Conophylline

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Conophylline
Conophylline.svg
Names
IUPAC name
Dimethyl 14,25-diethyl-24,33-dihydroxy-31,32-dimethoxy-12,22-dioxa-1,9,18,29-tetrazadodecacyclo[23.13.1.16,9.02,23.03,21.05,19.06,17.011,13.028,36.030,35.036,39.014,40]tetraconta-3,5(19),16,20,27,30,32,34-octaene-16,27-dicarboxylate
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
  • InChI=1S/C44H50N4O10/c1-7-41-16-20(37(51)55-5)34-44(23-14-25(49)30(53-3)31(54-4)28(23)46-34)10-12-48(40(41)44)29-19-13-22-24(15-26(19)57-32(29)35(41)50)45-33-21(38(52)56-6)17-42(8-2)36-27(58-36)18-47-11-9-43(22,33)39(42)47/h13-15,27,29,32,35-36,39-40,45-46,49-50H,7-12,16-18H2,1-6H3
    Key: QZRIMAMDGWAHPQ-UHFFFAOYSA-N
  • Conophylline: CCC12CC(=C3C4(C1N(CC4)C5C(C2O)OC6=CC7=C(C=C56)C89CCN1C8C(CC(=C9N7)C(=O)OC)(C2C(C1)O2)CC)C1=CC(=C(C(=C1N3)OC)OC)O)C(=O)OC
Properties
C44H50N4O10
Molar mass 794.902 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

Conophylline is a autophagy inducing[1] vinca alkaloid found in several species of Tabernaemontana including Ervatamia microphylla and Tabernaemontana divaricata. Among its many functional groups is an epoxide: the compound where that ring is replaced with a double bond is called conophyllidine and this co-occurs in the same plants.

History[]

Conophylline and conophyllidine were first reported in 1993 after isolation from the ethanol extract of leaves of Tabernaemontana divaricata. Their structures were confirmed by X-ray crystallography.[2][3] The class of vinca alkaloids to which these compounds belong also contains vincristine and vinblastine, well-known therapeutic agents for human cancers, so they were candidates for a number of biochemical assays to see if they had useful biological activity. By 1996, conophylline it had been reported to inhibit tumours in rats by its action on Ras-expressing cells.[4] This finding did not lead to a useful drug but the molecule continues to be investigated for its biological properties.[5][6][7]

Synthesis[]

Biosynthesis[]

Main article: Indole_alkaloid § Biosynthesis

As with other Indole alkaloids, the biosynthesis of conophylline and conophyllidine starts from the amino acid tryptophan. This is converted into strictosidine before further elaboration and dimerisation.[8]

Chemical synthesis[]

The natural products contain two indoline ring systems

Fukuyama and coworkers published a total synthesis of conophylline and conophyllidine in 2011. Their strategy was to couple two indoline-containing fragments using a type of Polonovski reaction. The synthesis was challenging owing to the eleven stereogenic centers which have to be controlled. The final products are chiral, and laevorotary.[9][10]

Natural occurrence[]

Conophylline and conophyllidine are found in species of the genus Tabernaemontana including Ervatamia microphylla and Tabernaemontana divaricata.[2][11] The latter species is known to produce many other alkaloids including catharanthine, ibogamine and voacristine.[citation needed]

Research[]

It has beneficial activity on animal model of diabetes.[12][13] It is researched as novel beta cell differentiating factor both alone and with compounds such as betacellulin-delta4.[14][15][16][17][18] It is also investigated as anticancer agent.[19]

See also[]

References[]

  1. ^ Kakegawa J, Ohtsuka S, Yokoyama M, Hosoi T, Ozawa K, Hatanaka T (June 2021). "Thermal proteome profiling reveals GPX4 as the target of the autophagy inducer conophylline". Molecular Pharmacology. 100 (3): 181–192. doi:10.1124/molpharm.121.000243. PMID 34127539.
  2. ^ a b Kam, Toh-Seok; Loh, Kah-Yeng; Wei, Chen (1993). "Conophylline and Conophyllidine: New Dimeric Alkaloids from Tabernaemontana divaricata". Journal of Natural Products. 56 (11): 1865–1871. doi:10.1021/np50101a001.
  3. ^ Saxton, J. Edwin (1996). "Recent progress in the chemistry of the monoterpenoid indole alkaloids". Natural Product Reports. 13 (4): 385–411. doi:10.1039/NP9961300327. PMID 7666980.
  4. ^ Umezawa, K; Taniguchi, T; Toi, M; Ohse, T; Tsutsumi, N; Yamamoto, T; Koyano, T; Ishizuka, M (1996). "Growth inhibition of K-ras-expressing tumours by a new vinca alkaloid, conophylline, in nude mice". Drugs Under Experimental and Clinical Research. 22 (2): 35–40. PMID 8879977.
  5. ^ Sridhar, S. N. C; Seshank, Mutya; Atish, T. Paul (2017). "Bis-indole alkaloids from Tabernaemontana divaricata as potent pancreatic lipase inhibitors: Molecular modelling studies and experimental validation". Medicinal Chemistry Research. 26 (6): 1268–1278. doi:10.1007/s00044-017-1836-7. S2CID 23580988.
  6. ^ Tezuka T, Ota A, Karnan S, Matsuura K, Yokoo K, Hosokawa Y, Vigetti D, Passi A, Hatano S, Umezawa K, Watanabe H (December 2018). "The plant alkaloid conophylline inhibits matrix formation of fibroblasts". Journal of Biological Chemistry. 293 (52): 20214–20226. doi:10.1074/jbc.RA118.005783. PMC 6311511. PMID 30377255.
  7. ^ Ohashi, Tomohiko; Nakade, Yukiomi; Ibusuki, Mayu; Kitano, Rena; Yamauchi, Taeko; Kimoto, Satoshi; Inoue, Tadahisa; Kobayashi, Yuji; Sumida, Yoshio; Ito, Kiyoaki; Nakao, Haruhisa; Umezawa, Kazuo; Yoneda, Masashi (2019). "Conophylline inhibits high fat diet-induced non-alcoholic fatty liver disease in mice". PLOS ONE. 14 (1): e0210068. Bibcode:2019PLoSO..1410068O. doi:10.1371/journal.pone.0210068. PMC 6349312. PMID 30689650.
  8. ^ Dewick, Paul M (2002). Medicinal Natural Products. A Biosynthetic Approach. Second Edition. Wiley. pp. 350–359. ISBN 0-471-49640-5.
  9. ^ Han-Ya, Yuki; Tokuyama, Hidetoshi; Fukuyama, Tohru (2011). "Total Synthesis of (−)-Conophylline and (−)-Conophyllidine". Angewandte Chemie International Edition. 50 (21): 4884–4887. doi:10.1002/anie.201100981. PMID 21500330.
  10. ^ Downer-Riley, Nadale K.; Jackson, Yvette A. (2012). "Highlight syntheses". Annual Reports, Section B. 108: 147. doi:10.1039/C2OC90006H.
  11. ^ Kam, Toh-Seok; Pang, Huey-Shen; Lim, Tuck-Meng (2003). "Biologically active indole and bisindole alkaloids from Tabernaemontana divaricata". Organic & Biomolecular Chemistry. 1 (8): 1292–1297. doi:10.1039/B301167D. PMID 12929658.
  12. ^ Fujii M, Takei I, Umezawa K (December 2009). "Antidiabetic effect of orally administered conophylline-containing plant extract on streptozotocin-treated and Goto-Kakizaki rats". Biomedicine & Pharmacotherapy. 63 (10): 710–6. doi:10.1016/j.biopha.2009.01.006. PMID 19217246.
  13. ^ Umezawa K, Kojima I, Simizu S, Lin Y, Fukatsu H, Koide N, Nakade Y, Yoneda M (April 2018). "Therapeutic activity of plant-derived alkaloid conophylline on metabolic syndrome and neurodegenerative disease models". . 31 (2): 95–101. doi:10.1007/s13577-017-0196-4. PMID 29249016. S2CID 3948048.
  14. ^ Ogata T, Li L, Yamada S, Yamamoto Y, Tanaka Y, Takei I, Umezawa K, Kojima I (October 2004). "Promotion of beta-cell differentiation by conophylline in fetal and neonatal rat pancreas". Diabetes. 53 (10): 2596–602. doi:10.2337/diabetes.53.10.2596. PMID 15448089.
  15. ^ Kojima I, Umezawa K (2006). "Conophylline: a novel differentiation inducer for pancreatic beta cells". The International Journal of Biochemistry & Cell Biology. 38 (5–6): 923–30. doi:10.1016/j.biocel.2005.09.019. PMID 16337165.
  16. ^ Kitamura R, Ogata T, Tanaka Y, Motoyoshi K, Seno M, Takei I, Umezawa K, Kojima I (April 2007). "Conophylline and betacellulin-delta4: an effective combination of differentiation factors for pancreatic beta cells". Endocrine Journal. 54 (2): 255–64. doi:10.1507/endocrj.k06-199. PMID 17303930.
  17. ^ Kodera T, Yamada S, Yamamoto Y, Hara A, Tanaka Y, Seno M, Umezawa K, Takei I, Kojima I (2009). "Administration of conophylline and betacellulin-delta4 increases the beta-cell mass in neonatal streptozotocin-treated rats". Endocrine Journal. 56 (6): 799–806. doi:10.1507/endocrj.k09e-158. PMID 19550075.
  18. ^ Kawakami M, Hirayama A, Tsuchiya K, Ohgawara H, Nakamura M, Umezawa K (March 2010). "Promotion of beta-cell differentiation by the alkaloid conophylline in porcine pancreatic endocrine cells". Biomedicine & Pharmacotherapy. 64 (3): 226–31. doi:10.1016/j.biopha.2009.09.025. PMID 20079600.
  19. ^ Umezawa K, Shirabe K (2021). "Direct and Indirect Anticancer Activity of Plant-Derived Alkaloid Conophylline". Critical Reviews in Oncogenesis. 26 (2): 67–72. doi:10.1615/CritRevOncog.2020034129. PMID 34347973.
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