Dichloroacetic acid

Dichloroacetic acid
Names
IUPAC name
Dichloroacetic acid
Other names
Dichloroethanoic acid, bichloroacetic acid, DCA, BCA, dichloracetic acid, bichloracetic acid
Identifiers
79-43-6 YesY
ChEBI CHEBI:36386 YesY
ChEMBL ChEMBL13960 YesY
ChemSpider 10771217 YesY
DrugBank DB08809 YesY
Jmol 3D model Interactive image
KEGG C11149 YesY
MeSH Dichloroacetate
PubChem 6597
RTECS number AG6125000
UNII 9LSH52S3LQ YesY
Properties
C2H2Cl2O2
Molar mass 128.94 g·mol−1
Appearance Colorless liquid
Density 1.5634 g/cm3 (20 °C)
Melting point 9 to 11 °C (48 to 52 °F; 282 to 284 K)
Boiling point 194 °C (381 °F; 467 K)
miscible
Solubility miscible with ethanol, diethyl ether[1]
Acidity (pKa) 1.35[1]
Thermochemistry
−496.3 kJ·mol−1[1]
Hazards
Safety data sheet MSDS (jtbaker)
R-phrases R35 R50
S-phrases (S1/2) S26 S45 S61
NFPA 704
Flammability code 1: Must be pre-heated before ignition can occur. Flash point over 93 °C (200 °F). E.g., canola oil Health code 3: Short exposure could cause serious temporary or residual injury. E.g., chlorine gas Reactivity code 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g., liquid nitrogen Special hazards (white): no codeNFPA 704 four-colored diamond
1
3
0
Related compounds
Chloroacetic acid
Trichloroacetic acid
Related compounds
 Acetic acid
Difluoroacetic acid
Dibromoacetic acid
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references

Dichloroacetic acid (DCA), sometimes called bichloroacetic acid (BCA), is the chemical compound with formula CHCl
2COOH. It is an acid, an analogue of acetic acid, in which 2 of the 3 hydrogen atoms of the methyl group have been replaced by chlorine atoms. Like the other chloroacetic acids, it has various practical applications. The salts and esters of dichloroacetic acid are called dichloroacetates. Salts of DCA have been studied as potential drugs because they inhibit the enzyme pyruvate dehydrogenase kinase.[2]

Although preliminary studies have shown DCA can slow the growth of certain tumors in animal studies and in vitro studies, there is currently insufficient evidence to support the use of DCA for cancer treatment.[3]

Chemistry and occurrence

The chemistry of dichloroacetic acid is typical for halogenated organic acids. It is a member of the chloroacetic acids family. The dichloroacetate ion is produced when the acid is mixed with water. As an acid with a pKa of 1.35,[1] pure dichloroacetic acid is classed as a strong organic acid; it is very corrosive and extremely destructive to tissues of the mucous membranes and upper respiratory tract via inhalation.[4]

DCA has been shown to occur in nature in at least one seaweed, Asparagopsis taxiformis.[5] It is a trace product of the chlorination of drinking water and is produced by the metabolism of various chlorine-containing drugs or chemicals.[6] DCA is typically prepared by the reduction of trichloroacetic acid (TCA). DCA is prepared from chloral hydrate also by the reaction with calcium carbonate and sodium cyanide in water followed by acidifying with hydrochloric acid.

As a laboratory reagent, both DCA and TCA are used as precipitants to prompt macromolecules such as proteins to precipitate out of solution.

Therapeutic uses

Topical chemoablation

Both DCA and TCA are used for cosmetic treatments (such as chemical peels and tattoo removal) and as topical medication for the chemoablation of warts, including genital warts. It can kill normal cells as well.

Lactic acidosis

A randomized controlled trial in children with congenital lactic acidosis found that while DCA was well tolerated, it was ineffective in improving clinical outcomes.[7] A separate trial of DCA in children with MELAS (a syndrome of inadequate mitochondrial function, leading to lactic acidosis) was halted early, as all 15 of the children receiving DCA experienced significant nerve toxicity without any evidence of benefit from the medication.[8] A randomized controlled trial of DCA in adults with lactic acidosis found that while DCA lowered blood lactate levels, it had no clinical benefit and did not improve hemodynamics or survival.[9]

Thus, while early case reports and pre-clinical data suggested that DCA might be effective for lactic acidosis, subsequent controlled trials have found no clinical benefit of DCA in this setting. In addition, clinical trial subjects were incapable of continuing on DCA as a study medication owing to progressive toxicities.

Cancer

Although preliminary studies have shown DCA can slow the growth of certain tumors in animal studies and in vitro studies "Available evidence does not support the use of DCA for cancer treatment at this time."[3] Physicians warned of potential problems if people attempt to try DCA outside a controlled clinical trial. "If it starts going badly, who is following you before it gets out of control? By the time you realize your liver is failing, you're in big trouble", said Laura Shanner, Associate Professor of Health Ethics at the University of Alberta.[10] Notably, at least one fraudster, Hazim Gaber, has been convicted and sentenced to 33 months in prison for selling fake DCA to cancer sufferers.[11]

The only monitored in vivo dosage of five human patients suffering from glioblastoma with DCA was not designed to test its efficacy vs. their cancer, but rather to ascertain whether it could be given at a specific dosage safely without causing e.g. neuropathy. All 5 patients were receiving other treatments during the study.[12][13] Observations in vitro and of tumours extracted from those 5 patients suggest that DCA might act against cancer cells by depolarising abnormal mitochondria found in glioblastoma cancer cells – allowing the mitochondria to induce apoptosis (cell death) of the malignant cells.[12] However, in vitro work with DCA on neuroblastomas (which have fewer recognised mitochondrial abnormalities) also showed some activity against very malignant, undifferentiated cells.[14] A recent case report discusses and reviews the potential application of DCA in central nervous system malignancies.[15]

Neuropathy

Neuropathy has been a problem in some clinical trials with DCA causing them to be effectively halted,[8] but a review found that it has not occurred in other trials.[16] The mechanism of DCA induced neuropathy is not well understood.[17] On the one hand in vitro work with nerves has suggested a mechanism for the neuropathic effect of DCA; with DCA showing a dose and exposure dependent demyelination of nerves (stripping of the nerve 'sheath'), which demyelination was partially reversible over time, following washout of DCA.[18] On the other hand, a review in BJC [16] states "This neurotoxicity resembled the pattern of length-dependent, axonal, sensorimotor polyneuropathy without demyelination." with regard to the 2006 study by Kaufman et al.[8]

Heart failure

DCA has been investigated as a treatment for post-ischemic recovery.[19] There is also evidence that DCA improves metabolism by NADH production stimulation, but may lead to a depletion of NADH in normoxia.[20]

References

  1. 1 2 3 4 Haynes, William M., ed. (2011). CRC Handbook of Chemistry and Physics (92nd ed.). Boca Raton, FL: CRC Press. ISBN 1439855110.
  2. ↑ Kato, Masato; Li, Jun; Chuang, Jacinta L.; Chuang, David T. (2007). "Distinct Structural Mechanisms for Inhibition of Pyruvate Dehydrogenase Kinase Isoforms by AZD7545, Dichloroacetate, and Radicicol". Structure 15 (8): 992–1004. doi:10.1016/j.str.2007.07.001. PMC 2871385. PMID 17683942.
  3. 1 2 "Dichloracetate (DCA)". American Cancer Society. Retrieved 1 December 2012.
  4. ↑ "Dichloroacetic Acid". Hazard.com. 1998-04-21. Retrieved 2015-04-17.
  5. ↑ Archived April 16, 2015, at the Wayback Machine.
  6. ↑ Stacpoole, Peter W.; Henderson, George N.; Yan, Zimeng; James, Margaret O. (1998). "Clinical Pharmacology and Toxicology of Dichloroacetate". Environmental Health Perspectives 106: 989–94. doi:10.2307/3434142. JSTOR 3434142. PMC 1533324. PMID 9703483.
  7. ↑ Stacpoole, P. W.; Kerr, D. S.; Barnes, C; Bunch, S. T.; Carney, P. R.; Fennell, E. M.; Felitsyn, N. M.; Gilmore, R. L.; Greer, M; Henderson, G. N.; Hutson, A. D.; Neiberger, R. E.; O'Brien, R. G.; Perkins, L. A.; Quisling, R. G.; Shroads, A. L.; Shuster, J. J.; Silverstein, J. H.; Theriaque, D. W.; Valenstein, E (2006). "Controlled Clinical Trial of Dichloroacetate for Treatment of Congenital Lactic Acidosis in Children". Pediatrics 117 (5): 1519–31. doi:10.1542/peds.2005-1226. PMID 16651305.
  8. 1 2 3 Kaufmann, P.; Engelstad, K.; Wei, Y.; Jhung, S.; Sano, M. C.; Shungu, D. C.; Millar, W. S.; Hong, X.; Gooch, C. L.; Mao, X.; Pascual, J. M.; Hirano, M.; Stacpoole, P. W.; Dimauro, S.; De Vivo, D. C. (2006). "Dichloroacetate causes toxic neuropathy in MELAS: A randomized, controlled clinical trial". Neurology 66 (3): 324–30. doi:10.1212/01.wnl.0000196641.05913.27. PMID 16476929.
  9. ↑ Stacpoole, Peter W.; Wright, Elizabeth C.; Baumgartner, Thomas G.; Bersin, Robert M.; Buchalter, Scott; Curry, Stephen H.; Duncan, Charles A.; Harman, Eloise M.; Henderson, George N.; Jenkinson, Steven; Lachin, John M.; Lorenz, Anthea; Schneider, Stephen H.; Siegel, John H.; Summer, Warren R.; Thompson, Douglas; Wolfe, Christopher L.; Zorovich, Barbara (1992). "A Controlled Clinical Trial of Dichloroacetate for Treatment of Lactic Acidosis in Adults". New England Journal of Medicine 327 (22): 1564–9. doi:10.1056/NEJM199211263272204. PMID 1435883.
  10. ↑ Andrea Sands (March 18, 2007). "Experts caution against patients compiling own data on unapproved cancer drug". Edmonton Journal.
  11. ↑
  12. 1 2 Michelakis, E. D.; Sutendra, G.; Dromparis, P.; Webster, L.; Haromy, A.; Niven, E.; Maguire, C.; Gammer, T. L.; MacKey, J. R.; Fulton, D.; Abdulkarim, B.; McMurtry, M. S.; Petruk, K. C. (2010). "Metabolic Modulation of Glioblastoma with Dichloroacetate". Science Translational Medicine 2 (31): 31ra34. doi:10.1126/scitranslmed.3000677. PMID 20463368.
  13. ↑ Archived February 18, 2011, at the Wayback Machine.
  14. ↑ Vella, Serena; Conti, Matteo; Tasso, Roberta; Cancedda, Ranieri; Pagano, Aldo (2012). "Dichloroacetate inhibits neuroblastoma growth by specifically acting against malignant undifferentiated cells". International Journal of Cancer 130 (7): 1484–93. doi:10.1002/ijc.26173. PMID 21557214.
  15. ↑ Lemmo, W; Tan, G (2016). "Prolonged Survival After Dichloroacetate Treatment of Non-Small-Cell Lung Carcinoma-Related Leptomeningeal Carcinomatosis". Journal of Medical Cases 7 (4): 136–142. doi:10.14740/jmc2456w.
  16. 1 2 Michelakis, E D; Webster, L; MacKey, J R (2008). "Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer". British Journal of Cancer 99 (7): 989–94. doi:10.1038/sj.bjc.6604554. PMC 2567082. PMID 18766181.
  17. ↑ Archived April 6, 2015, at the Wayback Machine.
  18. ↑ Felitsyn, Natalia; Stacpoole, Peter W.; Notterpek, Lucia (2007). "Dichloroacetate causes reversible demyelination in vitro: Potential mechanism for its neuropathic effect". Journal of Neurochemistry 100 (2): 429–36. doi:10.1111/j.1471-4159.2006.04248.x. PMID 17241159.
  19. ↑ "Dichloroacetate stimulation of glucose oxidation improves recovery of ischemic rat hearts.". Am J Physiol 259: H1079–85. Oct 1990. PMID 2221115.
  20. ↑ Jaimes, R 3rd (Jul 2015). "Functional response of the isolated, perfused normoxic heart to pyruvate dehydrogenase activation by dichloroacetate and pyruvate.". Pflugers Arch. doi:10.1007/s00424-015-1717-1. PMID 26142699.

External links

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