Antimalarial bioassay-guided fractionation of the swamp lily Crinum erubescens led to the isolation of four compounds with potent antiplasmodial activity. Compounds 1 and 2 were determined from their spectroscopic data to be the known pesticidal compound cripowellin A and the known pesticidal and antiproliferative compound cripowellin B. 1D and 2D-NMR techniques were used to determine the identities of 3 and 4 as the new compounds cripowellin C and D. A fifth compound was identified as the known alkaloid hippadine, which was inactive against Plasmodium falciparum. The antiplasmodial IC50 values of compounds 1 – 4 were determined to be 30 ± 2, 180 ± 20, 26 ± 2, and 260 ± 20 nM, respectively, and their antiproliferative IC50 values against the A2780 human ovarian cancer cell line were 11.1 ± 0.4, 16.4 ± 0.1, 25 ± 2, and 28 ± 1 nM.
Opium is the latex from the opium poppy Papaver somniferum L., which humankind has utilized since ancient Mesopotamia all the
way to modern times. Opium used to be surrounded in divine mystery
or magic-like abilities and was given to cure a wide variety of diseases
until its analgesic, antitussive, and antidiarrheal properties were
understood, the resulting alkaloids were isolated, and their structure
and properties unmasked. Opium went from being sold in any store front
in the form of pills or tinctures with no prescription necessary for
purchase or smoked in an opium den down the street, to then bringing
about consumer advocacy and the right to know what is in a medication.
Legislation was created to limit the prescribing and selling of medications
to doctors and pharmacists as well as outlawing opium dens and smoking
opium. This review focuses primarily on the uses of opium throughout
history, the isolation of the principle alkaloids, and their structure
elucidation.
Nine new compounds containing either a chromane or chromene ring moiety were isolated from the monotypic plant Koeberlinia spinosa. Compounds 1-4 are chromanes with all possible E and Z isomers of the isoprenoid side chain, with compound 5 a methylated derivative of 1. Compounds 6 and 7 were assigned as diastereomeric cyclized derivatives of 2 and were probably artifacts formed during the extraction or the isolation processes. Compounds 8 and 9 were characterized as new chromenes. Structure elucidation of 1-9 was conducted via 1D and 2D NMR spectroscopic data interpretation, and absolute configurations were determined by ECD spectroscopic analysis. Compounds 2, 5, 6, and 7 had weak antiplasmodial activity, while none of the compounds exhibited antiproliferative activity. The isolation, structure elucidation, and biological evaluation of these compounds are presented.
Antiplasmodial bioassay guided fractionation of a Madagascar collection of
Crinum firmifolium led to the isolation of seven compounds. Five of the
seven compounds were determined to be 2-alkylquinolin-4(1H)-ones with
varying side chains. Compounds 1 and 4 were determined to be
known compounds with reported antiplasmodial activities, while 5 was believed
to be a new branched 2-alkylquinolin-4(1H)-one, however, it was isolated
in limited quantities and in admixture and therefore was synthesized to confirm its
structure as a new antiplasmodial compound. Along with 5, two other new and
branched compounds 6 and 7 were synthesized as well.
Accompanying the five quinolones were two known compounds 2 and
3 which are inactive against Plasmodium falciparum. The
isolation, structure elucidation, total synthesis, and biological evaluation of these
compounds are discussed in this article.
Allosteric
ligands within a given chemotype can have the propensity
to display a wide range of pharmacology, as well as unexpected changes
in GPCR subtype selectivity, typically mediated by single-atom modifications
to the ligand. Due to the unexpected nature of these “molecular
switches”, chemotypes with this property are typically abandoned
in lead optimization. Recently, we have found that in vivo oxidative
metabolism by CYP
450
s can also engender molecular switches
within allosteric ligands, changing the mode of pharmacology and leading
to unwanted toxicity. We required a higher-throughput approach to
assess in vivo metabolic molecular switches, and we turned to a “synthetic
liver”, a 96 well kit of biomimetic catalysts (e.g., metalloporphyrins)
to rapidly survey a broad panel of synthetic CYP
450
s’
ability to oxidize/“metabolize” an mGlu
5
PAM
(VU0403602) known to undergo an in vivo CYP
450
-mediated
molecular switch. While the synthetic CYP
450
s did generate
a number of oxidative “metabolites” at known “hot
spots”, several of which proved to be pure mGlu
5
PAMs comparable in potency to the parent, the known CYP
450
-mediated in vivo ago-PAM metabolite, namely, VU0453103, was not
formed. Thus, this technology platform has potential to identify hot
spots for oxidative metabolism and produce active metabolites of small-molecule
ligands in a high-throughput, scalable manner.
Antiproliferative bioassay-guided fractionation of the ethanolic extract
of the endemic Madagascan plant Metaporana sericosepala led to
the first natural product isolation of a butenolide diterpene which was
synthesized during an anti-inflammatory study in 1988. The structure of the
compound was elucidated as 3-homofarnesyl-4-hydroxybutenolide (1)
by analysis of its spectroscopic data, including 1D- and 2D-NMR data and
chemical evidence. The once synthetic compound can now also be considered as a
natural product. Compound 1 had modest antiproliferative activity
towards the A2780 ovarian cancer cell line with an IC50 value of 8
μM.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.