The Ultimate Antioxidant Alpha Lipoic Acid The Ultimate Antioxidant

Identity & Structure R-Alpha S-Alpha Dihydro- Lipoic Acid Lipoic Acid “Thioctic acid” “Lipolate” (For you IUPAC nerdies): (R/S)-5-(1,2-dithiolan-3-yl)pentanoic acid Alpha Lipoic Acid (ALA), also known as lipoic acid, thioctic acid, lipolate or (R/S)-5-(1,2-dithiolan-3-yl)pentanoic acid, is an antioxidant species made up of a five-carbon carboxylic acid bound to a five-carbon cyclic disulfide. It exists as two enantiomers, R- and S- forms, as well as a reduced form called dihydrolipoic acid (DHLA) in which the disulfide bond is broken into two thiols (Scheme 1). R-Alpha S-Alpha Dihydro- Lipoic Acid Lipoic Acid Lipoic Acid Alpha Lipoic Acid. University of Maryland Medical Center. https://umm.edu/health/ medical/altmed/supplement/alphalipoic-acid. Maldonado-Rojas, W.; Olivero-Verbel, J.; Ortega-Zuniga, C.; J. Braz. Chem. Soc. 2011, 22(12), 2250-2259.

Function: Antioxidant “The Ultimate Antioxidant” Both water- and fat- soluble Multiple radical-fighting powers Antioxidant ROS Metal Antioxidant Scavenger Chelate Recycler ALA primarily functions as a powerful antioxidant, and is uniquely both water- and fat-soluble making it effective throughout the body.1 In this capacity, lipoic acid is able to directly scavenge reactive oxygen species which cause oxidative stress on cell membranes and DNA, and it is also capable of transition metal chelation which inhibits metal-catalyzed generation of free radicals within the body. DHLA is a potent reducing agent, and compounds its effectiveness by recycling other antioxidants such as vitamin C, glutathione, and coenzyme Q-10.  Directly Removes Free Radicals Inhibits Free Rad. Generation Re-enables Used Antioxidants Rochette, L.; Ghibu, S.; Richard, C.; Zeller, M.; Cottin, Y.; Vergely, C. Molecular Nutrition and Food Research. 2013, 57(1), 114-125. Lipoic Acid. Linus Pauling Institute. Oregon State University. http://lpi.oregonstate.edu/ infocenter/othernuts/la/index.html#safety (accessed March 2, 2014).

Function: Enzyme Cofactor Biologically active R- enantiomer binds to a specific lysine residue. Example: Stimulation of glucose metabolism via insulin-signaling pathway. Effective treatment for type 2 Diabetes. R-Alpha Lipoic Acid Lysine Residue Another important role of ALA is its action as a cofactor for various enzymatic process. This mechanism requires the biologically active R- enantiomer to bind to a specific lysine residue within individual enzyme complexes (Scheme 2).4 One example of this is the stimulation of glucose uptake by lipoic acid's interaction with the insulin-signaling pathway which is sensitive to redox status.3 This makes ALA an effective treatment for type 2 diabetes, in which impaired insulin uptake may lead to vascular disease and peripheral neuropathy. Lipoic Acid. Linus Pauling Institute. Oregon State University. http://lpi.oregonstate.edu/ infocenter/othernuts/la/index.html#safety. Ziegler D. Treatments in Endocrinology. 2004, 3(3), 173-189.

Recommended Amounts No established dosage recommendations or upper limit. No adverse side effects. Generally, 20-50 mg daily for antioxidant support. Eat all the vitamins! There are currently no established dosage recommendations for alpha-lipoic acid although 20-50 mg daily is considered adequate to gain general antioxidant support.1 For specific treatment, varying higher doses may be prescribed and doses as high as 1800 mg daily show no adverse side effects, yet there are risks of allergic reactions or harmful drug interactions.4 Alpha Lipoic Acid. University of Maryland Medical Center. https://umm.edu/health/ medical/altmed/supplement/alphalipoic-acid.

Characterization: IR Broad 3000 cm-1 peak: Carboxylic Acid Strong 1700 cm-1 peak: Ring Moiety Higher than typical aromatic. SBDS-1H NMR 399.65 MHz. AIST:RIO-DB Spectral Database. http://sdbs.db.aist.go.jp/sdbs/cgi-bin/direct_frame_disp.cgi?sdbsno=52043.

Characterization: H-NMR 10 Peaks Splitting indicates hydrocarbon chain. Group of peaks above 3 consistent with sulfur. SBDS-1H NMR 399.65 MHz. AIST:RIO-DB Spectral Database. http://sdbs.db.aist.go.jp/sdbs/cgi-bin/direct_frame_disp.cgi?sdbsno=52043.

Characterization: C-NMR Shifting Downfield Carbon 1 with carboxylic acid Carbons 2, 3, and 4 adjacent to sulfur atoms SBDS-1H NMR 399.65 MHz. AIST:RIO-DB Spectral Database. http://sdbs.db.aist.go.jp/sdbs/cgi-bin/direct_frame_disp.cgi?sdbsno=52043.

Characterization: UV/Vis Absorbance due to Carboxylic Acid UV range 203 nm, 302 nm Goti, P.; Savsani, J.; Patel, P. International Journal of Pharmacy and Pharmaceutical Sciences, 2012, 4, 519-522.

Synthesis Methods Fairly simple compound, Variety of sources. Easier to synthesize than to extract. Method 1: Octanoic Acid Reflux with Potassium Permanganate Ethanol solvent 8 Hours Subhash P.; Kale, Ramesh R.; Pasupathy, K.; Synlett, 2005, 1129-1132. Kim, Hyeon Jin; Kwon, Seung-Ryong; Kim, Kyuwon; Electrochemistry Communications, 2012, v20, 52-55.

Synthesis Methods Method 2: Tosylhydrazone Degenerations Reflux with NaOH Highly complex Many byproducts Subhash P.; Kale, Ramesh R.; Pasupathy, K.; Synlett, 2005, 1129-1132. Kim, Hyeon Jin; Kwon, Seung-Ryong; Kim, Kyuwon; Electrochemistry Communications, 2012, v20, 52-55.

Synthesis Methods Method 3: (BEST!) Substitute octanoic acid using Na2S to form thiols Bu4N+Br- catalyst in methanol to form sulfur ring Hydrolyze to carboxylic acid

Alpha Lipoic Acid Thank You!