Quinoline and isoquinoline alkaloids: natural sources and biological activities.
The alkaloids are a family of compounds widely found in nature. Therefore, they They are nitrogenous secondary metabolites heterocyclic derivatives of amino acids or by the transamination process, which confers basic character .
The term alkaloid, linguistically derived from the Arabic
Since the dawn of civilization, there are reports of the use of plant extracts containing alkaloids for various purposes. The death of Socrates in 399 BC, for example, was attributed to the consumption of the extract of
Several alkaloids (papaverine, morphine, and cocaine) can cause different stimuli in the nervous system of an animal; a common phenomenon in ecological relationships may constitute, for example, a defense mechanism by plants against herbivores .
The importance of alkaloids in the development of medicine is unquestionable since several advances made in the battle against diseases like malaria, leukemia, cancer, and neurodegenerative diseases would not have occurred without the use of these substances .
This chapter focuses on the occurrence occurring, chemistry, and biological activity of the quinoline and isoquinoline alkaloids, including the angustureine and congeneric alkaloids.
2. Quinoline and isoquinoline alkaloids
Among the various classes of alkaloid compounds, this section highlights the quinoline and isoquinoline alkaloids. They were originally obtained from natural sources, whose remarkable biological activities and relatively simple structures have attracted great interest in the scientific community, especially researchers involved in the chemistry of natural products. However, these compounds have also attracted the interest of synthetic organic chemists due to the need to obtain increased amounts aimed at additional biological research, as well as in developing efficient synthetic routes for these alkaloids and their derivatives, whose chemical and biological properties could become greatly enhanced by the design of new structures from these modifications.
2.1. Methods of extraction of quinoline and isoquinoline alkaloids
The general method for extracting and isolating alkaloids from plants consists of an acid-base extraction. The dried and pulverized plant is extracted with organic solvents or with acidified water. When the extraction is carried out with organic solvents immiscible with water, the plant sample is alkalized prior to being extracted. For this, the sample is wrapped in filter paper, as a cartridge, humidified with dilute basic solution, e.g., ammonium hydroxide, and extracted under heating using Soxhlet apparatus with organic solvent such as ethyl ether, chloroform, or dichloromethane. After extraction, the solvent volume is reduced by half in rotary evaporator under reduced pressure. The remaining volume of the solvent containing the alkaloid residue is transferred to a separatory funnel and extracted with aqueous phosphoric acid solution (pH 1 to 2) or hydrochloric acid. The wetting of the plant sample with basic solution allows the alkaloids are released from organic acids, thus facilitating its extraction by organic solvents. Meanwhile, when using an acidified solution, alkaloids tend to form salts with these strong acids, facilitating their removal from the two-phase system, water-solvent for the separation of these into the aqueous phase .
Another extraction technique uses polar solvent such as ethanol, for example. However, if a plant contains a high amount of lipids, a preextraction with a nonpolar solvent such as hexanes or petroleum ether is necessary for removing these lipids. Next, the organic solvent is concentrated under reduced pressure and the residue solubilized in water . As most alkaloids are basic or are found in salt form, aqueous solutions of phosphoric acid (pH 1 to 2) or hydrochloric acid are used for their removal. Neutral amide alkaloids, such as colchicine and piperine (Figure 1), remain in the organic phase when treated with an organic solvent (usually ethyl acetate) during the extraction process, while most of the other alkaloids may be extracted using an organic solvent only after neutralization of the aqueous phase with a base .
Generally, the crude extract is purified by column chromatography (CC), employing silica gel or alumina as the stationary phase and a mixture of appropriate solvents as the mobile phase, following an appropriate choice made via thin layer chromatography (TLC). Often, alkaloids still need additional purification by recrystallization, employing solvent systems such as ethanol/water, methanol/chloroform, or acetone/methanol .
While these techniques are successful to extract and to isolate most alkaloids, for those highly water soluble and, therefore, partially or totally insoluble in organic solvents, these methods are not appropriates .
Although generally higher solubility in aqueous solutions involves greater bioactivities , the employment of more suitable methods for the extraction of highly water-soluble alkaloids is very useful.
In the case of quaternary alkaloids, the residual aqueous solution should be tested with a reagent suitable for the detection of alkaloids (Dragendorff reagent, for example) after completion of conventional partition methods. If it is positive, one should employ methods such as direct crystallization, precipitation as insoluble salts, extraction with polar solvent water-immiscible, or formation of pseudobases to extract the alkaloids from the aqueous phase .
The methods employed to extract most common polyhydroxylated alkaloids are the direct extraction and ion exchange chromatography .
After extraction of alkaloids, a quantitative analysis that may be performed by traditional methods such as simple weighing or base titration after dilution under acidic conditions is recommended. Other widely used techniques for the quantification of alkaloids are by employing the HPLC apparatus with UV detection and by testing the refractive index depending on the structure of the isolated compound(s) .
2.2. Occurrence in nature of quinoline and isoquinoline alkaloids
The quinoline and isoquinoline alkaloids were initially extracted from coal tar in 1834 and 1835, respectively. Quinoline, which has high boiling temperature, is commonly employed in organic synthesis as a solvent. Isoquinoline has a low melting temperature and both have moderate basicity (p
Although the vast majority of quinoline and isoquinoline alkaloids derived from flowered plants, they can also be isolated from animals and microorganisms, some representative examples are given in Table 1 .
2.3. Biosynthetic origin of quinoline and isoquinoline alkaloids
The most One of the systems used for the classification of alkaloids is based on the kind of nitrogen heterocycle in the structure and its botanical origin (plant family which is extracted); thus, the name given to an alkaloid derived from the genus or species of organism produced, including the term “ine.” Another commonly used system takes into account its precursor amino acid. Thus, alkaloid derivatives of tryptophan and tyrosine are biosynthetically classified as quinoline and isoquinoline, respectively (Figure 3) .
Thus, quinoline alkaloids are derived from 3-hydroxyanthranilic acid, a metabolite formed from tryptophan through a sequence of enzymatic reactions (Figure 4). The condensation between 3-hydroxyanthranilic acid and malonyl-SCoA, followed by cyclization, produces quinoline alkaloid (Figure 4) [8-10].
In the case of isoquinoline systems, the biosynthesis proceeds from the cyclization of the Schiff base formed between the dopamine and an aliphatic aldehyde . Dopamine is obtained from the hydroxylation and decarboxylation of tyrosine. A second intermediate,
2.4. Biological activities of quinoline and isoquinoline alkaloids
In addition to the biological activities shown in Table 1, many quinoline alkaloids and their analogues represent the most important drugs currently used to combat malaria, with chloroquine, amodiaquine, piperaquine, primaquine, quinine, and mefloquine (Figure 6) being the most representative drugs of this group . Even today, many studies are still being conducted to increase the efficiency of quinoline derivatives such as AZT-chloro-quinoline, quinine-dihydroartemisinin, and MEFAS, a salt derived from mefloquine and artesunate  (Figure 7).
On the other hand, the quinoline nucleus has also demonstrated a critical role in the development of new anticancer drugs. Some of its derivatives showed excellent results on various types of cancer cells, through different mechanisms of action. Recently, three protein kinase inhibitors (Bosutinib, Lenvatinib, and Cabozantinib) and an inhibitor of farnesyltransferase (Tipifarnib) (Figure 8), considered as potential anticancer agents, entered into phase of clinical trials .
Knowing that functionalized quinolines have also shown high anti-carcinogenic potential, in addition to acting as anti-angiogenic agents, and inhibitors of telomerase in various human tumor cells, Muñoz and coworkers  selected the DM8 and DM12 tetrahydroquinolines (Figure 9) for testing cytotoxic activity. They observed that individually these compounds significantly inhibited cell growth of breast cancer, and when tested concomitantly with other two anticancer drugs, they work synergistically to increase their cytotoxic activities. The results obtained for the DM12 quinoline made this compound a promising candidate as a new adjunctive anticancer agent.
Furthermore, Villemagne and Okamura  obtained promising results with other quinoline derivatives used as selective ligands for Tau proteins, associated with brain damage, which represent a risk factor for diseases such as Alzheimer’s, which allowed the investigation of the causes, diagnosis, and treatment of neurodegenerative diseases, encephalopathy, and traumatic brain injury.
Biological activities of hundreds of other substituted quinolines have been reported, many of which are promising in terms of their potential as pharmaceutical agents. 2-Methyl-5-hydroxy-1,2,3,4-tetrahydroquinoline exhibits analgesic activity with a potency one-eighth that of morphine . 1,2,3,4-Tetrahydroquinoline-4-carboxylic acid is used in tissue-irrigating solutions . A wide array of other biological activities have been reported, including
In addition to the numerous utilities in the pharmacological area, studies are being performed in order to investigate the potential activities of these alkaloids as agrochemical agents. Sanguinarine and chelerythrine (Figure 10), for example, have shown high activity against fungi and phytopathogenic bacteria
3. Tetrahydroquinoline alkaloids angustureine, galipeine, galipinine, and cuspareine
Among the simplest natural alkaloids that contain the 1,2,3,4-tetrahydroquinoline core are angustureine and its congeners, galipeine, cuspareine, and galipinine (Figure 11). The structures are more narrowly described as 2-alkyl-1-methyl-1,2,3,4-tetrahydroquinolines. They are chiral by virtue of the stereogenic center at position 2. There is an excellent review of the chemistry and synthesis of 1,2,3,4-tetrahydroquinolines by Diaz and Dudley .
In 1999, Jacquemond-Collet and coworkers  isolated and characterized these four tetrahydroquinoline alkaloids (Figure 11) from the extract of the bark of
In later trials, galipinine and galipeine exhibited promising biological activities
Due to their structural simplicities associated with the promising pharmacological activities, these alkaloids, especially angustureine, have attracted the attention of the synthetic organic community. For this alkaloid alone, more than 24 different syntheses have already been described [62-85]. Some recent examples of the syntheses of these alkaloids are described below.
In turn, Lam
4. Concluding remarks
This chapter is an illustration of the fascinating world of chemistry of quinoline and isoquinoline alkaloids. The range of pharmacological and agrochemical activities, among others, associated with their biosynthetic routes and various natural sources demonstrates the creative universe of the nature of these alkaloids. This universe of compounds arouses interest to organic chemists in general, stimulated by the simplicity and its varied forms of exploitation throughout constant search for the discovery of novel pharmacological agents targeting the treatment of several diseases that affect society.
5. Future directions
In this chapter, we can verify the importance of quinoline and isoquinoline alkaloids due to their potent biological activities demonstrated by
The authors are grateful to CAPES and FAPEMIG for their financial support.
Aniszewski T. Alkaloids—Secrets of Life. Amsterdam: Elsevier Academic Press; 2007.
Kutchan TM. Alkaloid biosynthesis—the basis for metabolic engineering of medicinal plants. Plant Cell 1995;7(7) 1059-1070.
Ruiz PG. Productos Naturales. Pamplona: Universidad Pública de Navarra; 2002.
Mann J, Davidson RS, Hobbs JB, Banthorpe DV, Harborne JB. Natural Products: Their Chemistry and Biological Significance. London: Longman Scientific & Technical; 1996.
Simões CMO. Farmacognosia—Da planta ao medicamento. Editoras UFRGS e UFSC; 2010.
Colegate SM, Molyneus RJ. Bioactive Natural Products: Detection, Isolation and Structural Determination. Boca Raton, Florida: CRC Press; 1993.
Majumdar KC, Chattopadhyay SK. Heterocycles in Natural Product Synthesis. Singapura: Wiley-VCH; 2011.
Mann J. Secondary Metabolism. Oxford: Clarendon Press; 2005.
Souza MVN, Almeida MV, Hyaric M, Cardoso SH, Amarante WG. Métodos de preparação e atividade biológica do ácido quinolínico e derivados. Química Nova 2003;26(5) 694-698.
Sultana N. Medicinal properties and biosynthetic studies on indigenous medicinal plant Skimmia laureola. Critical Review in Pharmaceutical Sciences 2013;2(2) 13-42.
Civjan N. Natural Products in Chemical Biology. Hobokey, New Jersey: John Wiley & Sons; 2012.
Kaur K, Jain M, Reddy RP, Jain R. Quinolines and structurally related heterocycles as antimalarials. European Journal of Medicinal Chemistry 2010;45(8) 3245-3264.
Boechat N, Ferreira MLG, Pinheiro LCS, Jesus AML, Leite MMM, Junior CCS, Aguiar ACC, Andrade IM, Krettli AU. New Compounds Hybrids 1 H-1,2,3-Triazole-Quinoline Against Plasmodium falciparum. Chemical Biology and Drug Design 2014;84(3) 325-332.
Afzal O, Kumar S, Haider MR, Ali MR, Kumar R, Jaggi M, Bawa S. A review on anticancer potential of bioactive heterocycle quinoline. European Journal of Medicinal Chemistry 2014. DOI: 10.1016/j.ejmech.2014.07.044. In press.
Muñoz A, Sojo F, Arenas DRM, Kouznetsov VV, Arvelo F. Cytotoxic effects of new trans-2,4-diaryl-r-3-methyl-1,2,3,4-tetrahydroquinolines and their interaction with antitumoral drugs gemcitabine and paclitaxel on cellular lines of human breast cancer. Chemico-Biological Interactions 2011;189(3) 215-221.
Villemagne VL, Okamura N. In vivotau imaging: obstacles and progress. Alzheimer’s and Dementia 2014;10(3) 254-264.
Ferranti A, Garuti L, Giovanninetti G, Gaggi R, Roncada P, Nardi P. Preparation and analgesic activity of tetrahydroquinolines and tetrahydroisoquinolines. Farmaco Edizione Scientifica 1987;42(4) 237-249.
LeClerc G, Ruhland B, Andermann G, De Burlet G, Dietz M. For controlling tissue stability during eye surgery: antiswelling agent 1990; US Patent US 4,952,573, 1990.
Uchida M, Chihiro M, Morita S, Kanbe T, Yamashita H, Yamasaki K, Yabuuchi, Y, Nakagawa K. Studies on proton pump inhibitors. II. Synthesis and antiulcer activity of 8-[(2-benzimidazolyl)sulfinylmethyl]-1,2,3,4-tetrahydroquinolines and related compounds. Chemical and Pharmaceutical Bulletin 1989;37(8) 2109-2116.
Gracheva IN, Gridneva LI, Tochilkin AI, Gorkin VZ. Hydrazides and sulfonyl hydrazides from the series of quinoline are human serum amine oxidase inhibitors. Khimiko -Farmatsevticheskii Zhurnal 1988;22(11) 1336-1339.
Miller KE, Huang CT, Portlock DE, Wright GC. Angiotensin I converting enzyme inhibitors containing unnatural alpha-amino acid analogues of phenylalanine. Life Sciences 1987;40(1) 63-70.
Stevens RW, Ikeda T, Wakahayashi H, Nakane M. Antiinflammatory hydroxamic acids and N-hydroxyureas. US Patent 1993; US 5,256,789.
Kihara N, Tomino I, Tan H, Ishihara T. Novel nitrogen-containing compound. European Patent 1988; EP 0289.36.5.
Kojima E, Saito K. Cyclic anthranilic acid derivatives as therapeutic agents for treatment of metabolic bone disease. European Patent 1990; EP 402859.
Youssefyeh RD, Magnien E, Lee TDY, Chan WK, Lin CJ, Galemmo JrRA, Johnson JrWH, Tan J, Campbell HF, Huang FC, Nuss GW, Carnathan GW, Sutherland CA, Van Inwegen RG. Development of a novel series of (2-quinolinylmethoxy)phenyl-containing compounds as high-affinity leukotriene receptor antagonists. 1. Initial structure-activity relationships. Journal of Medicinal Chemistry 1990;33(4) 1186-1194.
Paris D, Cottin M, Demonchaux P, Augert G, Dupassieux P, Lenoir P, Peck MJ, Jasserand D. synthesis, structure-activity relationships, and pharmacological evaluation of pyrrolo[3,2,1-ij]quinoline derivatives: potent histamine and platelet activating factor antagonism and 5-lipoxygenase inhibitory properties. potential therapeutic application in asthma. Journal of Medicinal Chemistry 1995;38(4) 669-685.
Rauckman BS, Tidwell MY, Johnson JV, Roth B. 2,4-Diamino-5-benzylpyrimidines and analogs as antibacterial agents. 10. 2,4-Diamino-5-(6-quinolylmethyl)- and -[(tetrahydro-6-quinolyl)methyl]pyrimidine derivatives. Further specificity studies. Journal of Medicinal Chemistry 1989;32(8) 1927-1935.
Ogawa H, Miyamoto H, Kondo K, Yamashita H, Nakaya K, Komatsu H, Tanaka M, Takara S, Tominaga M, Yabuchi Y. Preparation of N-benzoyl benzo-fused heterocyclic compounds as vasopressin antagonists. Kokai Tokkyo Koho 1992; JP 04321669.
Bigg D, Mangane M. Tetrahydroquinoline derivatives, their preparation and their therapeutic application 1986; France Patent FR 2,576,308.
Nagasaka T, Kosugi Y, Kawahara T, Kakimoto M, Tamuru K, Hirata A. Preparation of 1,4-dihydro-4-phenyl-3,5-pyridinedicarboxylic acids as calcium antagonists 1993. Japanese Patent 05,339,263.
Moon MW, Morris JK, Heier RF, Chidester CG, Hoffmann WE, Piercey MF, Althaus JS, VonVoigtlander PF, Evans DL, Figur LM, Lahti RA. Dopaminergic and serotonergic activities of imidazoquinolinones and related compounds. Journal of Medicinal Chemistry 1992;35(6) 1076-1092.
Moon MW, His RSP. Synthesis of ( R)-5-(Di[2,3-3H2]propylamino)5,6-dihydro-4 H-imidazo[4,5,1- ij]quinolin-2(1 H)-one ([3H]U-86170) and ( R)-5-([2,3-3H2]Propylamino)-5,6-dihydro-4 H-imidazo[4,5,1- ij]quinolin-2(1 H)-one ([3H]U-91356). Journal of Labelled Compounds and Radiopharmaceuticals 1992;31(11), 933-943.
Buzas A, Ollivier R, El Ahmad Y, Laurent E. 1,4-Dialkylpiperazine derivatives, method for obtaining them, and pharmaceutical compositions containing them. PCT International Applications 1993; WO 9316057.
Agarwal SK, Saxena AK, Jain PC, Sur RN, Srimal RC, Dhawan BN, Anand N. Synthesis and structure activity relationship in 1-aryloxy-3-[ N′-N4-arylpiperazinyl)] propanes. Indian Journal of Chemistry, Section B 1987; 26B, 642-646.
Uchida M, Chihiro M, Morita S, Yamashita H, Yamasaki K, Kunbe T, Yabuuchi Y, Nakagawa K. Synthesis and antiulcer activity of 4-substituted 8-[(2-benzimidazol)sulfinylmethyl]-1,2,3,4-tetra-hydroquinolines and related compounds. Chemical and Pharmaceutical Bulletin 1990;38(6) 1575-1586.
Uchida M, Morita S, Chihiro M. Preparation of 8-[(2-benzimidazolylthio)alkyl]hydroquinolines and their sulfoxides as antiulcer agents. European Patent 1987; EP 239129.
Atwal K. Indanyl- and quinolylureas and related compounds as cardiovascular agents. European Patent 1992; EP 488616.
Santangelo F, Casagrande C, Miragoli G, Vecchietti V. Synthesis and positive inotropic effect of 1-alkyl- and 1-acyl-6,7-dimethoxy-3-dimethylamino-1,2,3,4-tetrahydroquinolines. European Journal of Medicinal Chemistry 1994;29(11), 877-882.
Galtier D, Lassalle G. Preparation of 1,2,3,4-tetrahydroquinolin-8-sulfonic acid and its chlorides as intermediates for antithrombotics. European Patent 1995; EP 643046.
Lassalle G, Galtier D, Galli F. Preparation of 1-[2-amino-5-[1-(triphenylmethyl)-1H-imidazol-4-yl]-1-oxopentyl]piperidines and their use as intermediates for antithrombotics. European Patent 1995; EP 643047.
Baumgarth M, Lues I, Minck KO, Beier N. Preparation of (benzocyclylethyl)arylpiperidines and -piperazines for treating arrhythmia and tachycardia. German Patent 1995; DE 4321366.
Biller SA, Misra RN. Inhibitors of leukotriene biosynthesis in macrophage cells. US Patent US 4,843,082, 1989.
Lukevics E, Lapina T, Segals I, Augustane I, Verovskii VN. synthesis and antiblastic activity of organosilicon derivatives of quinoline, isoquinoline, and n-methylpiperazine. Khimiko-Farmatsevticheskii Zhurnal 1988;22(8) 619-623.
Kohno Y, Kojima E. Preparation of 1,2,3,4-tetrahydroquinoline-4,8-dicarboxylates as drugs. European Patent 1990; EP 403980.
Kohno Y, Awano K, Ishizaki T, Kojima E, Kudoh S, Sekoe Y, Saito K. Preparation of tetrahydroquinoline acetic acid derivatives as immunosuppressants. PCT International Applications 1992; WO 9218482.
Kohno Y, Kojima E, Saito K, Kudoh S, Sekoe Y. Preparation of tetrahydroquinolines as immunosuppressants and inflammation inhibitors. Kokai Tokkyo Koho 1994; JP 06 56788.
Carling RW, Leeson PD, Moseley AM, Smith JD, Saywell K, Triclebank MD, Kemp JA, Marshall GR, Foster AC, Grimwood S. Anticonvulsant activity of glycine-site NMDA antagonists. 2. trans2-carboxy-4-substituted tetrahydroquinolines. Bioorganic and Medicinal Chemistry Letters 1993;3(1) 65-70.
Sangwan NK, Malik MS, Dhindsa KS. Synthesis of 3-benzyl-1,2,3,4-tetrahydro-7-methoxy-4-[4-(2-pyrolidinoethxy)phenyl]-1-tosylquinolines as potential antifertility agentes. Chimica Acta Turcica 1985;13(1) 129-134.
Stevenson GL, Leeson PD, Rowley M, Sanderson I, Stansfield I. Synthesis of cisand trans4-amido 2-carboxytetrahydroquinolines, high affinity ligands at the glycine site of the NMDA receptor. Bioorganic and Medicinal Chemistry Letters 1992;2(5) 371-374.
Regnier G, Guillonneau C, Lepagnol J, Lestage P. Morpholine derivatives, process for their preparation and pharmaceutical compositions containing them for treatment of cerebral conditions. European Patent 1991; EP 427605.
Boursier-Neyret C, Baune A, Klippert P, Castagne I, Sauveur C. Determination of S12024 enantiomers in human plasma by liquid chromatography after chiral pre-column derivatization. Journal of Pharmaceutical and Biomedical Analysis 1993;11(11-12) 1161-1166.
Ventura C, Miller R, Wolf HP, Beier N, Jonas R, Klockow M, Lues I, Hano O, Spurgeon HA, Lakatta EG, Capogrossi MC. Novel diazinone derivatives separate myofilament Ca2+ sensitization and phosphodiesterase III inhibitory effects in guinea pig myocardium. Circulation Research 1992;70(6) 1081-1090.
Regnier G, Guillonneau C, Lepagnol J. Preparation of (morpholinylmethoxy) tetrahydroquinoline derivatives as drugs for treatment of cerebral ischemia. European Patent 1988; EP 286495.
Kohno Y, Saito K, Sekoe Y, Kojima E. Preparation of 6-aryl-cyclic anthranilic acids and their use as therapeutics for treatment of metabolic bone disorder. Japanese Patent 1992; JP 04316557.
Cantrell CL, Dayan FE, Duke SO. Natural products as sources for new pesticides. Journal of Natural Products 2012;75(6) 1231-1242.
Diaz MG, Dudley BG. Synthesis of 1,2,3,4-tetrahydroquinolines including angustureine and congeneric alkaloids. Organic Preparations and Procedures International, 2014. In press.
Jacquemond-Collet I, Hannedouche S, Fabre N, Fourasté I, Moulis C. Two tetrahydroquinoline alkaloids from Galipea officinalis. Phytochemistry 1999;51(8) 1167-1169.
Taylor LL, Goldberg FW, Hii KK. Asymmetric synthesis of 2-alkyl-substituted tetrahydroquinolines by an enantioselective aza-Michael reaction. Organic Biomolecular Chemistry 2012;10(22) 4424-4432.
Jacquemond-Collet I, Benoit-Vical F, Mustofa Valentin A, Stanislas E, Mallié M, Fourasté I. Antiplasmodial and cytotoxic activity of galipinine and other tetrahydroquinolines from Galipea officinalis.Planta Medica 2002;68(1) 68-69.
Houghton PJ, Watabe Y, Woldemariam TZ, Yates M. Activity of alkaloids from Angostura bark against Mycobacterium tuberculosis. Journal of Pharmacy and Pharmacology, 1998;50(S9) 230.
Osório EJ, Robledo SM, Bastida J. The Alkaloids: Chemistry and Biology. Amsterdam: Elsevier Academic Press; 2008.
Wang WB, Lu SM, Yang PY, Han XW, Zhou YG. Highly enantioselective iridium-catalyzed hydrogenation of heteroaromatic compounds, quinolines. Journal of American Chemical Society 2003;125(35) 10536-10537.
Avemaria F, Vanderheiden S, Braese S. The aza-xylylene Diels-Alder approach for the synthesis of naturally occurring 2-alkyl tetrahydroquinolines. Tetrahedron 2003;59(35) 6785-6796.
Lin XF, Li Y, Ma DW. Total synthesis of tetrahydroquinoline alkaloid (+)-angustureine. Chinese Journal of Chemistry 2004;22(9) 932-934.
Theeraladanon C, Arisawa M, Nakagawa M, Nishida A. Total synthesis of (+)-(S)- angustureine and the determination of the absolute configuration of the natural product angustureine. Tetrahedron: Asymmetry 2005;16(4) 827-831.
Lu SM, Wang YQ, Han XW, Zhou YG. Asymmetric hydrogenation of quinolines and isoquinolines activated by chloroformates. Angewandte Chemie International Edition 2006;45(14) 2260-2263.
Rueping M, Antonchick AP, Theissmann T. A highly enantioselective Bronsted acid catalyzed cascade reaction: organocatalytic transfer hydrogenation of quinolones and their application in the synthesis of alkaloids. Angewandte Chemie International Edition 2006;45(22) 3683-3686.
Ryu JS. Hydroarylation for the facile synthesis of 2-substituted tetrahydroquinoline: a concise synthesis of (+)-( S)-angustureine. Bulletin of the Korean Chemical Society 2006;27(5) 631-632.
Patil NT, Wu H, Yamamoto Y. A route to 2-substituted tetrahydroquinolines via palladium-catalized intramolecular hydroamination of aniline-alkynes. Journal of Organic Chemistry 2007;72(17) 6577-6579.
O’Byrne A, Evans P. Rapid synthesis of the tetrahydroquinoline alkaloids: angustureine, cuspareine and galipinine. Tetrahedron 2008;64(35) 8067-8072.
Shahane S, Louafi F, Moreau J, Hurvois JP, Renaud JL, Van de Weghe P, Roisnel, T. Synthesis of alkaloids of Galipea officinalis by alkylation of an α-amino nitrile. European Journal of Organic Chemistry 2008;2008(27) 4622-4631.
Fustero S, Moscardó J, Jiménez D, Pérez-Carrión MD, Sánchez-Roselló M, del Pozo C. Organocatalytic approach to benzofused nitrogen-containing heterocycles: Enantioselective total synthesis of (+)-angustureine. Chemistry a European Journal 2008;14(32) 9868-9872.
Wang ZJ, Zhou HF, Wang TL, He YM, Fan QH. Highly enantioselective hydrogenation of quinolones under solvent-free or highly concentrated conditions. Green Chemistry 2009;11(6) 767-769.
Kothandaraman P, Foo SJ, Chan PW. H. Gold-catalyzed intramolecular allylic amination of 2-tosylaminophenylprop-1-en-3-ols. A concise synthesis of (±)-angustureine. Journal of Organic Chemistry 2009;74(16) 5947-5952.
Chen BL, Wang B, Lin GQ. Highly diastereoselective addition of alkynylmagnesium chlorides to N-tert-butanesulfinyl aldimines: a practical and general access to chiral α-branched amines. Journal of Organic Chemistry 2010;75(3) 941-944.
Cruz-Lopez O, Nunez MC, Conejo-Garcia A, Kimatrai M, Campos JM. Syntheses of 2,3-dihydro-1,4-benzodioxins and bioisosteres as structural motifs for biologically active compounds. Current Organic Chemistry 2011;15(6) 869-887.
Bentley SA, Davies SG, Lee JA, Roberts PM, Thomson JE. Conjugate addition of lithium N-phenyl-N-( α-methylbenzyl)amide: application to the asymmetric synthesis of (R)-( -)-angustureine. Organic Letters 2011;13(10) 2544-2547.
Wang T, Zhuo LG, Li Z, Chen F, Ding Z, He Y, Fan QH, Xiang J, Yu ZX, Chan ASC. Highly enantioselective hydrogenation of quinolones using phosphine-free chiral cationic ruthenium catalysts: scope, mechanism, and origin of enanioselectivity. Journal of the American Chemical Society 2011;133(25) 9878-9891.
Satyanarayana G, Pflästerer D, Helmchen G. Enantioselective synthesis of tetrahydroquinolines based on iridium-catalyzed allylic substitutions: total synthesis of (+)-angustureine and ( -)-cuspareine. European Journal of Organic Chemistry 2011;2011(34) 6877-6886.
Ye KY, He H, Liu WB, Dai LX, Helmchen G, You SL. Iridium-catalyzed allylic vinylation and asymmetric allylic amination reactions with o-aminostyrenes. Journal of the American Chemical Society 2011;133(46) 19006-19014.
Taylor LL, Goldberg FW, Hii KK. Asymmetric synthesis of 2-alkyl-substituted tetrahydroquinolines by an enantioselective aza-Michael reaction. Organic and Biomolecular Chemistry 2012;10(22) 4424-4432.
Tummatorn J, Diaz MG, Dudley GB. Synthesis of ( -)-(R)-aungustureine by formal alkynylation of a chiral β-amino ester. Tetrahedron Letters 2013;54(10) 1312-1314.
Diaz G, Diaz MAN, Reis MA. Enantioselective synthesis of both (-)-( R)- and (+)-( S)-angustureine controlled by enzymatic resolution. Journal of the Brazilian Chemical Society 2013;24(9) 1497-1503.
Sirvent JA, Foubelo F, Yus M. Enantioselective synthesis of tetrahydroquinoline alkaloids (-)-angustureine and (-)-cuspareine from chiral tert-butanesulfinyl imines. Heterocycles 2014;88(2) 1163-1174.
Sirvent JA, Foubelo F, Yus M. Stereoselective synthesis of indoline, tetrahydroquinoline, and tetrahydrobenzazepine derivatives from o-bromophenyl N-tert-butylsulfinyl aldiminas. Journal of Organic Chemistry 2014;79(3) 1356-1367.
Katayama S, Ae N, Nagata R. Enzymatic resolution of 2-substituted tetrahydroquinolines. Convenient approaches to tricyclic quinoxalinediones as potent NMDA-glycine antagonists. Tetrahedron: Asymmetry 1998;9(24) 4295-4299.
Nagata R, Tanno N, Kodo T, Ae N, Yamaguchi H, Nishimura T, Antoku F, Tatsuno T, Kato T, Yanaka Y, Nakamura M. Tricyclic quinoxalinediones: 5,6-dihydro-1H-pyrrolo[1,2,3-de]quinoxaline-2,3-diones and 6,7-Dihydro-1H,5H-pyrido[1,2,3-de]quinoxaline-2,3-diones as potent antagonists for the glycine binding site of the NMDA receptor. Journal of Medicinal Chemistry 1994;37(23) 3956-3968.
Lam K, Lee KK, Gambari R, Wong RS, Cheng GY, Tong S, Chan K, Lau F, Lai PB, Wong W, Chan AS, Kok SH, Tang JC, Chui C. Preparation of Galipea officinalisHancock type tetrahydroquinoline alkaloid analogues as anti-tumor agents. Phytomedicine 2013;20(2) 166-171.