Chemistry:Conophylline
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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
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3D model (JSmol)
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PubChem CID
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| 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
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
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
- ↑ "Thermal proteome profiling reveals GPX4 as the target of the autophagy inducer conophylline". Molecular Pharmacology 100 (3): 181–192. June 2021. doi:10.1124/molpharm.121.000243. PMID 34127539.
- ↑ 2.0 2.1 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ "The plant alkaloid conophylline inhibits matrix formation of fibroblasts". Journal of Biological Chemistry 293 (52): 20214–20226. December 2018. doi:10.1074/jbc.RA118.005783. PMID 30377255.
- ↑ Ohashi, Tomohiko; Nakade, Yukiomi; Ibusuki, Mayu; Kitano, Rena; Yamauchi, Taeko; Kimoto, Satoshi; Inoue, Tadahisa; Kobayashi, Yuji et al. (2019). "Conophylline inhibits high fat diet-induced non-alcoholic fatty liver disease in mice". PLOS ONE 14 (1): e0210068. doi:10.1371/journal.pone.0210068. PMID 30689650. Bibcode: 2019PLoSO..1410068O.
- ↑ Dewick, Paul M (2002). Medicinal Natural Products. A Biosynthetic Approach. Second Edition. Wiley. pp. 350–359. ISBN 0-471-49640-5. https://books.google.com/books?id=A4zptjOJfKQC&pg=PP1.
- ↑ 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.
- ↑ Downer-Riley, Nadale K.; Jackson, Yvette A. (2012). "Highlight syntheses". Annual Reports Section B, Organic Chemistry 108: 147. doi:10.1039/C2OC90006H.
- ↑ 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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