Antimalarial Natural Products.

Natural products have made a crucial and unique contribution to human health, and this is especially true in the case of malaria, where the natural products quinine and artemisinin and their derivatives and analogues, have saved millions of lives. The need for new drugs to treat malaria is still urgent, since the most dangerous malaria parasite, Plasmodium falciparum, has become resistant to quinine and most of its derivatives and is becoming resistant to artemisinin and its derivatives. This volume begins with a short history of malaria and follows this with a summary of its biology.

My 60-Year Love Affair with Natural Products.

The author describes his 60-year career in studying the chemistry of natural products, which includes structural, synthetic, and biosynthetic studies of natural products ranging from insect pigments, antibiotics, and fecal mutagens to taxol and other anticancer natural products as well as antimalarial natural products. One of the compounds discussed, napabucasin, is now an anticancer drug in phase III clinical trials.

Phloroglucinols from the Roots of Garcinia dauphinensis and Their Antiproliferative and Antiplasmodial Activities.

Garcinia dauphinensis is a previously uninvestigated endemic plant species of Madagascar. The new phloroglucinols dauphinols A-F and 3'-methylhyperjovoinol B (1-7) and six known phloroglucinols (8-13) together with tocotrienol 14 and the three triterpenoids 15-17 were isolated from an ethanolic extract of G. dauphinensis roots using various chromatographic techniques.

Antiplasmodial Diterpenoids and a Benzotropolone from Petradoria pumila.

An extract of Petradoria pumila from the Natural Products Discovery Institute was found to have moderate antiplasmodial activity, with an IC value between 5 and 10 μg/mL. The four new diterpenoids petradoriolides A-D (1-4), the new benzotropolone petradoriolone (5), and the two known lignans 6 and 7 were isolated after bioassay-directed fractionation. The structures and stereochemistries of the new compounds were determined by interpretation of NMR spectroscopy, mass spectrometry, and ECD spectra.

Novel Dual-Action Targeted Nanomedicine in Mice With Metastatic Thyroid Cancer and Pancreatic Neuroendocrine Tumors.

Background: The advantages of nanomedicines include preferential delivery of the payload directly to tumor tissues. CYT-21625 is the novel, first-in-class gold nanomedicine designed to target tumor vasculature and cancer cells by specifically delivering recombinant human tumor necrosis factor alpha (rhTNF) and a paclitaxel prodrug.

Methods: We analyzed TNF receptor expression in publicly available gene expression profiling data and in thyroid tissue samples.

Structure Reassignment of Cryptorigidifoliols E and K.

The structures of the α-pyrones cryptorigidifoliols E (5) and K (11) have been reassigned as 5C and 11C.

Antimalarial Use of Malagasy Plants is Poorly Correlated with Performance in Antimalarial Bioassays.

Bioassay screening of plant extracts can identify unique lead compounds for drug development, but the "hit rate" from random screening is very low. Targeted screening of medicinal plants has been repeatedly reported to increase the percentage of samples displaying bioactivity. Contrarily, Maranz (2012) suggested that African antimalarial plants were unsuitable sources of antimalarial drugs because high prevalence of malaria would result in rapid evolution of resistance to active compounds that directly targeted the parasite.

Furoquinoline Alkaloids and Methoxyflavones from the Stem Bark of Melicope madagascariensis (Baker) T.G. Hartley.

Melicope madagascariensis (Rutaceae) is an endemic plant species of Madagascar that was first classified as a member of the genus Euodia J. R. & G.

Synthesis and Evaluation of Paclitaxel-Loaded Gold Nanoparticles for Tumor-Targeted Drug Delivery.

The synthesis of a series of thiolated paclitaxel analogs is described as part of a novel nanomedicine program aimed at developing formulations of paclitaxel that will bind to gold nanoparticles for tumor targeted drug delivery. Preliminary evaluation of the new nanomedicine composed of 27 nm gold nanoparticles, tumor necrosis factor alpha (TNFα), thiolated polyethylene glycol (PEG-thiol), and one of several thiolated paclitaxel analogs is presented.

Synthesis and Antimalarial Activity of Mallatojaponin C and Related Compounds.

The phloroglucinol mallotojaponin C (1) from Mallotus oppositifolius, which was previously shown by us to have both antiplasmodial and cytocidal activities against the malaria parasite Plasmodium falciparum, was synthesized in three steps from 2',4',6'-trihydroxyacetophenone, and various derivatives were synthesized in an attempt to improve the bioactivity of this class of compounds. Two derivatives, the simple prenylated phloroglucinols 12 and 13, were found to have comparable antiplasmodial activities to that of mallotojaponin C.

Antiproliferative and antiplasmodial compounds from selected Streptomyces species.

In continuation of our ongoing search for bioactive compounds from microbial extracts, we performed antiproliferative and/or antimalarial assays on extracts of 806 microbial species isolated from Madagascan marine organisms, on 1317 species isolated from Madagascan soil samples and on a Streptomyces species (S.4) from a marine sponge collected from the Florida Keys. This work identified active extracts from four Streptomyces isolates (S.

Antimalarial 5,6-Dihydro-α-pyrones from Cryptocarya rigidifolia: Related Bicyclic Tetrahydro-α-Pyrones Are Artifacts1.

Antimalarial bioassay-guided fractionation of an EtOH extract of the root wood of Cryptocarya rigidifolia (Lauraceae) led to the isolation of the five new 5,6-dihydro-α-pyrones cryptorigidifoliols A-E (1-5) and the six bicyclic tetrahydro-α-pyrone derivatives cryptorigidifoliols F-K (6-11). The structure elucidations of all compounds were made on the basis of the interpretation of spectroscopic data and chemical derivatization, and the relative and absolute configurations were determined by NOESY, electronic circular dichroism (ECD), and (1)H NMR analysis of α-methoxyphenylacetyl (MPA) derivatives. The bicyclic tetrahydro-α-pyrone derivatives were identified as products of acid-catalyzed intramolecular Michael addition of the 5,6-dihydro-α-pyrones in the presence of silica gel.

Antiproliferative Compounds from from the Madagascar Dry Forest.

Bioassay-directed fractionation of an antiproliferative ethanol extract of the roots of (Lauraceae) afforded the new butanolide macrocarpolide A (), and the two new secobutanolides macrocarpolides B () and C (), together with the known butanolides linderanolide B () and isolinderanolide (). The structure elucidation of all compounds was carried out based on NMR and mass spectroscopic data analyses. The absolute configurations of all compounds isolated were determined by comparison of their optical rotation values with those found in literature.

Isolation of antiplasmodial anthraquinones from Kniphofia ensifolia, and synthesis and structure-activity relationships of related compounds.

Bioassay-guided separation of the South African plant Kniphofia ensifolia for antiplasmodial activity led to the isolation of two new anthraquinones, named kniphofiones A and B (3 and 4), together with three known bioactive anthraquinone monomers (1, 2 and 5), and four known bisanthraquinones (6-9). The structures of the two new compounds were elucidated based on analyses of their 1D and 2D NMR spectra and mass spectrometric data. The dimeric compounds 6 and 7 displayed the strongest antiplasmodial activity among all the isolated compounds, with IC₅₀ values of 0.

Bioactive compounds from Stuhlmannia moavi from the Madagascar dry forest.

Bioassay-directed fractionation of the leaf and root extracts of the antiproliferative Madagascar plant Stuhlmannia moavi afforded 6-acetyl-5,8-dihydroxy-2-methoxy-7-methyl-1,4-naphthoquinone (stuhlmoavin, 1) as the most active compound, with an IC50 value of 8.1 μM against the A2780 human ovarian cancer cell line, as well as the known homoisoflavonoid bonducellin (2) and the stilbenoids 3,4,5'-trihydroxy-3'-methoxy-trans-stilbene (3), piceatannol (4), resveratrol (5), rhapontigenin (6), and isorhapontigenin (7). The structure elucidation of all compounds was based on NMR and mass spectroscopic data, and the structure of 1 was confirmed by a single crystal X-ray analysis.

Structure elucidation of antiproliferative bisbenzylisoquinoline alkaloids from Anisocycla grandidieri from the Madagascar dry forest.

Antiproliferative bioassay-guided fractionation of the ethanol extract of the stems of Anisocycla grandidieri led to the isolation of the known alkaloids stebisimine (1), (+)-1,2-dehydrotelobine (2), (+)-2'-norcocsuline (3) and puetogaline B (4). Herein, we report the full NMR assignments of all compounds and the X-ray crystallography of single crystals of compounds 1 and 3. Compounds 2 and 3 showed moderate antiproliferative activity against the A2780 human ovarian cancer cell line with IC50 values of 4.

Antiproliferative Homoisoflavonoids and Bufatrienolides from Urginea depressa.

Investigation of the South African plant Urginea depressa Baker (Asparagaceae Juss.) for antiproliferative activity against the A2780 ovarian cancer cell line led to the isolation of the six new homoisoflavonoids urgineanins A-F (1-6), the two known bufatrienolides 7 and 9, and the new bufatrienolides urginins B and C (8 and 10). Structures were elucidated based on analysis of their 1D and 2D NMR spectra, electronic circular dichroism, and mass spectrometric data.

Isolation and synthesis of two antiproliferative calamenene-type sesquiterpenoids from Sterculia tavia from the Madagascar rain forest.

Investigation of the endemic Madagascan plant Sterculia taiva Baill. (Malvaceae) for antiproliferative activity against the A2780 ovarian cancer cell line led to the isolation of two new bioactive calamenene-type sesquiterpenoids, named tavinin A (2) and epi-tavinin A (3) together with the known sesquiterpenoid mansonone G (1). The structures of the two new compounds were elucidated based on analysis of their 1D and 2D NMR spectra and mass spectrometric data, and were confirmed by de novo synthesis.