ResveratrolXXXXChemistry 377 – Section 001Dr. WoydziakNevada State CollegeSpring 2015

Introduction• IUPAC Name: 3,4',5-

trihydroxystilbene• Molecular Formula:

▫ C14H12O3

• Molar Mass:▫ 228.24 g·mol−1

• Natural Product Category:▫ Small Molecule▫ Unclassified

• Stilbene▫ Two Phenyl Rings▫ Ethylene Bridge

• Phytoalexin

trans-resveratrol

cis-resveratrol

History – Michio Takaoka

• First to discover resveratrol in 1940

• Isolated in white hellebore flowers

• Research at Hokkaido University

• Published first article to mention resveratrol

• Proposed first synthesis of resveratrol

Veratrum album [1]

[2] [3]

History – Nonomura, Kanagawa, and Makimoto

• Discovered resveratrol in Japanese knotweed in 1963▫ Ko-Jo-Kon

• Medicinal uses:▫ Fungal infections▫ Liver diseases▫ Skin inflammations▫ Cardiovascular disease

[4]

Polygonum cuspidatum [5]

History – David Sinclair

• Professor at Harvard Medical School• Pioneer in TIME’s 100 Most Influential People• Glenn Laboratories for Aging Research• Sirtuins Studies and Lifespan Effects (2003)• Calorie Restriction Mouse Studies (2006)• Sirtris Pharmaceuticals

▫ SRT-501 Activator of SIRT1 Enzyme

• Genocea Biosciences

[10]

[11]

[12]

[13]

Uses by Humans• Possible treatments for the

following pathologies:▫ Cancer▫ Heart Disease▫ Heart Attack▫ Stroke▫ Acne▫ Analgesia▫ Hearing Loss▫ Reduction of Injuries

Kidneys Spinal Cord Liver Lungs Intestine Colon

[14]

SkinCeuticals [15]

Biological Activity - Cancer• Inhibition of Cyclooxygenase

Enzymes▫ Selective Inhibition of COX1▫ Transcriptional Reduction of COX2

• Reduced Expression of Ornithine Decarboxylase

• Prevention of Angiogenesis• Effects on Cytochrome P450

▫ Inhibits Activity▫ Blocks Transcription Via Antagonism of

Receptor

• Increased Expression of Phase II Drug Metabolism Enzymes▫ i.e. Conjugating and Antioxidant Enzymes

• Antioxidant Effects▫ Increased Plasma Antioxidant Capacity▫ Decreased Lipid Peroxidation

[18]

Biological Activity – Cardiovascular Disease

• Prevents Platelet Aggregation▫ Preferential Inhibition of COX1

Blocks Prostaglandin Thromboxane A2

• Roles in Vasodilation▫ Aforementioned Inhibition of COX1▫ Stimulation of Ca2+-activated K+ Channels▫ Enhancement of Nitric Oxide Signaling

• Antioxidant Effects▫ Activation of Nitric Oxide Synthases▫ Prevention of LDL Oxidation

• Inhibits Cholesterol and Triglyceride Deposition in Liver

• Decreased Rates of Hepatic Triglyceride Synthesis

[19]

Biological Activity – Prevention of Atherosclerosis

[21]

Biological Activity - Aging

[20]

Biological Activity - Overview

[16]

[17]

Do Winos Get Enough Resveratrol?

[24]

Biosynthesis

• Steps:1. Deamination2. Hydroxylatio

n3. Conversion4. Condensatio

n

[22]

[23]

Chemical Synthesis – Michio Takaoka

• Steps:1. Condensation Reaction in the Presence of Acetic

Anhydride2. Decarboxylation with Copper Powder3. Hydrolysis with Sodium Hydroxide in a Current of

Nitrogen

Chemical Synthesis – Moreno-Manas and Pleixats (1985)

• Wittig Reaction Steps:1. Nucleophillic Attack on the Carbonyl2. Formation of 4-membered Heterocyclic Oxaphosphatane

Structure3. Formation of Alkene and Phosphine Oxide

[25]

Chemical Synthesis – Ferré-Filmon, Delaude, Demonceau, and Noels (2004)

• Heck Reaction Steps:1. Oxidative Addition 2. Syn-Addition3. Syn-intramolecular β-Elimination with a

Hydride Shift 4. Quench Formed Hydrogen Halide with

Triethylamine

Picture References(1) A Modern Herbal | Hellebore, White http://www.botanical.com/botanical/mgmh/h/helwhi17.html (accessed Apr 12, 2015).

(2) Sapporo Premium https://www.liquorbarons.com.au/Beer/Product/Detail/sapporo-premium-b11/ (accessed Apr 12, 2015).

(3) Hokkaido University | CAKE: Climate Adaptation Knowledge Exchange http://www.cakex.org/directory/organizations/hokkaido-university (accessed Apr 12, 2015).

(4) https://www.jstage.jst.go.jp/browse/yakushi (accessed Apr 12, 2015).

(5) Polygonum cuspidatum - Japanese Knotweed -- Discover Life http://www.discoverlife.org/20/q?search=Polygonum cuspidatum (accessed Apr 12, 2015).

(6) WHO. Cardiovascular Disease http://www.who.int/cardiovascular_diseases/en/cvd_atlas_29_world_data_table.pdf?ua=1 (accessed Apr 12, 2015).

(7) Skinny with Wine: The French Paradox http://winefolly.com/update/french-paradox-diet/ (accessed Apr 12, 2015).

(8) Boyd, J. 0728-TALLOW-Siemann-med http://news.rice.edu/2011/07/28/invasive-tree-afflicting-gulf-coast-was-not-brought-to-us-by-ben-franklin/0728-tallow-siemann-med/ (accessed Apr 12, 2015).

(9) Australian Politics Forum - Should Greece be bailed out a second time ? http://www.ozpolitic.com/forum/YaBB.pl?num=1308587143/24 (accessed Apr 12, 2015).

(10) Timmerman, L. GlaxoSmithKline Shuts Down Sirtris, Five Years After $720M Buyout http://www.xconomy.com/boston/2013/03/12/glaxosmithkline-shuts-down-sirtris-five-years-after-720m-buyout/ (accessed Apr 12, 2015).

(11) David Sinclair http://www.tedmed.com/speakers/show?id=6542 (accessed Apr 12, 2015).

(12) Ghogomu, M. WOW! Aging Was Just Successfully Reversed in Mice; Human Trials Are Up Next http://thehigherlearning.com/2014/03/31/wow-aging-was-just-successfully-reversed-in-mice-human-trials-are-up-next/ (accessed Apr 12, 2015).

(13) Resveratrol from red wine and plants may extend lifespan - Nutrition Express Articles http://www.nutritionexpress.com/showarticle.aspx?id=1127 (accessed Apr 12, 2015).

(14) Optimal Medical Therapy | Cardiologydoc’s Blog on WordPress.com https://cardiologydoc.wordpress.com/2012/02/14/optimal-medical-therapy/ (accessed Apr 12, 2015).

(15) Resveratrol B E http://www.skinceuticals.de/Antioxidantien/Resveratrol-B-E/p1295.aspx (accessed Apr 12, 2015).

(16) B, C.; K, R.; M, M.; M, C.; J, P.; B, S.; A, M. Pleiotropic mechanisms facilitated by resveratrol and its metabolites http://www.biochemj.org/bj/429/0273/bj4290273.htm (accessed Apr 12, 2015).

(17) High Potency Resveratrol | Pure Resveratrol | Resveratrol Extract | Concentrated Resveratrol | Trans Resveratrol Supplement http://www.naturalbiology.com/high_potency_resveratrol_p/resveratrol60.htm (accessed Apr 12, 2015).

(18) http://www.equithrive.com/inflammation/what-is-resveratrol/ (accessed Apr 12, 2015).

(19) Heart Disease Facts http://www.cdc.gov/heartdisease/facts.htm (accessed Apr 12, 2015).

(20) Heitman, L. 5 Incredible Nutrients That Mimic the Health & Longevity Effects of Calorie Restriction | Live Long & Thrive on WordPress.com https://livelongthrive.wordpress.com/2014/05/26/5-incredible-nutrients-that-mimic-the-health-longevity-effects-of-calorie-restriction/ (accessed Apr 12, 2015).

(21) https://journals.prous.com/journals/servlet/xmlxsl/pk_journals.xml_summary_pr?p_JournalId=3 (accessed Apr 12, 2015).

(22) Cichewicz, R.; Kouzi, S. In Studies in Natural Products Chemistry: Volume 38; Rahman, A.-, Ed.; Elsevier Science: United Kingdom, 2012.

(23) Ferre-Filmon, K.; Delaude, L.; Demonceau, A.; Noels, A. Catalytic methods for the synthesis of stilbenes with an emphasis on their phytoalexins. Coordination Chemistry Reviews 2004, 248 (21), 2323–2336.

(24) On TRAC with DrMark drmarkcrapo.typepad.com (accessed Apr 12, 2015).

(25) Reusch, W.; Farmer, S. The Wittig Reaction http://chemwiki.ucdavis.edu/?title=Organic_Chemistry/Aldehydes_and_Ketones/Reactions_of_Aldehydes_%26_Ketones/The_Wittig_Reaction (accessed Apr 1, 2015).

References (1) Soleas, G. J.; Diamandis, E. P.; Goldberg, D. M. Resveratrol: A molecule whose time has come? And gone? Clinical Biochemistry 1997, 30 (2), 91–113.

(2) Takaoka, M. The Synthesis of Resveratrol and its Derivatives, 8th ed.; Sapporo, Japan, 1940; Vol. 16, pp 405–407.

(3) Hokkaido University. Discover Our History. http://www.oia.hokudai.ac.jp/about/a-proud-history/ (accessed Apr 1, 2015).

(4) Nonomura, S.; Kanagawa, H.; Makimoto, A. Journal of the Pharmaceutical Society of Japan 1963, 83, 988–990.

(5) Siemann, E.; Creasy, L. American Journal of Enology and Viticulture 1992, 43 (1), 49–52.

(6) Higdon, J.; Drake, V.; Steward, W. Linus Pauling Institute Micronutrient Research for Optimum Health. http://lpi.oregonstate.edu/infocenter/phytochemicals/resveratrol/ (accessed Jan 27, 2015).

(7) Rice University. PI Evan Siemann of the Population and Community Ecology at Rice PI Evan Siemann http://www.ruf.rice.edu/~siemann/evan.html (accessed Mar 31, 2015).

(8) Cornell University. Leroy Creasy | Horticulture Section http://hort.cals.cornell.edu/people/leroy-creasy (accessed Mar 31, 2015).

(9) Howitz, K. T.; Bitterman, K. J.; Cohen, H. Y.; Lamming, D. W.; Lavu, S.; Wood, J. G.; Zipkin, R. E.; Chung, P.; Kisielewski, A.; Zhang, L.-L.; et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 2003, 425 (6954), 191–196.

(10) Harvard School of Medicine. David Sinclair | The Sinclair Lab | Harvard Medical School, Department of Genetics http://genetics.med.harvard.edu/sinclair/people-sinclair.php (accessed Mar 25, 2015).

(11) Baur, J. A.; Pearson, K. J.; Price, N. L.; Jamieson, H. A.; Lerin, C.; Kalra, A.; Prabhu, V. V.; Allard, J. S.; Lopez-Lluch, G.; Lewis, K.; et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 2006, 444 (7117), 337–342.

(12) SIRTRIS PHARMACEUTICALS, INC. (SIRT) IPO http://www.nasdaq.com/markets/ipos/company/sirtris-pharmaceuticals-inc-736622-53568 (accessed Mar 25, 2015).

(13) Pervaiz, S. In Herbal and Traditional Medicine: Biomolecular and Clinical Aspects; Benzie, I. F. F., Packer, L., Wachtel-Galor, S., Eds.; CRC Press: United States, 2004; pp 489–507.

(14) Cichewicz, R.; Kouzi, S. In Studies in Natural Products Chemistry: Volume 38; Rahman, A.-, Ed.; Elsevier Science: United Kingdom, 2012.

(15) Jeandet, P.; Clément, C.; Courot, E. Resveratrol production at large scale using plant cell suspensions. Engineering in Life Sciences 2014,14 (6), 622–632.

(16) The University of Maine. A Stilbene Synthase. Resveratrol, 2014.

(17) Ferre-Filmon, K.; Delaude, L.; Demonceau, A.; Noels, A. Catalytic methods for the synthesis of stilbenes with an emphasis on their phytoalexins. Coordination Chemistry Reviews 2004, 248 (21), 2323–2336.

(18) Woydziak, Z. Catalytic Cycle. Alkaloids Part 1, 2015, 18.

(19) Chem, S. Heck Reaction. YouTube, 2014.

(20) Reusch, W.; Farmer, S. The Wittig Reaction http://chemwiki.ucdavis.edu/?title=Organic_Chemistry/Aldehydes_and_Ketones/Reactions_of_Aldehydes_%26_Ketones/The_Wittig_Reaction (accessed Apr 1, 2015).

(21) Figueiras, T. S.; Neves-Petersen, M. T.; Petersen, S. B. Activation Energy of Light Induced Isomerization of Resveratrol. Journal of Fluorescence 2011, 21 (5), 1897–1906.

(22) Aggarwal, B.; Bhardwaj, A.; Aggarwal, R.; Seeram, N.; Shishodia, S.; Takada, Y. Role of Resveratrol in Prevention and Therapy of Cancer: Preclinical and Clinical Studies. Anticancer Research 2004, 24 (5a), 2783–2840.

(23) American Heart Association. What is Cardiovascular Disease? http://www.heart.org/HEARTORG/Caregiver/Resources/WhatisCardiovascularDisease/What-is-Cardiovascular-Disease_UCM_301852_Article.jsp (accessed Apr 1, 2015).

(24) Baur, J. A.; Sinclair, D. A. Therapeutic potential of resveratrol: the in vivo evidence. Nature Reviews Drug Discovery 2006, 5 (6), 493–506.

(25) Heitman, L. 5 Incredible Nutrients That Mimic the Health & Longevity Effects of Calorie Restriction | Live Long & Thrive on WordPress.com https://livelongthrive.wordpress.com/2014/05/26/5-incredible-nutrients-that-mimic-the-health-longevity-effects-of-calorie-restriction/ (accessed Apr 3, 2015).