Precursor-directed Biosynthesis in Tabernaemontana catharinensis as a New Avenue for Alzheimerʼs Disease-modifying Agents

Abstract

Plants produce a high diversity of metabolites that can act as regulators of cholinergic dysfunction. Among plants, the potential of species of the genus Tabernaemontana to treat neurological disorders has been linked to iboga-type alkaloids that are biosynthesized by those species. In this context, precursor-directed biosynthesis approaches were carried out using T. catharinensis plantlets to achieve new-to-nature molecules as promising agents against Alzheimerʼs disease. Aerial parts of T. catharinensis, cultured in vitro, produced 7 unnatural alkaloids (5-fluoro-ibogamine, 5-fluoro-voachalotine, 5-fluoro-12-methoxy-Nb-methyl-voachalotine, 5-fluoro-isovoacangine, 5-fluoro-catharanthine, 5-fluoro-19-(S)-hydroxy-ibogamine, and 5-fluoro-coronaridine), while root extracts showed the presence of the same unnatural iboga-type alkaloids and 2 additional ones: 5-fluoro-voafinine and 5-fluoro-affinisine. Moreover, molecular docking approaches were carried out to evaluate the potential inhibition activity of T. catharinensis’ natural and unnatural alkaloids against AChE and BChE enzymes. Fluorinated iboga alkaloids (5-fluoro-catharanthine, 5-fluoro-voachalotine, 5-fluoro-affinisine, 5-fluoro-isovoacangine, 5-fluoro-corinaridine) were more active than natural ones and controls against AchE, while 5-fluoro-19-(S)-hydroxy-ibogamine, 5-fluoro-catharanthine, 5-fluoro-isovoacangine, and 5-fluoro-corinaridine showed better activity than natural ones and controls against BChE. Our findings showed that precursor-directed biosynthesis strategies generated “new-to-nature” alkaloids that are promising Alzheimerʼs disease drug candidates. Furthermore, the isotopic experiments also allowed us to elucidate the initial steps of the biosynthetic pathway for iboga-type alkaloids, which are derived from the MEP and shikimate pathways.

Key words

Tabernaemontana catharinensis - Apocynaceae - iboga-alkaloids - Alzheimerʼs - fluorinated analogues - molecular docking - cholinergic dysfunction - cholinesterase inhibitors

Publication History

Received: 02 September 2020

Accepted after revision: 19 November 2020

Article published online:
15 December 2020

• References

• 1 Kim K, Kim MJ, Kim DW, Kim SY, Park S, Park CB. Clinically accurate diagnosis of Alzheimerʼs disease via multiplexed sensing of core biomarkers in human plasma. Nat Commun 2020; 119: 1-9
• 2 Nichols E, Szoeke CE, Vollset SE, Abbasi N, Abd-Allah F, Abdela J, Aichour MTE, Akinyemi RO, Alahdab F, Asgedom SW. Global, regional, and national burden of Alzheimerʼs disease and other dementias, 1990–2016: a systematic analysis for the Global Burden of Disease study 2016. Lancet Neurol 2019; 18: 88-106
• 3 Demetrius LA, Magistretti PJ, Pellerin L. Alzheimerʼs disease: the amyloid hypothesis and the inverse Warburg effect. Front Physiol 2015; 5: 1-20
• 4 Castillo WO, Aristizabal-Pachon AF. Galantamine protects against beta amyloid peptide-induced DNA damage in a model for Alzheimerʼs disease. Neural Regen Res 2017; 12: 916-917
• 5 Hampel H, Mesulam MM, Cuello AC, Khachaturian AS, Vergallo A, Farlow MR, Snyder PJ, Giacobini E, Khachaturian ZS. Revisiting the cholinergic hypothesis in Alzheimerʼs disease: emerging evidence from translational and clinical research. J Prev Alzheimers Dis 2019; 6: 2-15
• 6 Chakravorty A, Jetto CT, Manjithaya R. Dysfunctional mitochondria and mitophagy as drivers of Alzheimerʼs disease pathogenesis. Front Aging Neurosci 2019; 11: 1-16
• 7 Arslan J, Jamshed H, Qureshi H. Early detection and prevention of Alzheimerʼs disease: role of oxidative markers and natural antioxidants. Front Aging Neurosci 2020; 12: 1-7
• 8 Deutsch JA. The cholinergic synapse and the site of memory. Science 1971; 174: 788-794
• 9 Drachman DA, Leavitt J. Human memory and the cholinergic system: a relationship to aging?. Arch Neurol 1974; 30: 113-121
• 10 Hampel H, Mesulam MM, Cuello AC, Khachaturian AS, Vergallo A, Farlow M, Snyder P, Giacobini E, Khachaturian Z. Group CSW. Revisiting the cholinergic hypothesis in Alzheimerʼs disease: emerging evidence from translational and clinical research. J Alzheimerʼs Dis 2019; 6: 1-14
• 11 Darvesh S. Butyrylcholinesterase as a diagnostic and therapeutic target for Alzheimerʼs disease. Curr Alzheimer Res 2016; 13: 1173-1177
• 12 Košak U, Brus B, Knez D, Šink R, Žakelj S, Trontelj J, Pišlar A, Šlenc J, Gobec M, Živin M, Tratnjek L, Perše M, Sałat K, Podkowa A, Filipek B, Nachon F, Brazzolotto X, Więckowska A, Malawska B, Stojan J, Raščan IM, Kos J, Coquelle N, Colletier J-P, Gobec S. Development of an in-vivo active reversible butyrylcholinesterase inhibitor. Sci Rep 2016; 39495: 1-16
• 13 Daoud I, Melkemi N, Salah T, Ghalem S. Combined qsar, molecular docking and molecular dynamics study on new acetylcholinesterase and butyrylcholinesterase inhibitors. Comput Biol Chem 2018; 74: 304-326
• 14 Castillo-Ordóñez WO, Tamarozzi ER, da Silva GM, Aristizabal-Pachón AF, Sakamoto-Hojo ET, Takahashi CS, Giuliatti S. Exploration of the acetylcholinesterase inhibitory activity of some alkaloids from amaryllidaceae family by molecular docking in silico. Neurochem Res 2017; 42: 2826-2830
• 15 Castillo WO, Aristizabal-Pachon AF, Sakamoto-Hojo E, Gasca CA, Cabezas-Fajardo FA, Takahashi C. Caliphruria subedentata (Amaryllidaceae) decreases genotoxicity and cell death induced by β-amyloid peptide in sh-sy5y cell line. Mutat Res 2018; 836: 54-61
• 16 Fawzi MM, Abdallah HH, Suroowan S, Jugreet S, Zhang Y, Hu X. In silico exploration of bioactive phytochemicals against neurodegenerative diseases via inhibition of cholinesterases. Curr Pharm Des 2020; 26: 4151-4162
• 17 Silveira D, De Melo AMMF, Magalhães PO, Fonseca-Bazzo YM. Tabernaemontana species: promising sources of new useful drugs. Stud Nat Prod Chem 2017; 54: 227-289
• 18 Vieira IJC, Medeiros WLB, Monnerat CS, Souza JJ, Mathias L, Braz-Filho R, Epifanio RDA. Two fast screening methods (gc-ms and tlc-chei assay) for rapid evaluation of potential anticholinesterasic indole alkaloids in complex mixtures. An Acad Bras Ciênc 2008; 80: 419-426
• 19 Athipornchai A, Ketpoo P, Saeeng R. Acetylcholinesterase inhibitor from Tabernaemontana pandacaqui flowers. Nat Prod Commun 2020; 15: 1-5
• 20 Garcellano RC, Cort JR, Moinuddin SG, Franzblau SG, Ma R, Aguinaldo AM. An iboga alkaloid chemotaxonomic marker from endemic Tabernaemontana ternifolia with antitubercular activity. Nat Prod Res 2020; 34: 1175-1179
• 21 Masondo N, Stafford G, Aremu A, Makunga N. Acetylcholinesterase inhibitors from Southern African plants: an overview of ethnobotanical, pharmacological potential and phytochemical research including and beyond Alzheimerʼs disease treatment. S Afr J Bot 2019; 120: 39-64
• 22 Seong S, Lim H, Han S. Biosynthetically inspired transformation of iboga to monomeric post-iboga alkaloids. Cell 2018; 5: 353-363
• 23 Andrade MT, Lima JA, Pinto AC, Rezende CM, Carvalho MP, Epifanio RA. Indole alkaloids from Tabernaemontana australis (Müell. Arg) Miers that inhibit acetylcholinesterase enzyme. Bioorg Med Chem 2005; 13: 4092-4095
• 24 Farrow SC, Kamileen MO, Caputi L, Bussey K, Mundy JEA, McAtee RC, Stephenson CRJ, OʼConnor SE. Biosynthesis of an anti-addiction agent from the iboga plant. J Am Chem Soc 2019; 141: 12979-12983
• 25 Pereira PS, França SDC, Oliveira PVA, Breves CMS, Pereira SIV, Sampaio SV, Nomizo A, Dias DA. Chemical constituents from Tabernaemontana catharinensis root bark: a brief NMR review of indole alkaloids and in vitro cytotoxicity. Quim Nova 2008; 31: 20-24
• 26 Nicola C, Salvador M, Gower AE, Moura S, Echeverrigaray S. Chemical constituents antioxidant and anticholinesterasic activity of Tabernaemontana catharinensis . Sci World J 2013; 519858: 1-10
• 27 Mullard A. 2019, FDA drug approvals. Nat Rev Drug Discov 2020; 19: 79-84
• 28 Newman DJ, Cragg GM. Natural products as sources of new drugs over the nearly four decades from 01/1981 to 0/9/2019. J Nat Prod 2020; 83: 770-803
• 29 Runguphan W, OʼConnor SE. Metabolic reprogramming of periwinkle plant culture. Nat Chem Biol 2009; 5: 151-153
• 30 Lopes AA, Chioca B, Musquiari B, Crevelin EJ, França SDC, Da Silva MFDGF, Pereira AMS. Unnatural spirocyclic oxindole alkaloids biosynthesis in Uncaria guianensis . Sci Rep 2019; 9: 1-8
• 31 Sears JE, Boger DL. Total synthesis of vinblastine, related natural products, and key analogues and development of inspired methodology suitable for the systematic study of their structure-function properties. Acc Chem Res 2015; 48: 653-662
• 32 Nicola C, Salvador M, Gower AE, Moura S, Echeverrigaray S. Chemical constituents antioxidant and anticholinesterasic activity of Tabernaemontana catharinensis . Sci World J 2013; 2013: 519858-519868
• 33 Kam TS, Sim KM. Five new iboga alkaloids from Tabernaemontana corymbose . J Nat Prod 2002; 65: 669-672
• 34 Kam TS, Pang HS, Lim TM. Biologically active indole and bisindole alkaloids from Tabernaemontana divaricate . Org Biomol Chem 2003; 1: 1292-1297
• 35 Nakabayahi RM. MassBank of North America. Accessed October 15, 2020 at: https://mona.fiehnlab.ucdavis.edu/
• 36 Qu Y, Easson MEAM, Simionescu R, Hajicek J, Thamm AMK, Salim V, De Luca V. Solution of the multistep pathway for assembly of corynanthean, strychnos, iboga, and aspidosperma monoterpenoid indole alkaloids from 19e-geissoschizine. Proc Natl Acad Sci U S A 2018; 115: 3180-3185
• 37 Caputi L, Franke J, Farrow SC, Chung K, Payne RME, Nguyen T, Dang TT, Carqueijeiro IST, Koudounas K, Bernonville TD, Ameyaw B, Jones DM, Vieira IJC, Courdavault V, OʼConnor SE. Missing enzymes in the biosynthesis of the anticancer drug vinblastine in Madagascar periwinkle. Science 2018; 6394: 1235-1239
• 38 Farrow SC, Kamileen MO, Meades J, Ameyaw B, Xiao XY, OʼConnor SE. Cytochrome P450 and O-methyltransferase catalyze the final steps in the biosynthesis of the anti-addictive alkaloid ibogaine from Tabernanthe iboga . J Biol Chem 2018; 293: 13821-13833
• 39 Farrow SC, Kamileen MO, Caputi L, Bussey K, Mundy JEA, Mcatee RC, Stephenson CRJ, OʼConnor SE. Biosynthesis of an anti-addiction agent from the iboga plant. J Am Chem Soc 2019; 33: 12979-12983
• 40 Ferreira DF. Sisvar: a computer statistical system. Ciênc agrotec 2011; 35: 1039-1042
• 41 Scott AJ, Knott M. A cluster analysis method for grouping means in the analysis of variance. Biometrics 1974; 30: 507-512
• 42 Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissing H, Shindyalov IN, Bourne PE. The protein data bank. Nucleic Acids Res 2000; 28: 235-242
• 43 Jones G, Willett P, Glen RC, Leach AR, Taylor R. Development and validation of a genetic algorithm for flexible docking. J Mol Bio 1997; 267: 727-748
• 44 Banerjee P, Eckert AO, Schrey AK, Preissner R. Protox-II: a webserver for the prediction of toxicity of chemicals. Nucleic Acids Res 2018; 46: 257-263
• 45 Daina A, Michielin O, Zoete V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep 2017; 7: 1-13