Chemistry:Indoloquinolizidine alkaloids

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Short description: Chemical group of natural compounds
File:Indoloquinolizidine ABCD.svg
Indoloquinolizidine, basic skeleton of indoloquinolizidine alkaloids. The letters ABCD represent cycles
File:Yohimban num.svg
Numbered structure of yohimban

Indoloquinolizidine alkaloids — is a chemical group of monoterpene indole alkaloids, natural compounds of heterocyclic, tetracyclic, or pentacyclic structure, which are derivatives of indoloquinolizidine. Their structure consists of fused indole and quinolizidine systems that are divided into ABCD rings, which can be complicated by additional carbocycles. Classic examples of this group are the pentacyclic alkaloid yohimbine and rauhimbine. Among others, reserpine is also a compound containing an indolo[2,3-a]quinolizidine fragment with an additional substitution.

Classification

Mitragynine is a representative of indoloquinolizidine alkaloids, where substitution occurs in 2 cycles.
File:Tacaman-type alkaloid.png
Tacaman-type alkaloid
Strychnos-type alkaloid

Depending on the spatial orientation of the hydrogen atom at C-3 and the unshared electron pair of nitrogen N-4, indoloquinolizidine alkaloids are divided into trans-articulated isomers (having a rigid planar structure) and cis-articulated isomers (with a pronounced spatial bend in the molecule), indoloquinolizidines are related to tryptoline compounds because the chemical structure of indoloquinolizidines contains a completely preserved three-ring tetrahydro-β-carboline core (rings A, B, and C), which is additionally condensed with a piperidine or other carbon ring (forming ring D), yohimban is an indoloquinolizidine that has been fused with an additional six-membered carbocycle at positions C-15 and C-20, resulting in a rigid pentacyclic system (rings A, B, C, D, E) that serves as the basic scaffold for yohimbine, reserpine, and their isomers. According to the nature of substitution, compounds are divided into those in which substitution occurs only in the carbocycle E, and compounds in which substitution occurs both in the carbocycle E and in the benzene ring A; they can be called "substituted indoloquinolizidines"; substitution most often occurs in position 16, 17 and 18 on the ring E, and in position 9 on the ring A, this is most often an ester or methoxyl group; in reserpine it is residue 3,4,5-trimethoxybenzoic acid, some compounds differ in functional groups, therefore, within the general group, other subgroups of compounds are distinguished based on the isolation method and chemical structure; it is permissible to apply the terms "types of alkaloids" to them; among many examples, these include pentacyclic alkaloids of the tacaman-type, corynanthe-type or alkaloids of the ajmaline-type; The term “structural type” is more often used for them, describing certain subtypes within large types, although compounds are more often combined into general types according to their biosynthetic origin, so the alkaloid strychnine forms an independent "strychnos-type" of alkaloids, which is a variety of corynanthe-type, since its precursor in biosynthesis is strictosidine, which is characteristic in the biosynthesis of almost every corynanthe-type compound. Is important to note that strychnine does not belong to the indoloquinolizidine alkaloids.[1] Indoloquinolizidine alkaloids is generally considered an umbrella term, and therefore can include any compounds that retain the indolo[2,3-a]quinolizidine framework in their structure.

Natural occurrence

Indoloquinolizidine alkaloids are common within families such as Apocynaceae, Rubiaceae, and Loganiaceae, and are isolated from plants of the genera Rauwolfia,[2] Corynanthe [3](and the sometimes isolated genus Pausinystalia), Mitragyna,[4] Vinca,[5] Tabernaemontana,[6] Kopsia,[7] Hunteria,[8] Melodinus,[9][10] Catharanthus,[11] Leuconotis,[12][13] Uncaria,[14] Alstonia,[15] Ochrosia,[16] Aspidosperma,[17] Picralima,[18] Amsonia,[19] Strychnos.[20][21]

The most famous sources of plant material include the species Yohimbine tree (Pausinystalia johimbe)[22] where the main source is the bark of the tree containing yohimbine (up to 0.56 mg/g).[23]

Biosynthesis

Corynanthe-type

Indoloquinolizidine alkaloids of the corynanthe-type are biosynthesized in plants of the Apocynaceae, Loganiaceae, and Rubiaceae families by enzymatic Pictet-Spengler condensation between tryptamine and secologanin to form the universal precursor strictosidine, which, after deglycosylation by the SGD protein, spontaneously rearranges into 4,21-dehydrogeissoschisine and undergoes further oxidation-reduction modifications by enzymes of the CYP450, ADH, reductases, and methyltransferase families, which form the structural diversity of the molecules through modular.[24][25]

Yohimbine-type

Indoloquinolizidine alkaloids of the yohimbine-type are biosynthesized from the central intermediate 4,21-dehydrogeissoschizine through highly stereo-flexible pathways regulated by heteroyohimbine synthase (HYS), medium-chain dehydrogenases/reductases, and tetrahydroalstonine synthase (THAS), which generate diastereomeric mixtures; the stereoselectivity of these downstream conversions is primarily determined by architectural configurations within the active site of HYS, specifically an extended, flexible "loop 2" that positions a critical histidine residue (His127) to mediate face-selective substrate protonation.[24][25][26]

Mitragynine-type

Indoloquinolizidine alkaloids of the mitragynine-type are biosynthesized through a stereo-controlled pathway where a family of dihydrogeissoschizine synthases (DCS1–4) selectively reduces the strictosidine aglycone into either (20R)-demethylcorynantheidine (the precursor to mitragynine) or (20S)-demethyldihydrocorynantheine (the precursor to speciogynine) based on specific amino acid residues within the enzyme's active site, followed by an unprecedented functionalization step where a SABATH-family methyltransferase (MsC17OMT) oversightes the C-17 O-methylation of a non-aromatic enol.[24][27]

Reserpine-type

Indoloquinolizidine alkaloids of the reserpine-type are biosynthesized through sequential enzymatic reactions starting with strictosidine. In the first step, its initial C-3α-configuration is converted to the C-3β-form, which is critical for biological activity, via a two-step epimerization: flavin-dependent oxidase RvYOO oxidizes the substrate to an iminium intermediate, which is then reduced by NADPH-dependent reductase RvDYR. Subsequent modification of the resulting scaffold includes 18β-hydroxylation by cytochrome CYP71D820, С-11 hydroxylation by cytochrome CYP72A270, and final O-methylation.[24][28]

Ajmaline-type

Indoloquinolizidine alkaloids of the ajmaline-type are biosynthesized from 19E-geissochisine, which is oxidized by specific enzymes to polyneuridinaldehyde and converted to vomilenine. The final ajmaline structure is formed through the sequential reduction of intermediates by specific reductases: first, vomilenine-1,2(R)-reductase (VR) reduces vomilenine, after which 1,2-dihydrovomilenine-19,20(S)-reductase (DHVR) converts it to 17-O-acetylnorajmaline, which is finally deacetylated by acetylesterase AAE.[24][29]

Representatives

References

  1. ↑ Tatsis, Evangelos C.; Carqueijeiro, Inês; Dugé de Bernonville, Thomas; Franke, Jakob; Dang, Thu-Thuy T.; Oudin, Audrey; Lanoue, Arnaud; Lafontaine, Florent et al. (2017-08-22). "A three enzyme system to generate the Strychnos alkaloid scaffold from a central biosynthetic intermediate" (in en). Nature Communications 8 (1): 316. doi:10.1038/s41467-017-00154-x. ISSN 2041-1723. PMID 28827772. Bibcode: 2017NatCo...8..316T. 
  2. ↑ Leete, Edward (1961). "Biogenesis of the Rauwolfia alkaloids alkaloids—II". Tetrahedron 14 (1–2): 35–41. doi:10.1016/0040-4020(61)80084-7. ISSN 0040-4020. https://doi.org/10.1016/0040-4020(61)80084-7. 
  3. ↑ Li, Jun; Li, Jia-Xing; Jiang, Hua; Li, Min; Chen, Lin; Wang, Yue-Yue; Wang, Lu; Zhang, Ning et al. (2023). "Phytochemistry and biological activities of corynanthe alkaloids". Phytochemistry 213. doi:10.1016/j.phytochem.2023.113786. ISSN 0031-9422. PMID 37422009. Bibcode: 2023PChem.213k3786L. https://doi.org/10.1016/j.phytochem.2023.113786. 
  4. ↑ Keawpradub, Niwat (1990). Alkaloids from the fresh leaves of Mitragyna speciosa (Korth.) Havil (Thesis). Office of Academic Resources, Chulalongkorn University. doi:10.58837/chula.the.1990.863.
  5. ↑ Zhukovich, E. N. (1987). "Alkaloids of the roots of Vinca major introduced into Georgia". Chemistry of Natural Compounds 23 (4): 515–516. doi:10.1007/bf00597827. ISSN 0009-3130. Bibcode: 1987CNatC..23..515Z. https://doi.org/10.1007/bf00597827. 
  6. ↑ Naidoo, Clarissa Marcelle; Naidoo, Yougasphree; Dewir, Yaser Hassan; Murthy, Hosakatte Niranjana; El-Hendawy, Salah; Al-Suhaibani, Nasser (2021-02-05). "Major Bioactive Alkaloids and Biological Activities of Tabernaemontana Species (Apocynaceae)". Plants (Basel, Switzerland) 10 (2): 313. doi:10.3390/plants10020313. ISSN 2223-7747. PMID 33562893. Bibcode: 2021Plnts..10..313N. 
  7. ↑ Hop, Nguyen Quang; Son, Ninh The (2022-06-29). "A comprehensive review on phytochemistry and pharmacology of genus Kopsia: monoterpene alkaloids - major secondary metabolites". RSC Advances 12 (30): 19171–19208. doi:10.1039/d2ra01791a. ISSN 2046-2069. PMID 35865593. Bibcode: 2022RSCAd..1219171H. 
  8. ↑ Indole Alkaloids from Hunteria zeylanica. doi:10.1021/acs.jnatprod.5b01035.s001. https://doi.org/10.1021/acs.jnatprod.5b01035.s001. Retrieved 2026-06-18. 
  9. ↑ Zhang, Yan Wen; Yang, Rui; Cheng, Qian; Ofuji, Katsuya (2003). "Henrycinols A and B, Two Novel Indole Alkaloids Isolated from Melodinus henryi Craib" (in en). Helvetica Chimica Acta 86 (2): 415–419. doi:10.1002/hlca.200390042. ISSN 0018-019X. Bibcode: 2003HChAc..86..415Z. https://onlinelibrary.wiley.com/doi/10.1002/hlca.200390042. 
  10. ↑ Feng, Tao; Cai, Xiang-Hai; Liu, Ya-Ping; Li, Yan; Wang, Yuan-Yuan; Luo, Xiao-Dong (2010-01-22). "Melodinines A−G, Monoterpenoid Indole Alkaloids from Melodinus henryi". Journal of Natural Products 73 (1): 22–26. doi:10.1021/np900595v. ISSN 0163-3864. PMID 20041704. Bibcode: 2010JNAtP..73...22F. https://doi.org/10.1021/np900595v. 
  11. ↑ Basu, N. K.; Sarkar, B. (1958). "Isolation of Reserpine from Vinca rosea Linn." (in en). Nature 181 (4608): 552–553. doi:10.1038/181552a0. ISSN 1476-4687. PMID 13517211. Bibcode: 1958Natur.181..552B. https://www.nature.com/articles/181552a0. 
  12. ↑ Tan, Yi-Sheng; Wong, Soon-Kit; Yong, Kien-Thai; Lim, Kuan-Hon; Lim, Siew-Huah; Low, Yun-Yee (2023-01-27). "Eugeniifoline, a Pentacyclic Indole Alkaloid from Leuconotis eugeniifolia, and Configurational Revision of Synthetic Eugeniifoline Isolated from a Diversity-Enhanced Extract". Journal of Natural Products 86 (1): 232–236. doi:10.1021/acs.jnatprod.2c00731. ISSN 0163-3864. PMID 36651825. Bibcode: 2023JNAtP..86..232T. https://doi.org/10.1021/acs.jnatprod.2c00731. 
  13. ↑ Tan, Yi-Sheng; Ng, Min-Phin; Tan, Chun-Hoe; Tang, Wai-Kit; Sim, Kae-Shin; Yong, Kien-Thai; Krishnan, Premanand; Lim, Kuan-Hon et al. (2024-02-23). "Quinoline, Indole, and Isogranatanine Alkaloids from Malayan Leuconotis eugeniifolia". Journal of Natural Products 87 (2): 286–296. doi:10.1021/acs.jnatprod.3c00960. ISSN 0163-3864. PMID 38284153. Bibcode: 2024JNAtP..87..286T. https://doi.org/10.1021/acs.jnatprod.3c00960. 
  14. ↑ Chear, Nelson Jeng-Yeou; Ching-Ga, Tan Ai Fein; Khaw, Kooi-Yeong; León, Francisco; Tan, Wen-Nee; Yusof, Siti R.; McCurdy, Christopher R.; Murugaiyah, Vikneswaran et al. (2023-03-07). "Natural Corynanthe-Type Cholinesterase Inhibitors from Malaysian Uncaria attenuata Korth.: Isolation, Characterization, In Vitro and In Silico Studies". Metabolites 13 (3): 390. doi:10.3390/metabo13030390. ISSN 2218-1989. PMID 36984830. 
  15. ↑ Kam, T. S.; Choo, Y. M. (2004). "New Indole Alkaloids from Alstonia macrophyllaClick to copy article link". Journal of Natural Products 67 (4): 547–552. doi:10.1021/np034041v. PMID 15104482. https://pubs.acs.org/action/cookieAbsent. Retrieved 2026-06-18. 
  16. ↑ Doy, FA; Moore, BP (1962-09-01). "Alkaloids of Ochrosia poweri Bailey. I. The Leaf-bases". Australian Journal of Chemistry 15 (3): 548–554. doi:10.1071/ch9620548. ISSN 0004-9425. https://doi.org/10.1071/ch9620548. 
  17. ↑ Anthoni, Uffe; Christophersen, Carsten; Nielsen, Per Halfdan (1999), "Naturally Occurring Cyclotryptophans and Cyclotryptamines", Alkaloids: Chemical and Biological Perspectives, Elsevier, pp. 163–236, doi:10.1016/s0735-8210(99)80025-9, ISBN 978-0-08-043403-2, https://doi.org/10.1016/s0735-8210(99)80025-9, retrieved 2026-06-18 
  18. ↑ Menzies, J. R.; Paterson, S. J.; Duwiejua, M.; Corbett, A. D. (1998-05-29). "Opioid activity of alkaloids extracted from Picralima nitida (fam. Apocynaceae)". European Journal of Pharmacology 350 (1): 101–108. doi:10.1016/s0014-2999(98)00232-5. ISSN 0014-2999. PMID 9683021. 
  19. ↑ Sauerwein, Martina; Shimomura, Koichiro (1991). "Degradation of 17α-O-methylyohimbine in Amsonia elliptica roots". Phytochemistry 30 (5): 1449–1450. doi:10.1016/0031-9422(91)84183-s. ISSN 0031-9422. Bibcode: 1991PChem..30.1449S. https://doi.org/10.1016/0031-9422(91)84183-s. 
  20. ↑ Frédérich, Michel; Tits, Monique; Angenot, Luc (1998). "Qualitative and quantitative evaluation of bisindole usambarane alkaloids inStrychnos usambarensis roots by high performance liquid chromatography-diode-array" (in en). Phytochemical Analysis 9 (2): 63–66. doi:10.1002/(SICI)1099-1565(199803/04)9:2<63::AID-PCA388>3.0.CO;2-9. ISSN 0958-0344. Bibcode: 1998PChAn...9...63F. https://onlinelibrary.wiley.com/doi/10.1002/(SICI)1099-1565(199803/04)9:23.0.CO;2-9. 
  21. ↑ Frédérich, Michel; Tits, Monique; Hayette, Marie-Pierre; Brandt, Viviane; Penelle, Jacques; DeMol, Patrick; Llabrès, Gabriel; Angenot, Luc (1999-04-01). "10'-Hydroxyusambarensine, a New Antimalarial Bisindole Alkaloid from the Roots of Strychnos u sambarensis" (in en). Journal of Natural Products 62 (4): 619–621. doi:10.1021/np980375m. ISSN 0163-3864. PMID 10217724. Bibcode: 1999JNAtP..62..619F. https://pubs.acs.org/doi/10.1021/np980375m. 
  22. ↑ "Yohimbe Bark and Yohimbine ( Pausinystalia yohimbe Pierre ex Beille)". Medical Toxicology of Natural Substances. 2008-01-02. pp. 627–631. doi:10.1002/9780470330319.ch96. ISBN 978-0-471-72761-3. https://doi.org/10.1002/9780470330319.ch96. 
  23. ↑ Singh, Amar; Alvi, Naved (2011). "High-performance thin-layer chromatographic quantification of yohimbine in the stem bark of Pausinystalia yohimbe". Journal of Planar Chromatography – Modern TLC 24 (3): 253–256. doi:10.1556/jpc.24.2011.3.15. ISSN 0933-4173. https://doi.org/10.1556/jpc.24.2011.3.15. 
  24. ↑ 24.0 24.1 24.2 24.3 24.4 Liu, Chenxu; Tong, Mengqi; Otsuki, Kouharu; Li, Wei; Feng, Feng; Zhang, Jie (2026). "Structure, bioactivity, biosynthesis, and synthesis of corynanthe alkaloids". Natural Product Reports 43 (4): 746–778. doi:10.1039/d5np00051c. ISSN 0265-0568. PMID 41586474. 
  25. ↑ 25.0 25.1 Rueffer, Martina; Kan-Fan, Christiane; Husson, Henri-Phillipe; Stöckigt, Joachim; Zenk, Meinhart H. (1979). "4,21-Dehydrogeissoschizine, an intermediate in heteroyohimbine alkaloid biosynthesis". J. Chem. Soc., Chem. Commun. (22): 1016–1018. doi:10.1039/c39790001016. ISSN 0022-4936. 
  26. ↑ Kan-Fan, C.; Husson, H.-P. (1980). "Biomimetic synthesis of yohimbine and heteroyohimbine alkaloids from 4,21-dehydrogeissoschizine". Tetrahedron Letters 21 (15): 1463–1466. doi:10.1016/s0040-4039(00)92746-1. ISSN 0040-4039. 
  27. ↑ Sakamoto, Jukiya; Ishikawa, Hayato (2022-02-19). "Bioinspired Transformations Using Strictosidine Aglycones: Divergent Total Syntheses of Monoterpenoid Indole Alkaloids in the Early Stage of Biosynthesis" (in en). Chemistry: A European Journal 28 (10). doi:10.1002/chem.202104052. ISSN 1521-3765. PMID 34854134. Bibcode: 2022ChEuJ..28E4052S. https://chemistry-europe.onlinelibrary.wiley.com/doi/abs/10.1002/chem.202104052. 
  28. ↑ Cao, Jiaqing; Zhong, Jingxiao; Li, Feng; Jiang, Yindi (2025-07-09). "Enzymatic Basis of Stereochemical Control in Reserpine Biosynthesis". Journal of the American Chemical Society 147 (29): 25233–25241. doi:10.1021/jacs.5c02863. ISSN 0002-7863. PMID 40632683. Bibcode: 2025JAChS.14725233C. 
  29. ↑ Guo, Jun; Gao, Di; Lian, Jiazhang; Qu, Yang (2024-01-11). "De novo biosynthesis of antiarrhythmic alkaloid ajmaline". Nature Communications 15 (1). doi:10.1038/s41467-024-44797-z. ISSN 2041-1723. PMID 38212296. Bibcode: 2024NatCo..15..457G. 



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