Conophylline

Last updated
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
PubChem CID
  • 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).

Conophylline is a autophagy inducing [1] vinca alkaloid found in plants of the genus Tabernaemontana . Among the many functional groups in this molecule 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.

Contents

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

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 Indoline.svg
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. ↑ 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. 1 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. Bibcode:1993JNAtP..56.1865K. 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 on the Progress of Chemistry, 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.
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