Special Issue "Alkaloids"

Guest Editor
Prof. Dr. Patricia Valentao
Pharmacognosy Laboratory, Pharmacy Faculty, University of Oporto, R. Aníbal Cunha, 164, 4050 054 Porto
E-Mail:

Guest Editor
Prof. Dr. Mariana Sottomayor
Department of Botany, Faculty of Sciences and Institute for Molecular and Cell Biology (IBMC) , University of Porto Rua do Campo Alegre, 823 4150-180 Porto
E-Mail:

Submission

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed Open Access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1400 CHF (Swiss Francs).

• Pyridine group: piperine, coniine, trigonelline, arecaidine, guvacine, pilocarpine, cytisine, nicotine, sparteine, pelletierine. Pyrrolidine group: hygrine, cuscohygrine, nicotine. Tropane group: atropine, cocaine, ecgonine, scopolamine, catuabine. Quinoline group: quinine, quinidine, dihydroquinine, dihydroquinidine, strychnine, brucine, veratrine, cevadine. Isoquinoline group: The opium alkaloids (morphine, codeine, thebaine, Isopapa-dimethoxy-aniline, papaverine, narcotine, sanguinarine, narceine, hydrastine, berberine). Phenethylamine group: mescaline, ephedrine, dopamine, amphetamine, Indole group: Tryptamines: DMT, N-methyltryptamine, psilocybin, serotonin. Ergolines: the ergot alkaloids (ergine, ergotamine, lysergic acid, etc.). Beta-carbolines: harmine, harmaline, yohimbine, reserpine, emetine. Rauwolfia alkaloids: Reserpine. Purine group: Xanthines: caffeine, theobromine, theophylline. Terpenoid group: Aconite alkaloids: aconitine. Steroids: solanine, samandaris (quaternary ammonium compounds): muscarine, choline, neurine.
• organic chemistry, natural product chemistry, medicinal chemistry, analytical chemistry, etc.

Type of the Paper: Article
Author: Leonardo S. Santos
Affiliation: Laboratory of Asymmetric Synthesis, Chemistry Institute of Natural Resources and Technological Center for NanoSciences, Talca University, Chile; E-Mail: lssantos@utalca.cl
Title: Synthesis of Indolo[2,3-a]quinolizidine Ring through the Addition of 1-Siloxyfurans to Imines.
Abstract: A concise asymmetric diastereoselective strategy for the synthesis of indolo[2,3-a]quinolizidine derivative (1) was developed using diastereoselective addition of 1-siloxyfurans 4 to imine 3 through chiral auxiliary induction. The addition of ionic liquids as addictives in the reactions favored the threo configuration in the major adduct compounds. The stereochemical outcome of the threo/erythro selectivity was rationalized based on transition state and IRC calculations at DFT (B3LYP) and MP2 theories. MP2 calculations showed to be the method of choice in these systems, which orbital desymmetrizations were observed
in the threo transition state of the addition of 4 to 3 and secondary orbital interactions allowed us to rationalize the production of the major adduct 6. Furthermore, the work also suggested that 1-siloxyfuran 4a was the nucleophile of choice in this kind of Mannich reactions. Moreover, the strategy features the use of Mitsunobu reaction to insert an amino group with the correct configuration into amine 2, key intermediate to achieve 1. The synthetic route can also be applied in the total synthesis of promising aza-beta-carboline
compounds.

Type of Paper: Review
Title: Alkaloids rom Marine Ascidians
Authors: Marialuisa Menna, Ernesto Fattorusso and Concetta Imperatore.
Affiliation: Dipartimento di Chimica delle Sostanze Naturali, Università degli Studi di Napoli “Federico II”, Via D. Montesano 49, 80131, Napoli, Italy. E-Mail: mlmenna@unina.it (M.M.)
Abstract. Marine ascidians’ chemistry is dominated by the presence of nitrogenous metabolites, among which there is a large variety of structures. Particularly, these organisms have been a source of a huge variety of alkaloid structures with different skeletal types. About 300 alkaloid structures isolated from marine ascidians are here discussed in term of their occurrence, structural type and reported pharmacological activity. Some  major groups (e.g. the pyridoacridines ,b-carbolines,  lamellarins, and ecteinascidins)  are discussed in detail, highlighting their potential as therapeutic agents for the treatment of cancer or viral infections.

Type of Paper: Article
Title: Chirality and Numbering of Substituted Tropane Alkaloids
Authors: Munir Humam ¹, Tarik Shoul ¹, Damien Jeannerat ², Orlando Muñoz ³ and Philippe Christen ¹
Affiliations: ¹ School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Quai Ernest-Ansermet 30, CH-1211 Geneva 4, Switzerland;
E-Mail: philippe.christen@unige.ch
² Department of Organic Chemistry, University of Geneva, Quai Ernest-Ansermet 30, CH-1211 Geneva 4, Switzerland
³ Universidad de Chile, Facultad de Ciencias, Departamento de Química, Casilla 653, Santiago, Chile
Abstract: The strict application of IUPAC rules for the numbering of tropane alkaloids is not always applied by the authors and there is a lot of confusion in the literature. In most cases, the notation of 3, 6/7-disubstituted derivatives has been chosen arbitrarily based on NMR and MS data only without taking into account the absolute configuration of these 2 positions. The paper reports on the use of ¹H-NMR anisochrony (Δd) induced by the Mosher’s chiral auxiliary reagents, (R)-(-)- and (S)-(+)-α-methoxy-α-trifluoromethyl-phenylacetyl chlorides (MTPA-Cl), to determine the absolute configuration of this class of alkaloids and confront the results with circular dichroism data. We applied this methodology to (3R,6R)-3α-hydroxy-6b-senecioyloxytropane, a disubstituted tropane alkaloid isolated from the aerial parts of Schizanthus grahamii (Solanaceae). This method should prove to be widely applicable in assigning the configuration of additional 3, 6/7 disubstituted tropane derivatives.

Type of Paper: Review
Title: Recent Advances in the Study on Luotonins, Topoisomerase Inhibitory Alkaloids
Authors: Jing Lu Liang, Hyo Chang Cha and Yurngdong Jahng
Affiliation: College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Korea; E-Mail: ydjahng@ynu.ac.kr (Y.J.)
Abstract: The plants Peganum nigellastrum Bunge (Zygophyllaceae) has long been used in Chinese traditional medical practice for the treatment of rheumatism, abscesses, and diseases accompanying inflammation. The basic fractions of P. nigellastrum showed potent anti-tumor activity, and the origin of such activity was revealed by identifying its constituent luotonin A (1a) and B (1b) which inhibited the growth of leukemia P-388 cells (IC₅₀ of luotonin A = 1.8 μg/mL). Later additional luotonins such as luotonin E (1c) and F (2) as well as luotonin E (3a) and F (3b) were consecutively isolated from the same plant. All of these luotonins showed cytotoxicity against leukemia P-388 cells. The origin of such cytotoxicity was first revealed by Hecht and his coworkers. Luotonin A stabilizes the human DNA Topo I-DNA covalent binary complex and mediates topoisomerase I (Topo I)-dependent cytotoxicity in intact cells (IC₅₀ = 5.7-12.6 μg/mL), like camptothecin (CPT) that is the selective inhibitor of DNA Topo I even though luotonin A is less selective to Topo I than CPT. In fact, inhibitory activities of luotonin A (IC₅₀ = 28.5 μM) and F against DNA topoisomerase II (Topo II) with a feature related to their their cytotoxicities [6a,10]. More than a decade has passed since the first discovery of luotonin A and B, only one full review paper was written by Ma et al. in 2005 focusing on the total synthesis of luotonin A based on the synthetic strategies covering thirty papers. Natural Products Reports reported an annual review covering quinoline, quinazoline, and acridine alkaloids by J. P. Michael, in which annual progress in the studies on luotonins was included since 1999. SCI Finder affords 64 papers covering six luotonins. After the first review more than 25 papers have been published and most of them cover the development of synthetic methods for total synthesis and the structural modification of luotonin A for the development of anticancer agents. Present review, thus, covers the total synthesis of all the six luotonins based on the synthetic strategies for the ring formation and the structure-activity relationship study in chronological order.

Title: Application of Preparative High-Speed Counter-Current Chromatography for the Separation of Alkaloids from the Roots of Tabernaemontana Catharinensis (Apocynaceae)
Authors: Milena S. Gonçalves, Ivo J. Curcino Vieira, Rodrigo R. Oliveira and Raimundo Braz-Filho
Affiliation: Laboratório de Ciências Químicas, Universidade Estadual do Norte Fluminense Darcy Ribeiro, 28013-602, Campos dos Goytacazes, Rio de Janeiro, Brazil; E-Mail: curcino@uenf.br (I.J.C.)
Abstract: The methanolic extract of the roots of Tabernaemontana catharinensis (Apocynaceae) contain alkaloids with several biological activities. They were separated in a preparative scale using high-speed counter-current chromatography. The optimum solvent system used was composed of a mixture of ethylacetate-n-propanol-water (140:8:80 (v/v/v) and led to a successful separation between two monoterpenic indole alkaloids, voachalotine (1) and 12-methoxyvoachalotine (2) in only 3.5 hours. The purities of alkaloids were all isolated at purity over 95%. Their structures have been established on basis of spectroscopy methods, including 1D and 2D NMR and EI/MS.
Keywords: Counter-current chromatography; Tabernaemontana catharinensis; Alkaloids

Type of the Paper: Review
Title: Molecular Biological and Metabolomic Approaches for Understanding Ephedra Plant-Specific Metabolism
Authors: Taketo Okada et al.
Affiliation: Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, Shido 1314-1, Sanuki-City, Kagawa 769-2193, Japan; E-Mail: okadat@kph.bunri-u.ac.jp
Abstract: Ephedra plants are medicinally important natural resources and the several species contain ephedrine alkaloids as major secondary metabolites. The basic skeleton of ephedrine alkaloids is biosynthesized by the condensation of a C6-C1 unit derived from L-phenylalanine and pyruvic acid, which is a donor of a C2 unit. Although the biosynthetic pathway of ephedrine alkaloids was chemically characterized in detail, recently the cloning of a cDNA and the characterization of catalytic enzymes involved in its pathway have been demonstrated. Moreover, the metabolome analyses of Ephedra species, which are based on the multivariate analysis of comprehensive metabolite analysis data, have also been reported. In this review, the recent advances in research on Ephedra plant-specific metabolism are described.

Type of Paper: Review
Title: New Advances with C₂₀-Diterpenoid Alkaloids as Anticancer Agents
Authors: Koji Wada ^1,3, Kuo-Hsiung Lee ²Chin-yu Lai ³ and Kenneth F. Bastow ⁴
Affiliations: ¹ School of Pharmacy, Hokkaido Pharmaceutical University, 7-1, Katsuraoka-cho, Otaru 047-0264, Japan; E-Mail: kowada@hokuyakudai.ac.jp
² Natural Products Research Laboratories, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA and Chinese Medicine Research and Development Center, China Medical University and Hospital, Taichung, Taiwan
³ Natural Products Research Laboratories, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA
⁴ Division of Medicinal Chemistry and Natural Products, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA
Abstract: A large number of diterpenoid alkaloids have been isolated from various species of Aconitum and Delphinium (Ranunculaceae) and are classified according to their chemical structure as C₁₉-diterpenoid alkaloids and C₂₀-diterpenoid alkaloids. The former group includes aconitine, mesaconitine, hypaconitine, and jesaconitine, all having extremely high toxicity, whereas the latter group, including lucidusculine, kobusine, pseudokobusine, and atisine, are far less toxic. The roots of Aconitum plants have been used as "bushi," an herbal drug in some prescriptions of traditional Chinese medicine for the treatment of hypometabolism, dysuria, cardiac weakness, chills, neuralgia, gout, and certain rheumatic diseases. The pharmacological properties of the C₁₉-diterpenoid alkaloids have been studied extensively and reviewed. However, there is little information about the pharmacological properties of the C₂₀-diterpenoid alkaloids and their chemically transformed products.
The cytotoxicity against lung (A549), prostate (DU145), nasopharyngeal (KB), and vincristine-resistant nasopharyngeal (KB-VIN) cancer cell lines was examined for 32 natural diterpenoid alkaloids and 76 semi-synthetic alkaloid derivatives. C₁₉-diterpenoid alkaloids had no activity or only very weak activity. Nine acylated C₂₀-diterpenoid alkaloid derivatives, 11-p-nitrobenzoylkobusine, 11-(p-trifluoromethylbenzoyl)- kobusine, 11-(4-trifluoromethoxylbenzoyl)kobusine, 6,11-dibenzoylpseudokobusine, 11-anisoylpseudokobusine, 11-veratroylpseudokobusine, 15-veratroylpseudokobusine, 6,11-diveratroylpseudokobusine, 6,15-diveratroyl- pseudokobusine, and 11-(p-trifluoromethylbenzoyl)pseudokobusine exhibited more potent activity, while 11,15-dibenzoylkobusine, 11,15-dianisoylkobusine, 11,15-di-p-nitrobenzoylkobusine, 11,15-di-(4-fluoro- benzoyl)kobusine, 11,15-di-(trans-3-trifluoromethylcinnamoyl)kobusine, 11,15-dibenzoylpseudokobusine, 11-p-nitrobenzoylpseudokobusine, 11,15-di-m-nitrobenzoylpseudokobusine, 11-(m-trifluoromethylbenzoyl)- pseudokobusine, 11-cinnamoylpseudokobusine, and 11-tritylpseudokobusine were found to be the most potent cytotoxic agents (ED₅₀ < 3.5 μg/ml).
In the occurrence of cytotoxic effects of atisine-type alkaloids, replacement by an acyl group at both C-11 and C-15 resulted in enhancement of activity of the parent alkaloids compared to those having hydroxy groups at this position, and the presence of a hydroxy group at the C-6 position was required for the cytotoxic effects. 6,11-Diveratroylpseudokobusine and 6,15-diveratroylpseudokobusine appear to be promising new leads for further development into antitumor agents as these compounds exhibited stronger inhibitory activity against KB-VIN cells than KB cells.