Conophylline Explained
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.[11] The latter species is known to produce many other alkaloids including catharanthine, ibogamine and voacristine.
See also
Notes and References
- Kakegawa J, Ohtsuka S, Yokoyama M, Hosoi T, Ozawa K, Hatanaka T . Thermal proteome profiling reveals GPX4 as the target of the autophagy inducer conophylline . . 100. 3. 181–192. June 2021 . 34127539 . 10.1124/molpharm.121.000243 . 8626788 . free .
- 10.1021/np50101a001 . Conophylline and Conophyllidine: New Dimeric Alkaloids from Tabernaemontana divaricata . 1993 . Kam . Toh-Seok . Loh . Kah-Yeng . Wei . Chen . Journal of Natural Products . 56 . 11 . 1865–1871 .
- 10.1039/NP9961300327 . Recent progress in the chemistry of the monoterpenoid indole alkaloids . 1996 . Saxton . J. Edwin . Natural Product Reports. 13 . 4 . 385–411 . 7666980 .
- Umezawa . K. Taniguchi. T. Toi. M. Ohse. T. Tsutsumi. N. Yamamoto . T. Koyano. T. Ishizuka. M. Growth inhibition of K-ras-expressing tumours by a new vinca alkaloid, conophylline, in nude mice. Drugs Under Experimental and Clinical Research . 1996. 22. 2. 35–40. 8879977.
- 10.1007/s00044-017-1836-7 . Bis-indole alkaloids from Tabernaemontana divaricata as potent pancreatic lipase inhibitors: Molecular modelling studies and experimental validation . 2017 . Sridhar . S. N. C. Mutya . Seshank . T. Paul . Atish . . 26 . 6 . 1268–1278 . 23580988 .
- Tezuka T, Ota A, Karnan S, Matsuura K, Yokoo K, Hosokawa Y, Vigetti D, Passi A, Hatano S, Umezawa K, Watanabe H . The plant alkaloid conophylline inhibits matrix formation of fibroblasts . . 293 . 52 . 20214–20226 . December 2018 . 30377255 . 6311511 . 10.1074/jbc.RA118.005783 . free .
- 10.1371/journal.pone.0210068 . free. Conophylline inhibits high fat diet-induced non-alcoholic fatty liver disease in mice . 2019 . 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 . PLOS ONE . 14 . 1 . e0210068 . 30689650 . 6349312 . 2019PLoSO..1410068O .
- Book: Dewick, Paul M . Medicinal Natural Products. A Biosynthetic Approach. Second Edition. 350–359. 2002. Wiley. 0-471-49640-5.
- 10.1002/anie.201100981 . Total Synthesis of (−)-Conophylline and (−)-Conophyllidine . 2011 . Han-Ya . Yuki . Tokuyama . Hidetoshi . Fukuyama . Tohru . Angewandte Chemie International Edition . 50 . 21 . 4884–4887 . 21500330 .
- 10.1039/C2OC90006H . Highlight syntheses . 2012 . Downer-Riley . Nadale K. . Jackson . Yvette A. . Annual Reports Section B, Organic Chemistry . 108 . 147 .
- 10.1039/B301167D . Biologically active indole and bisindole alkaloids from Tabernaemontana divaricata . 2003 . Kam . Toh-Seok . Pang . Huey-Shen . Lim . Tuck-Meng . Organic & Biomolecular Chemistry. 1 . 8 . 1292–1297 . 12929658 .