DOCSLIB.ORG

Biocatalysis in the Chemistry of Lupane Triterpenoids

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Biocatalysis in the Chemistry of Lupane Triterpenoids molecules Review Biocatalysis in the Chemistry of Lupane Triterpenoids Jan Bachoˇrík 1 and Milan Urban 2,* 1 Department of Organic Chemistry, Faculty of Science, Palacký University in Olomouc, 17. listopadu 12, 771 46 Olomouc, Czech Republic; [email protected] 2 Medicinal Chemistry, Faculty of Medicine and Dentistry, Institute of Molecular and Translational Medicine, Palacký University in Olomouc, Hnˇevotínská 5, 779 00 Olomouc, Czech Republic * Correspondence: [email protected] Abstract: Pentacyclic triterpenes are important representatives of natural products that exhibit a wide variety of biological activities. These activities suggest that these compounds may represent potential medicines for the treatment of cancer and viral, bacterial, or protozoal infections. Naturally occurring triterpenes usually have several drawbacks, such as limited activity and insufficient solubility and bioavailability; therefore, they need to be modified to obtain compounds suitable for drug development. Modifications can be achieved either by methods of standard organic synthesis or with the use of biocatalysts, such as enzymes or enzyme systems within living organisms. In most cases, these modifications result in the preparation of esters, amides, saponins, or sugar conjugates. Notably, while standard organic synthesis has been heavily used and developed, the use of the latter methodology has been rather limited, but it appears that biocatalysis has recently sparked considerably wider interest within the scientific community. Among triterpenes, derivatives of lupane play important roles. This review therefore summarizes the natural occurrence and sources of lupane triterpenoids, their biosynthesis, and semisynthetic methods that may be used for the production of betulinic acid from abundant and inexpensive betulin. Most importantly, this article compares chemical transformations of lupane triterpenoids with analogous reactions performed by Citation: Bachoˇrík,J.; Urban, M. biocatalysts and highlights a large space for the future development of biocatalysis in this field. The Biocatalysis in the Chemistry of results of this study may serve as a summary of the current state of research and demonstrate the Lupane Triterpenoids. Molecules 2021, potential of the method in future applications. 26, 2271. https://doi.org/ 10.3390/molecules26082271 Keywords: lupane; betulinic acid; betulin; lupeol; biocatalysis; extraction; biotransformation; synthe- sis; prodrugs; enzyme Academic Editor: Irina Ivshina Received: 27 March 2021 Accepted: 11 April 2021 1. Introduction Published: 14 April 2021 Natural products have been used in traditional medicine for a long time, and since the appearance of modern science, they have been recognized as valuable sources of Publisher’s Note: MDPI stays neutral new drugs [1–5]. Considerable money has been invested in their isolation from natural with regard to jurisdictional claims in sources and characterization of their structures and biological activities. High-throughput published maps and institutional affil- screening was introduced for fast and efficient testing of large numbers of new compounds iations. from nature or chemistry labs [6–9]. In 2015, David et al. wrote a very informative review in which the authors summarized some of the most successful drug leads in history that came from natural products [10]. This review also reports that there was a significant decline in investment in natural drug discovery programs during the early 2000s because more Copyright: © 2021 by the authors. attention was paid to combinatorial chemistry and rational drug design, which appeared Licensee MDPI, Basel, Switzerland. to be considerably more promising. Pharmaceutical companies expected new methods to This article is an open access article enable the production of a number of new drugs, aiming at new molecular targets that distributed under the terms and may be game changers for many diseases. The new approach, however, has exhibited conditions of the Creative Commons Attribution (CC BY) license (https:// lower productivity in bringing new drugs to the market than previously expected, and creativecommons.org/licenses/by/ over the years, some of its disadvantages have appeared. One of these drawbacks is that 4.0/). rational design and solid-phase combinatorial chemistry usually use limited structural Molecules 2021, 26, 2271. https://doi.org/10.3390/molecules26082271 https://www.mdpi.com/journal/molecules Molecules 2021, 26, x 2271 FOR PEER REVIEW 2 of 28 26 structuralvariability, variability, which also which limits thealso outcome limits the [11 outcome]. Natural [11]. compounds, Natural co onmpounds, the other on hand, the other have hand,almost have unlimited almost variability unlimited of variability molecules, of and molecules, they occupy and a considerablythey occupy largera considerably chemical largerspace chemical than the space more focusedthan the more libraries focused obtained libraries as a obtained result of as the a result previously of the mentionedpreviously mentionedmethods [11 methods]. Although [11]. it Although is often difficult it is often to obtain difficult a unique to obtain active a unique molecule active from molecule natural frommaterial natural and material uncover and its uncover structure its and structure activity, and in activity, many cases, in many this cases, effort this has effort paid has off, paidleading off, toleading a commercial to a commercial drug. Within drug. theWithin past the several past years,several the years, search the for search new for natural new naturalproducts products started started to reemerge to reemerge as a source as a ofsour newce of drugs new [10drugs]. In [10]. our opinion,In our opinion, equilibrium equi- libriumhas been has achieved been achieved between between the two the approaches, two approaches, which which are both are important both important in the in drug the drugdiscovery discovery process. process. OneOne of of the largest and most important gr groupsoups of of natural products, products, which which has has at- at- tractedtracted considerable considerable attention attention from from researchers, researchers, is isterpenes. terpenes. Hundreds Hundreds of terpenes of terpenes are iso- are latedisolated every every year year from from natural natural resources, resources, and and even even more more are are prepared prepared by by semisynthetic methodsmethods [12,13]. [12,13]. Terpenes Terpenes can can have have a a variety of of different roles in living organisms; for example,example, they they can participate in such proce processessses as transferring messages and defending organismsorganisms [14–16]. [14–16]. TerpenesTerpenes can be formally divided into sm smalleraller subclasses based on the number of carbons.carbons. Triterpenes areare thethe subclass subclass that that contains contains 30 30 carbons carbons in itsin structures.its structures. This This subclass sub- classis composed is composed of a large of a large number number of compounds of compounds that may that bemay divided be divided according according to their to basictheir basicskeletons skeletons into into several several structural structural families. families. The The most most important important families families ofof triterpenes areare derivatives derivatives of of protostane, protostane, cycloartane, cycloartane, dammarane, dammarane, and and euphane, euphane, and and pentacyclic pentacyclic de- rivatives,derivatives, such such as asoleanane, oleanane, ursane, ursane, gammacerane, gammacerane, lupane, lupane, and and hopane. hopane. Figure Figure 11 showsshows thethe structures ofof selectedselected main main skeletons skeletons of of pentacyclic pentacyclic triterpenes—lupane triterpenes—lupane (1), ( hopane1), hopane (2), (ursane2), ursane (3), ( and3), and oleanane oleanane (4)[ (174), 18[17,18].]. Figure 1. ExamplesExamples of structural famili familieses of triterpenes—lupane ( 1), hopane ( 2), ursane (3), and oleanane (4). TriterpenesTriterpenes oftenoften have have a varietya variety of biologicalof biological activities, activities, and amongand among them, betulinicthem, betulinic acid (5) acidplays (5 an) plays important an important role, along role, with along ursolic with (6 )ursolic and oleanolic (6) and acidoleanolic (7) (Figure acid 2(7)[) 19(Figure–27]. 2) [19–27].The biological activities of betulinic acid (5) will be discussed later. However, the potential use of 5 as a commercially available drug may be limited by its insufficient solubility in water and low bioavailability [28,29]. This low bioavailability is also the main complication encountered when performing biological experiments; therefore, the optimization of pharmacological parameters, including solubility, is always an important part of the development of derivatives of acid 5. Many studies have focused on structural modifications of betulinic acid (5) that improve its solubility and bioavailability, especially the enhancement of solubility in polar media, and many studies have also focused on the improvement of selectivity [29–31]. In this review, we mostly focus on the biosynthesis of lupane triterpenoids, including betulinic acid (5), biocatalyzed modifications of acid 5, and its derivatives, and we compare those methods to classical approaches of synthetic organic chemistry that are commonly used. Our research group has been focused on the chemical modification of 5 for many years, and currently, we see biocatalysis as an important alternative for the preparation of new molecules
Load more

Recommended publications
  • Betulinic Acid and Its Derivatives As Anti-Cancer Agent: a Review
    Available online a t www.scholarsresearchlibrary.com Scholars Research Library Archives of Applied Science Research, 2014, 6 (3):47-58 (http://scholarsresearchlibrary.com/archive.html) ISSN 0975-508X CODEN (USA) AASRC9 Betulinic acid and its derivatives as anti-cancer agent: A review Gomathi Periasamy*, Girma Teketelew, Mebrahtom Gebrelibanos, Biruk Sintayehu, Michael Gebrehiwot, Aman Karim and Gereziher Geremedhin Department of Pharmacy, College of Health Sciences, Mekelle University, Mekelle, Ethiopia _____________________________________________________________________________________________ ABSTRACT Betulinic acid is a known natural product which has gained a lot of attention in the recent years since it exhibits a variety of biological and medicinal properties. This review provides the most important anticancer properties of betulinic acid and its derivatives. _____________________________________________________________________________________________ INTRODUCTION Cancer is a group of diseases that cause cells in the body to change and grow out of control[1]. Cancer cell growth is different from normal cell growth. Instead of dying, cancer cells keep on growing and form new cancer cells. These cancer cells can grow into (invade) other tissues, something that normal cells cannot do. In most cases the cancer cells form a tumor. But some cancers, like leukemia, rarely form tumors. Instead, these cancer cells are in the blood and bone marrow[2]. Cancer cell escape from many of the normal homeostatic mechanism that control proliferation. They invade surrounding tissues, gets into the body’s circulating system and set up areas of proliferation away from the site of their original appearance[3]. Cancer is the second most important disease leading to death in both the developing and developed countries nowadays. The global burden of cancer continues to increase largely because of the aging and growth of the world population alongside an increasing adoption of cancer-causing behaviors, particularly smoking, in economically developing countries[4].
    [Show full text]
  • Biologically Active Pentacyclic Triterpenes and Their Current Medicine Signification
    Journal of Applied Biomedicine 1: 7 – 12, 2003 ISSN 1214-0287 Biologically active pentacyclic triterpenes and their current medicine signification Jiří Patočka Department of Toxicology, Military Medical Academy, Hradec Králové and Department of Radiology, Faculty of Health and Social Care, University of South Bohemia, České Budějovice, Czech Republic Summary Pentacyclic triterpenes are produced by arrangement of squalene epoxide. These compounds are extremely common and are found in most plants. There are at least 4000 known triterpenes. Many triterpenes occur freely but others occur as glycosides (saponins) or in special combined forms. Pentacyclic triterpenes have a wide spectrum of biological activities and some of them may be useful in medicine. The therapeutic potential of three pentacyclic triterpenes – lupeol, betuline and betulinic acid – is discussed in this paper. Betulinic acid especially is a very promising compound. This terpene seems to act by inducing apoptosis in cancer cells. Due to its apparent specificity for melanoma cells, betulinic acid seems to be a more promising anti-cancer substance than drugs like taxol. Keywords: pentacyclic triterpene – lupeol – betuline – betulinic acid – biological activity INTRODUCTION structural analysis of these compounds, as by the fact of their wide spectrum of biological activities;they are Terpenes are a wide-spread group of natural bactericidal, fungicidal, antiviral, cytotoxic, analgetic, compounds with considerable practical significance anticancer, spermicidal, cardiovascular, antiallergic and which are produced by arrangement of squalene so on In recent years, a considerable number of epoxide in a chair-chair-chair-boat arrangement studies conducted in many scientific centres have been followed by condensation. In our everyday life we all devoted to the three compounds of this group, encounter either directly or indirectly various terpenes, especially: lupeol, betulin and betulinic acid.
    [Show full text]
  • ATP-Citrate Lyase Has an Essential Role in Cytosolic Acetyl-Coa Production in Arabidopsis Beth Leann Fatland Iowa State University
    Iowa State University Capstones, Theses and Retrospective Theses and Dissertations Dissertations 2002 ATP-citrate lyase has an essential role in cytosolic acetyl-CoA production in Arabidopsis Beth LeAnn Fatland Iowa State University Follow this and additional works at: https://lib.dr.iastate.edu/rtd Part of the Molecular Biology Commons, and the Plant Sciences Commons Recommended Citation Fatland, Beth LeAnn, "ATP-citrate lyase has an essential role in cytosolic acetyl-CoA production in Arabidopsis " (2002). Retrospective Theses and Dissertations. 1218. https://lib.dr.iastate.edu/rtd/1218 This Dissertation is brought to you for free and open access by the Iowa State University Capstones, Theses and Dissertations at Iowa State University Digital Repository. It has been accepted for inclusion in Retrospective Theses and Dissertations by an authorized administrator of Iowa State University Digital Repository. For more information, please contact [email protected]. ATP-citrate lyase has an essential role in cytosolic acetyl-CoA production in Arabidopsis by Beth LeAnn Fatland A dissertation submitted to the graduate faculty in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Major: Plant Physiology Program of Study Committee: Eve Syrkin Wurtele (Major Professor) James Colbert Harry Homer Basil Nikolau Martin Spalding Iowa State University Ames, Iowa 2002 UMI Number: 3158393 INFORMATION TO USERS The quality of this reproduction is dependent upon the quality of the copy submitted. Broken or indistinct print, colored or poor quality illustrations and photographs, print bleed-through, substandard margins, and improper alignment can adversely affect reproduction. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted.
    [Show full text]
  • Antiviral Activities of Oleanolic Acid and Its Analogues
    molecules Review Antiviral Activities of Oleanolic Acid and Its Analogues Vuyolwethu Khwaza, Opeoluwa O. Oyedeji and Blessing A. Aderibigbe * Department of Chemistry, University of Fort Hare, Alice Campus, Alice 5700, Eastern Cape, South Africa; [email protected] (V.K.); [email protected] (O.O.O) * Correspondence: [email protected]; Tel.: +27-406022266; Fax: +08-67301846 Academic Editors: Patrizia Ciminiello, Alfonso Mangoni, Marialuisa Menna and Orazio Taglialatela-Scafati Received: 27 July 2018; Accepted: 5 September 2018; Published: 9 September 2018 Abstract: Viral diseases, such as human immune deficiency virus (HIV), influenza, hepatitis, and herpes, are the leading causes of human death in the world. The shortage of effective vaccines or therapeutics for the prevention and treatment of the numerous viral infections, and the great increase in the number of new drug-resistant viruses, indicate that there is a great need for the development of novel and potent antiviral drugs. Natural products are one of the most valuable sources for drug discovery. Most natural triterpenoids, such as oleanolic acid (OA), possess notable antiviral activity. Therefore, it is important to validate how plant isolates, such as OA and its analogues, can improve and produce potent drugs for the treatment of viral disease. This article reports a review of the analogues of oleanolic acid and their selected pathogenic antiviral activities, which include HIV, the influenza virus, hepatitis B and C viruses, and herpes viruses. Keywords: HIV; influenza virus; HBV/HCV; natural product; triterpenoids; medicinal plant 1. Introduction Viral diseases remain a major problem for humankind. It has been reported in some reviews that there is an increase in the number of viral diseases responsible for death and morbidity around the world [1,2].
    [Show full text]
  • Possible Fungistatic Implications of Betulin Presence in Betulaceae Plants and Their Hymenochaetaceae Parasitic Fungi Izabela Jasicka-Misiak*, Jacek Lipok, Izabela A
    Possible Fungistatic Implications of Betulin Presence in Betulaceae Plants and their Hymenochaetaceae Parasitic Fungi Izabela Jasicka-Misiak*, Jacek Lipok, Izabela A. S´wider, and Paweł Kafarski Faculty of Chemistry, Opole University, Oleska 48, 45-052 Opole, Poland. Fax: +4 87 74 52 71 15. E-mail: [email protected] * Author for correspondence and reprint requests Z. Naturforsch. 65 c, 201 – 206 (2010); received September 23/October 26, 2009 Betulin and its derivatives (especially betulinic acid) are known to possess very interesting prospects for their application in medicine, cosmetics and as bioactive agents in pharmaceu- tical industry. Usually betulin is obtained by extraction from the outer layer of a birch bark. In this work we describe a simple method of betulin isolation from bark of various species of Betulaceae trees and parasitic Hymenochaetaceae fungi associated with these trees. The composition of the extracts was studied by GC-MS, whereas the structures of the isolated compounds were confi rmed by FTIR and 1H NMR. Additionally, the signifi cant fungistatic activity of betulin towards some fi lamentous fungi was determined. This activity was found to be strongly dependent on the formulation of this triterpene. A betulin-trimyristin emul- sion, in which nutmeg fat acts as emulsifi er and lipophilic carrier, inhibited the fungal growth even in micromolar concentrations – its EC50 values were established in the range of 15 up to 50 μM depending on the sensitivity of the fungal strain. Considering the lack of fungistatic effect of betulin applied alone, the application of ultrasonic emulsifi cation with the natural plant fat trimyristin appeared to be a new method of antifungal bioassay of water-insoluble substances, such as betulin.
    [Show full text]
  • Assessment of Betulinic Acid Cytotoxicity and Mitochondrial Metabolism Impairment in a Human Melanoma Cell Line
    International Journal of Molecular Sciences Article Assessment of Betulinic Acid Cytotoxicity and Mitochondrial Metabolism Impairment in a Human Melanoma Cell Line Dorina Coricovac 1,2,† , Cristina Adriana Dehelean 1,2,†, Iulia Pinzaru 1,2,* , Alexandra Mioc 1,2,*, Oana-Maria Aburel 3,4, Ioana Macasoi 1,2, George Andrei Draghici 1,2 , Crina Petean 1, Codruta Soica 1,2, Madalina Boruga 3, Brigitha Vlaicu 3 and Mirela Danina Muntean 3,4 1 Faculty of Pharmacy, “Victor Babes, ” University of Medicine and Pharmacy Timis, oara, Eftimie Murgu Square No. 2, RO-300041 Timis, oara, Romania; [email protected] (D.C.); [email protected] (C.A.D.); [email protected] (I.M.); [email protected] (G.A.D.); [email protected] (C.P.); [email protected] (C.S.) 2 Research Center for Pharmaco-toxicological Evaluations, Faculty of Pharmacy, “Victor Babes” University of Medicine and Pharmacy Timis, oara, Eftimie Murgu Square No. 2, RO-300041 Timis, oara, Romania 3 Faculty of Medicine “Victor Babes, ” University of Medicine and Pharmacy Timis, oara, Eftimie Murgu Square No. 2, RO-300041 Timis, oara, Romania; [email protected] (O.-M.A.); [email protected] (M.B.); [email protected] (B.V.); [email protected] (M.D.M.) 4 Center for Translational Research and Systems Medicine, Faculty of Medicine,” Victor Babes, ” University of Medicine and Pharmacy Timis, oara, Eftimie Murgu Sq. no. 2, RO-300041 Timis, oara, Romania * Correspondence: [email protected] (I.P.); [email protected] (A.M.); Tel.: +40-256-494-604 † Authors with equal contribution. Citation: Coricovac, D.; Dehelean, Abstract: Melanoma represents one of the most aggressive and drug resistant skin cancers with C.A.; Pinzaru, I.; Mioc, A.; Aburel, poor prognosis in its advanced stages.
    [Show full text]
  • Download Product Insert (PDF)
    Product Information Betulin Item No. 11041 CH2 CAS Registry No.: 473-98-3 H3C β Formal Name: lup-20(29)-ene-3 ,28-diol H Synonyms: NSC 4644, Trochol OH H MF: C30H50O2 CH CH FW: 442.7 3 3 Purity: ≥98% H CH3 Stability: ≥2 years at -20°C Supplied as: A crystalline solid OH H Laboratory Procedures For long term storage, we suggest that betulin be stored as supplied at -20°C. It should be stable for at least two years. Betulin is supplied as a crystalline solid. A stock solution may be made by dissolving the betulin in the solvent of choice. Betulin is soluble in dimethyl formamide (DMF), which should be purged with an inert gas. The solubility of betulin in DMF is approximately 2.5 mg/ml. Betulin is sparingly soluble in aqueous solutions. To enhance aqueous solubility, dilute the organic solvent solution into aqueous buffers or isotonic saline. If performing biological experiments, ensure the residual amount of organic solvent is insignificant, since organic solvents may have physiological effects at low concentrations. We do not recommend storing the aqueous solution for more than one day. Sterol regulatory element binding protein 2 (SREBP-2) regulates cholesterol synthesis by activating the transcription of genes for HMG-CoA reductase and other enzymes of the cholesterol synthetic pathway.1,2 When cellular sterol levels are high, SREBP is bound by SCAP and Insig to ER membranes as a glycosylated precursor protein. Upon cholesterol depletion, the protein is cleaved to its active form and translocated into the nucleus to stimulate transcription of genes involved in the uptake and synthesis of cholesterol.3 Betulin, the precursor of betulinic acid, is a pentacyclic triterpene found in the bark of birch trees.
    [Show full text]
  • Plant-Derived Triterpenoid Biomarkers and Their Applications In
    Plant-derived triterpeonid biomarkers: chemotaxonomy, geological alteration, and vegetation reconstruction Res. Org. Geochem. 35, 11 − 35 (2019) Reviews-2015 Taguchi Award Plant-derived triterpenoid biomarkers and their applications in paleoenvironmental reconstructions: chemotaxonomy, geological alteration, and vegetation reconstruction Hideto Nakamura＊ （Received November 22, 2019; Accepted December 27, 2019） Abstract Triterpenoids and their derivatives are ubiquitous in sediment samples. Land plants are major sources of non- hopanoid triterpenoids; these terpenoids comprise a vast number of chemotaxonomically distinct biomolecules. Hence, geologically occurring plant-derived triterpenoids (geoterpenoids) potentially record unique characteristics of paleovegetation and sedimentary environments, and serve as source-specific markers for studying paleoenviron- ments. This review is aimed at explaining the origin of triterpenoids and their use as biomarkers in elucidating paleo- environments. Herein, application of plant-derived triterpenoids is discussed in terms of: (i) their biosynthetic pathways. These compounds are primarily synthesized via oxidosqualene cyclase (OSCs) and serve as precursors for a variety of membrane sterols and steroid hormones. Studies on OSCs and resulting compounds have helped elucidate the diversity and origin of the parent terpenoids. (ii) their chemotaxonomic significance. Geochemically important classes of triterpenoid skeletons are useful in gathering and substantiating information on botanical ori- gin of
    [Show full text]
  • Review Article Small Molecules from Nature Targeting G-Protein Coupled Cannabinoid Receptors: Potential Leads for Drug Discovery and Development
    Hindawi Publishing Corporation Evidence-Based Complementary and Alternative Medicine Volume 2015, Article ID 238482, 26 pages http://dx.doi.org/10.1155/2015/238482 Review Article Small Molecules from Nature Targeting G-Protein Coupled Cannabinoid Receptors: Potential Leads for Drug Discovery and Development Charu Sharma,1 Bassem Sadek,2 Sameer N. Goyal,3 Satyesh Sinha,4 Mohammad Amjad Kamal,5,6 and Shreesh Ojha2 1 Department of Internal Medicine, College of Medicine and Health Sciences, United Arab Emirates University, P.O. Box 17666, Al Ain, Abu Dhabi, UAE 2Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, P.O. Box 17666, Al Ain, Abu Dhabi, UAE 3DepartmentofPharmacology,R.C.PatelInstituteofPharmaceuticalEducation&Research,Shirpur,Mahrastra425405,India 4Department of Internal Medicine, College of Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059, USA 5King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia 6Enzymoics, 7 Peterlee Place, Hebersham, NSW 2770, Australia Correspondence should be addressed to Shreesh Ojha; [email protected] Received 24 April 2015; Accepted 24 August 2015 Academic Editor: Ki-Wan Oh Copyright © 2015 Charu Sharma et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The cannabinoid molecules are derived from Cannabis sativa plant which acts on the cannabinoid receptors types 1 and 2 (CB1 and CB2) which have been explored as potential therapeutic targets for drug discovery and development. Currently, there are 9 numerous cannabinoid based synthetic drugs used in clinical practice like the popular ones such as nabilone, dronabinol, and Δ - tetrahydrocannabinol mediates its action through CB1/CB2 receptors.
    [Show full text]
  • The Phytochemistry of Cherokee Aromatic Medicinal Plants
    medicines Review The Phytochemistry of Cherokee Aromatic Medicinal Plants William N. Setzer 1,2 1 Department of Chemistry, University of Alabama in Huntsville, Huntsville, AL 35899, USA; [email protected]; Tel.: +1-256-824-6519 2 Aromatic Plant Research Center, 230 N 1200 E, Suite 102, Lehi, UT 84043, USA Received: 25 October 2018; Accepted: 8 November 2018; Published: 12 November 2018 Abstract: Background: Native Americans have had a rich ethnobotanical heritage for treating diseases, ailments, and injuries. Cherokee traditional medicine has provided numerous aromatic and medicinal plants that not only were used by the Cherokee people, but were also adopted for use by European settlers in North America. Methods: The aim of this review was to examine the Cherokee ethnobotanical literature and the published phytochemical investigations on Cherokee medicinal plants and to correlate phytochemical constituents with traditional uses and biological activities. Results: Several Cherokee medicinal plants are still in use today as herbal medicines, including, for example, yarrow (Achillea millefolium), black cohosh (Cimicifuga racemosa), American ginseng (Panax quinquefolius), and blue skullcap (Scutellaria lateriflora). This review presents a summary of the traditional uses, phytochemical constituents, and biological activities of Cherokee aromatic and medicinal plants. Conclusions: The list is not complete, however, as there is still much work needed in phytochemical investigation and pharmacological evaluation of many traditional herbal medicines. Keywords: Cherokee; Native American; traditional herbal medicine; chemical constituents; pharmacology 1. Introduction Natural products have been an important source of medicinal agents throughout history and modern medicine continues to rely on traditional knowledge for treatment of human maladies [1]. Traditional medicines such as Traditional Chinese Medicine [2], Ayurvedic [3], and medicinal plants from Latin America [4] have proven to be rich resources of biologically active compounds and potential new drugs.
    [Show full text]
  • The Wound Healing Properties of Betulin from Birch Bark from Bench to Bedside
    Published online: 2019-03-11 Reviews The Wound Healing Properties of Betulin from Birch Bark from Bench to Bedside Author Armin Scheffler Affiliation ABSTRACT Niefern-Öschelbronn, Germany, With central European approval in January 2016 for a betulin- oleogel (Episalvan), used to accelerate wound closure in par- Key words tial thickness wounds, the herbal active ingredient triterpene ‑ wound healing, split thickness skin graft, burn wounds, dry extract (betulin), from birch bark, was introduced into Betula pendula Betula pubescens Betulaceae, , ,betulin therapy for the first time. Clinical evidence of accelerated wound healing was provided in a new study design by means received October 30, 2018 of intraindividual comparison of split-thickness skin graft do- revised January 28, 2019 nor wounds and burn wounds. Clinical results of a phase II accepted January 29, 2019 study evidencing accelerated wound healing in the rare dis- Bibliography ease epidermolysis bullosa are also available, and a pivotal DOI https://doi.org/10.1055/a-0850-0224 multi-centre phase III study is currently being conducted. Published online March 11, 2019 | Planta Med 2019; 85: 524– The mode of action affects all three phases of wound healing 527 © Georg Thieme Verlag KG Stuttgart · New York | (inflammation, migration, and differentiation), and it has ISSN 0032‑0943 been possible, in some cases, to shed light on this down to the molecular level. After temporary stimulation of the in- Correspondence flammatory phase, the keratinocytes migrate more rapidly to Dr. Armin Scheffler the wound closure and, finally, epidermal differentiation is Bussardweg 15/1, 75223 Niefern-Öschelbronn, Germany stimulated. With this project, we have shown that scientifi- Phone: + 4972333580, Fax: + 497233974138 cally founded new developments in phytotherapy are possible [email protected] in Europe.
    [Show full text]
  • Recent Developments in the Functionalization of Betulinic Acid and Its Natural Analogues: a Route to New Bioactive Compounds
    Review Recent Developments in the Functionalization of Betulinic Acid and Its Natural Analogues: A Route to New Bioactive Compounds Joana L. C. Sousa 1,2,*, Carmen S. R. Freire 2, Armando J. D. Silvestre 2 and Artur M. S. Silva 1,* 1 QOPNA & LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal 2 CICECO, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal; [email protected] (C.S.R.F.); [email protected] (A.J.D.S.) * Correspondence: [email protected] (J.L.C.S.); [email protected] (A.M.S.S.); Tel.: +351-234-370-714 (A.M.S.S.) Received: 29 December 2018; Accepted: 17 January 2019; Published: 19 January 2019 Abstract: Betulinic acid (BA) and its natural analogues betulin (BN), betulonic (BoA), and 23- hydroxybetulinic (HBA) acids are lupane-type pentacyclic triterpenoids. They are present in many plants and display important biological activities. This review focuses on the chemical transformations used to functionalize BA/BN/BoA/HBA in order to obtain new derivatives with improved biological activity, covering the period since 2013 to 2018. It is divided by the main chemical transformations reported in the literature, including amination, esterification, alkylation, sulfonation, copper(I)-catalyzed alkyne-azide cycloaddition, palladium-catalyzed cross-coupling, hydroxylation, and aldol condensation reactions. In addition, the synthesis of heterocycle-fused BA/HBA derivatives and polymer‒BA conjugates are also addressed. The new derivatives are mainly used as antitumor agents, but there are other biological applications such as antimalarial activity, drug delivery, bioimaging, among others. Keywords: triterpenes; betulinic acid; betulin; betulonic acid; 23-hydroxybetulinic acid; synthesis; functionalization; derivatization 1.
    [Show full text]