Conophylline#Research

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.{{cite journal |doi=10.1021/np50101a001 |title=Conophylline and Conophyllidine: New Dimeric Alkaloids from Tabernaemontana divaricata |year=1993 |last1=Kam |first1=Toh-Seok |last2=Loh |first2=Kah-Yeng |last3=Wei |first3=Chen |journal=Journal of Natural Products |volume=56 |issue=11 |pages=1865–1871 |bibcode=1993JNAtP..56.1865K }}{{cite journal |doi=10.1039/NP9961300327 |title=Recent progress in the chemistry of the monoterpenoid indole alkaloids |year=1996 |last1=Saxton |first1=J. Edwin |journal= Natural Product Reports|volume=13 |issue=4 |pages=385–411 |pmid=7666980 }} 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.{{cite journal|last1=Umezawa |first1=K|last2=Taniguchi|first2=T|last3=Toi|first3=M|last4=Ohse|first4=T|last5=Tsutsumi|first5= N|last6=Yamamoto |first6=T|last7=Koyano|first7=T|last8=Ishizuka|first8=M|title= Growth inhibition of K-ras-expressing tumours by a new vinca alkaloid, conophylline, in nude mice|journal=Drugs Under Experimental and Clinical Research |year=1996|volume=22|issue=2|pages=35–40|pmid=8879977}} This finding did not lead to a useful drug but the molecule continues to be investigated for its biological properties.{{cite journal |doi=10.1007/s00044-017-1836-7 |title=Bis-indole alkaloids from Tabernaemontana divaricata as potent pancreatic lipase inhibitors: Molecular modelling studies and experimental validation |year=2017 |last1=Sridhar |first1=S. N. C|first2=Mutya |last2=Seshank |first3=T. Paul |last3=Atish |journal=Medicinal Chemistry Research |volume=26 |issue=6 |pages=1268–1278 |s2cid=23580988 }}

{{cite journal |vauthors=Tezuka T, Ota A, Karnan S, Matsuura K, Yokoo K, Hosokawa Y, Vigetti D, Passi A, Hatano S, Umezawa K, Watanabe H |title=The plant alkaloid conophylline inhibits matrix formation of fibroblasts |journal=Journal of Biological Chemistry |volume=293 |issue=52 |pages=20214–20226 |date=December 2018 |pmid=30377255 |pmc=6311511 |doi=10.1074/jbc.RA118.005783 |doi-access=free }}{{cite journal |doi=10.1371/journal.pone.0210068 |doi-access=free|title=Conophylline inhibits high fat diet-induced non-alcoholic fatty liver disease in mice |year=2019 |last1=Ohashi |first1=Tomohiko |last2=Nakade |first2=Yukiomi |last3=Ibusuki |first3=Mayu |last4=Kitano |first4=Rena |last5=Yamauchi |first5=Taeko |last6=Kimoto |first6=Satoshi |last7=Inoue |first7=Tadahisa |last8=Kobayashi |first8=Yuji |last9=Sumida |first9=Yoshio |last10=Ito |first10=Kiyoaki |last11=Nakao |first11=Haruhisa |last12=Umezawa |first12=Kazuo |last13=Yoneda |first13=Masashi |journal=PLOS ONE |volume=14 |issue=1 |pages=e0210068 |pmid=30689650 |pmc=6349312 |bibcode=2019PLoSO..1410068O }}

{{Main|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.{{cite book|author = Dewick, Paul M |title = Medicinal Natural Products. A Biosynthetic Approach. Second Edition|pages=350–359|url = https://books.google.com/books?id=A4zptjOJfKQC&pg=PP1|year = 2002|publisher = Wiley|isbn = 0-471-49640-5}}

File:Indoline.svg

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.{{cite journal |doi=10.1002/anie.201100981 |title=Total Synthesis of (−)-Conophylline and (−)-Conophyllidine |year=2011 |last1=Han-Ya |first1=Yuki |last2=Tokuyama |first2=Hidetoshi |last3=Fukuyama |first3=Tohru |journal=Angewandte Chemie International Edition |volume=50 |issue=21 |pages=4884–4887 |pmid=21500330 }}{{cite journal |doi=10.1039/C2OC90006H |title=Highlight syntheses |year=2012 |last1=Downer-Riley |first1=Nadale K. |last2=Jackson |first2=Yvette A. |journal= Annual Reports on the Progress of Chemistry, Section B |volume=108 |page=147 }}

Conophylline and conophyllidine are found in species of the genus Tabernaemontana including Ervatamia microphylla and Tabernaemontana divaricata.{{cite journal |doi=10.1039/B301167D |title=Biologically active indole and bisindole alkaloids from Tabernaemontana divaricata |year=2003 |last1=Kam |first1=Toh-Seok |last2=Pang |first2=Huey-Shen |last3=Lim |first3=Tuck-Meng |journal= Organic & Biomolecular Chemistry|volume=1 |issue=8 |pages=1292–1297 |pmid=12929658 }} The latter species is known to produce many other alkaloids including catharanthine, ibogamine and voacristine.{{cn|date=November 2021}}

• Conofoline

{{Reflist}}

Category:Carbazoles

Category:Tryptamine alkaloids