Conophylline

Conophylline

Conophylline

Chemical compound

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.

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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]

See also

References

  1. [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. PMC 8626788. PMID 34127539.
  2. [2]
    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. [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. [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. [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. [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. [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. [8]
    Dewick, Paul M (2002). Medicinal Natural Products. A Biosynthetic Approach. Second Edition. Wiley. pp. 350–359. ISBN 0-471-49640-5.
  9. [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. [10]
    Downer-Riley, Nadale K.; Jackson, Yvette A. (2012). "Highlight syntheses". Annual Reports Section B, Organic Chemistry. 108: 147. doi:10.1039/C2OC90006H.
  11. [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.
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