic metabolite (Schneider et al., 2016). Sarin is vulnerable to heat and water (see Fig. 16.4.2). When sarin (1) is thrown into water, it is easily decomposed into hydrogen fluoride (HF) and isopropyl methylphosphonate (2) by hydrolysis. Isopropyl methylphosphonate (2) further becomes (3) methylphosphonic acid and (4) isopropyl alcohol.
(A)
1
Fig. 16.4.2 Hydrolysis of sarin.
(B)
2
(C)
3
4
202
Biochemistry for Materials Science
REFERENCES Guo, D.-S., Liu, Y., 2014. Supramolecular chemistry of p-sulfonatocalix[n]arenes and its biological applications. Acc. Chem. Res. 47, 1925–1934. Hof, F., 2016. Host-guest chemistry that directly targets lysine methylation: synthetic host molecules as alternatives to bio-reagents. Chem. Commun. 52, 10093–10108. Peplow, M., 2018. Nerve agent attack on spy used ‘Novichok’ poison. C&EN 96 (12), 3. Perret, F., Lazar, A.N., Coleman, A.W., 2006. Biochemistry of the para-sulfonato-calix[n] arenes. Chem. Commun. 0, 2425–2438. Schneider, C., Bierwisch, A., Koller, M., Worek, F., Kubik, S., 2016. Detoxification of VX and other V-type nerve agents in water at 37°C and pH 7.4 by substituted sulfonatocalix [4]arenes. Angew. Chem. Int. Ed. 55, 12668–12672.
Detoxification of Toxic Gases of VX and Sarin Contents 16.1 Introduction to VX 16.2 Introduction to Sarin 16.3 How VX Works as Toxic Materials in the Human Body 16.4 Detoxification of VX References
197 198 199 200 202
16.1 INTRODUCTION TO VX In 2017, Jong-nam Kim was said to have been assassinated using O-ethyl S-[2-(diisopropylamino)ethyl] methylphosphonothioate (VX) in front of security cameras at the airport. He was half-brother to Jong-un Kim, the Chairman of the Workers’ Party of Korea (WPK) and supreme leader of the Democratic People’s Republic of Korea (DPRK). This episode may remind Japanese people of when the Japanese cult Aum Shinrikyo killed one person and injured two more using VX in 1994–1995; they were the first victims of VX. V-type nerve agents (structural formulas of VX-families are shown in Fig. 16.1.1) are toxic organophosphonates (OPs), and used as chemical weapons. The materials that have phosphono-thioester bonds with the amino group in the side chain are harmful, being VX. VX is a tasteless and odorless liquid with an amber-like color. It destroys the nervous system of the body. As little as ten milligrams is fatal for a human through skin contact. Therefore, detoxifying VX in vitro (out of the body) as well as in vivo (in the body) is very important. In 2018, Sergei Skripal, who was a retired Russian military intelligence officer, and his daughter, Yuliya were poisoned on March 4 in Salisbury, England. U.K. Prime Minister Theresa May said, “It is now clear that Biochemistry for Materials Science https://doi.org/10.1016/B978-0-12-817054-0.00016-3
© 2019 Elsevier Inc. All rights reserved.
197
198
Biochemistry for Materials Science
(A)
(B)
(C)
(D)
(E)
(F)
(G)
(H)
(I)
Fig. 16.1.1 Structural formulas of V-type nerve agents. (A) VX, (B) VM, (C) CVX, (D) n-propyl VX, (E) VR, (F) VE. A family of “Novichok” poisons. (G) A-230. (H) A-232. (I) A-234.
Mr. Skripal and his daughter were poisoned with a military-grade nerve agent of a type developed by Russia.” VR-family nerve agents such as A-230, A-232, and A-234, which are called “Novichok” poisons (see Fig. 16.1.1G–I) could have been used (Peplow, 2018).
16.2 INTRODUCTION TO SARIN Sarin is a colorless, odorless, and venomous liquid, which is used as a chemical weapon, because it is one of the strongest nerve agents. Sarin is an organophosphorus compound expressed as [(CH3)2CHO]CH3P(O)F, of which the IUPAC name is Propan-2-yl-methylphosphonofluoridate (see Fig. 16.2.1). Sarin has history regarding the politics of America. In 2003, the Iraq War started with the invasion of the US-led troops ordered by their President,
Detoxification of Toxic Gases of VX and Sarin
199
Fig. 16.2.1 Sarin.
George Bush. The reason for the invasion was that Iraq was believed to possess chemical weapons of mass destruction including sarin, and to use them in the military. In April 2017, the U.S. President, Donald Trump, ordered the strikes by cruise missiles on Syria due to believed suspicious use of sarin. In 1995, the Japanese cult Aum Shinrikyo caused the Tokyo subway sarin attack, in which 12 persons were killed, 50 were severely injured, and about 5000 more were injured.
16.3 HOW VX WORKS AS TOXIC MATERIALS IN THE HUMAN BODY How VX works is schematically shown in Fig. 16.3.1. This figure shows the nerve terminal when VX does not exist. The nerve signal is transmitted from the terminal of the presynaptic cell to the target cell. There are synaptic vesicules at the terminal of the cell, in which acetylcholine (ACh) is accumulated (shown as dots in Fig. 16.3.1A-1). When the nerve signal comes, the synaptic vesicules are opened, and ACh is released. ACh attaches at the ion channel of the target cell, and opens the ion channels. This allows Na+ ions to enter the target cell (Fig. 16.3.1A-2). This changes the membrane potential of the target cell, resulting in transmitting signals from the terminal cell to the target cell. After a few tens of milliseconds, acetylcholinesterase (AChE), which exists ubiquitously at the synapse, attaches to the ACh (Fig. 16.3.1A-3). Finally, both ACh and AChE are released from the ion channel, resulting in the ion channel closing (Fig. 16.3.1A-4). The used ACh is scavenged and returned into the terminal of the cell, and ACh and AChE are prepared to be reused. When VX (diamonds) exists, VX reacts with acetylcholinesterase (AChE) (Fig. 16.3.1B-30 ). In this form, AChE cannot react with ACh, which is attached to the ion channel. As result, the ion channel is kept open, and the signal cannot be transmitted properly at the synapse. Ultimately, this causes death.
200
Biochemistry for Materials Science
(3) (2)
(1) Terminal of cell
(4)
Na+
Na+
Target cell
Without VX Acetylcholine (ACh)
VX
Acetylcholinesterase (AChE)
(A)
(3¢) (4)
(B)
With VX
Fig. 16.3.1 Nerve terminal and function of acetylcholine (ACh). (A) Without VX and (B) with VX.
Sarin works similarly to VX, as it also reacts with AChE, so that ACh is not decomposed. Thus, the ion channel is kept open and the signal cannot be transmitted properly at the synapse any more.
16.4 DETOXIFICATION OF VX Schneider et al. (2016) succeeded in detoxifying VX using sulfonatocalix[4]arenes which are strong cation binders in water. These calixarenes were decorated with a substituent containing a hydroxamic acid, which is known to detoxify organophosphonates (OPs) (e.g. Perret et al., 2006; Guo and Liu, 2014; Hof, 2016). The compounds shown in Fig. 16.4.1A (X ¼ N) and Fig. 16.4.1B (X ¼ CH) have highly promising
201
Detoxification of Toxic Gases of VX and Sarin
Fig. 16.4.1 Sulfonatocalix[4]arenes. (A) X ¼ N. (B) X ¼ CH.
properties under 37°C and pH 7.40 (Schneider et al., 2016). Their study showed that both compounds effectively detoxified VX (Fig. 16.1.1A) as well as V-type nerve agents (Fig. 16.1.1B–F). The compound of Fig. 16.4.1A detoxified 78% of VX within the first hour under 37°C and pH 7.40 at the same amount, and 94% under two equivalent of VX. The compound of Fig. 16.4.1B detoxified similarly to that of Fig. 16.4.1A. However, the residual VX reached plateaus of 5% and 20% after 24 h with one equivalent of the compounds of Fig. 16.4.1A and B, respectively. As a result, the calixarenes mediate the selective cleavage of the PdS bond of VX, and efficiently suppress the formation of the toxic metabolite (Schneider et al., 2016). Sarin is vulnerable to heat and water (see Fig. 16.4.2). When sarin (1) is thrown into water, it is easily decomposed into hydrogen fluoride (HF) and isopropyl methylphosphonate (2) by hydrolysis. Isopropyl methylphosphonate (2) further becomes (3) methylphosphonic acid and (4) isopropyl alcohol.
(A)
1
Fig. 16.4.2 Hydrolysis of sarin.
(B)
2
(C)
3
4
202
Biochemistry for Materials Science
REFERENCES Guo, D.-S., Liu, Y., 2014. Supramolecular chemistry of p-sulfonatocalix[n]arenes and its biological applications. Acc. Chem. Res. 47, 1925–1934. Hof, F., 2016. Host-guest chemistry that directly targets lysine methylation: synthetic host molecules as alternatives to bio-reagents. Chem. Commun. 52, 10093–10108. Peplow, M., 2018. Nerve agent attack on spy used ‘Novichok’ poison. C&EN 96 (12), 3. Perret, F., Lazar, A.N., Coleman, A.W., 2006. Biochemistry of the para-sulfonato-calix[n] arenes. Chem. Commun. 0, 2425–2438. Schneider, C., Bierwisch, A., Koller, M., Worek, F., Kubik, S., 2016. Detoxification of VX and other V-type nerve agents in water at 37°C and pH 7.4 by substituted sulfonatocalix [4]arenes. Angew. Chem. Int. Ed. 55, 12668–12672.