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
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 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.

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

Related Research Articles

<i>Vinca</i> alkaloid

Vinca alkaloids are a set of anti-mitotic and anti-microtubule alkaloid agents originally derived from the periwinkle plant Catharanthus roseus and other vinca plants. They block beta-tubulin polymerization in a dividing cell.

<span class="mw-page-title-main">Voacangine</span> Chemical compound

Voacangine is an alkaloid found predominantly in the root bark of the Voacanga africana tree, as well as in other plants such as Tabernanthe iboga, Tabernaemontana africana, Trachelospermum jasminoides, Tabernaemontana divaricata and Ervatamia yunnanensis. It is an iboga alkaloid which commonly serves as a precursor for the semi-synthesis of ibogaine. It has been demonstrated in animals to have similar anti-addictive properties to ibogaine itself. It also potentiates the effects of barbiturates. Under UV-A and UV-B light its crystals fluoresce blue-green, and it is soluble in ethanol.

<span class="mw-page-title-main">Indole alkaloid</span> Class of alkaloids

Indole alkaloids are a class of alkaloids containing a structural moiety of indole; many indole alkaloids also include isoprene groups and are thus called terpene indole or secologanin tryptamine alkaloids. Containing more than 4100 known different compounds, it is one of the largest classes of alkaloids. Many of them possess significant physiological activity and some of them are used in medicine. The amino acid tryptophan is the biochemical precursor of indole alkaloids.

<span class="mw-page-title-main">Vincamine</span> Chemical compound

Vincamine is a monoterpenoid indole alkaloid found in the leaves of Vinca minor, comprising about 25–65% of its indole alkaloids by weight. It can also be synthesized from related alkaloids.

<i>Tabernaemontana corymbosa</i> Species of plant

Tabernaemontana corymbosa is a species of plant in the family Apocynaceae. It is found in Brunei, China, Indonesia, Laos, Malaysia, Myanmar, Singapore, Thailand, and Vietnam. Glossy green leaves and faintly sweet scented flower. Flowers continuously all year. Frost tolerant. Grows to about 2 metres. Likes full sun to part shade. A number of cultivars are available.

<span class="mw-page-title-main">Coronaridine</span> Chemical compound

Coronaridine, also known as 18-carbomethoxyibogamine, is an alkaloid found in Tabernanthe iboga and related species, including Tabernaemontana divaricata for which it was named.

<span class="mw-page-title-main">Ibogamine</span> Anti-convulsant, anti-addictive CNS stimulant alkaloid

Ibogamine is an anti-convulsant, anti-addictive, CNS stimulant alkaloid found in Tabernanthe iboga and Crepe Jasmine. Basic research related to how addiction affects the brain has used this chemical.

<span class="mw-page-title-main">Conolidine</span> Chemical compound

Conolidine is an indole alkaloid. Preliminary reports suggest that it could provide analgesic effects with few of the detrimental side-effects associated with opioids such as morphine, though at present it has only been evaluated in mouse models.

<i>Tabernaemontana divaricata</i> Species of plant

Tabernaemontana divaricata, commonly called pinwheel flower, crape jasmine, East India rosebay, and Nero's crown, is an evergreen shrub or small tree native to South Asia, Southeast Asia and China. In zones where it is not hardy it is grown as a house/glasshouse plant for its attractive flowers and foliage. The stem exudes a milky latex when broken, whence comes the name milk flower

<span class="mw-page-title-main">Akuammicine</span> Alkaloid

Akuammicine is a monoterpene indole alkaloid of the Vinca sub-group. It is found in the Apocynaceae family of plants including Picralima nitida, Vinca minor and the Aspidosperma.

<span class="mw-page-title-main">Catharanthine</span> Chemical compound

Catharanthine is a terpene indole alkaloid produced by the medicinal plant Catharanthus roseus and Tabernaemontana divaricata. Catharanthine is derived from strictosidine, but the exact mechanism by which this happens is currently unknown. Catharanthine is one of the two precursors that form vinblastine, the other being vindoline.

<span class="mw-page-title-main">Affinisine</span> Chemical compound

Affinisine is a monoterpenoid indole alkaloid which can be isolated from plants of the genus Tabernaemontana. Structurally, it can be considered a member of the sarpagine alkaloid family and may be synthesized from tryptophan via a Pictet-Spengler reaction.

<span class="mw-page-title-main">Apparicine</span> Chemical compound

Apparicine is a monoterpenoid indole alkaloid. It is named after Apparicio Duarte, a Brazilian botanist who studied the Aspidosperma species from which apparicine was first isolated. It was the first member of the vallesamine group of alkaloids to be isolated and have its structure established, which was first published in 1965. It has also been known by the synonyms gomezine, pericalline, and tabernoschizine.

<span class="mw-page-title-main">Tabernaemontanine</span> Chemical compound

Tabernaemontanine is a naturally occurring monoterpene indole alkaloid found in several species in the genus Tabernaemontana including Tabernaemontana divaricata.

<span class="mw-page-title-main">Isovoacangine</span> Chemical compound

Isovoacangine is a naturally occurring substance that has action on heart muscles in pigs.

<span class="mw-page-title-main">Dregamine</span> Chemical compound

Dregamine is a naturally occurring monoterpene indole alkaloid found in several species in the genus Tabernaemontana including Ervatamia hirta and Tabernaemontana divaricata.

<span class="mw-page-title-main">Vobasine</span> Chemical compound

Vobasine is a naturally occurring monoterpene indole alkaloid found in several species in the genus Tabernaemontana including Tabernaemontana divaricata.

<span class="mw-page-title-main">Voacristine</span> Chemical compound

Voacristine is a indole alkaloid occurring in Voacanga and Tabernaemontana genus. It is also an iboga type alkaloid.

<span class="mw-page-title-main">Vinervine</span> Vinca alkaloid

Vinervine is a monoterpene indole alkaloid of the Vinca sub-group. It is a derivative of akuammicine, with one additional hydroxy (OH) group in the indole portion, hence it is also known as 12-hydroxyakuammicine.

<span class="mw-page-title-main">19,20-Dihydroervahanine A</span> Chemical compound

19,20-Dihydroervahanine A is an alkaloid, a natural product which is found in the root of the South-East Asian plant Tabernaemontana divaricata. It inhibits acetylcholinesterase more potently than galantamine in vitro.

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. 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, Organic Chemistry. 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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