Conophylline

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.

Conophylline

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
CAS Number	Conophylline: 142741-24-0
3D model (JSmol)	Conophylline: Interactive image
ChEMBL	Conophylline: ChEMBL506768 Conophyllidine: ChEMBL455807
ChemSpider	Conophylline: 23339619 Conophyllidine: 17596709
PubChem CID	Conophylline: 9853848 Conophyllidine: 44566831
InChI 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
SMILES 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
Chemical formula	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

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

• Conofoline