Ammosamides E-F (1-2), are amidine analogs of the ammosamide family of alkaloids isolated from a marine-derived Streptomyces variabilis. Further studies with S. variabilis revealed a variety of aryl and alkyl amines added into the fermentation media could be efficiently incorporated into the ammosamide framework to generate a library of precursor-directed amidine analogs, ammosamides G-P (9 – 18). We demonstrate that the amines are introduced via non-enzymatic addition to the iminium ion of ammosamide C. Biological evaluation of the amidine analogs against quinone reductase 2 (QR2) showed low nM potency for a number of analogs. When tested for in vivo activity against a panel of non-small cell lung cancer (NSCLC) cell-lines there was a clear increase in potency by incorporation of lipophilic alkylamines, with the most potent compounds having sub μM IC50 values (0.4 to 0.8 μM).
Investigation of the endemic Malagasy plant Bussea sakalava Du Puy & R. Rabev. (Fabaceae) for antiproliferative activity against the A2780 ovarian cancer cell line led to the isolation of the four new diphenylpropanes 1-4 and the new cycloheptadibenzofuran 5; compound 5 has a previously unreported natural product skeleton. The structure elucidation of these compounds was based on the analysis of their 1D and 2D NMR and mass spectroscopic data. Compounds 1-5 were tested for antiproliferative activity against the A2780 human ovarian cancer cell line.In our continuing search for biologically active natural products from tropical rainforests as part of an International Cooperative Biodiversity Group (ICBG) program, we obtained an ethanol extract from the roots of a plant identified as Bussea sakalava Du Puy & R. Rabev. (Fabaceae) from Madagascar. This extract showed moderate antiproliferative activity against the A2780 human ovarian cancer cell line with an IC 50 value of 10 µg/mL. The extract was selected for examination on the basis of this activity and the absence of previous phytochemical studies of the species.Previous studies on the genus Bussea indicated the presence of azetidine-2-carboxylic acid and 3-hydroxyproline in seeds of different Bussea species,2 , 3 and the cytotoxicity and high trypanocidal activity of a methanol extract of stem bark of Bussea occidentalis has been reported.4Fractionation of a dichloromethane fraction of an ethanol extract of B. sakalava by C-18 open column and high performance liquid chromatography (HPLC) yielded four new diphenylpropanes named bussealins A-D (1 -4) and a cycloheptadibenzofuran derivative named bussealin E (5). Herein we report the structural elucidation of these new compounds and their antiproliferative properties against the A2780 human ovarian cancer cell line.* To whom correspondence should be addressed. Tel: (540) (Table 1) and were consistent with the molecular formula. The above data suggested that 1 had a diphenyl propane skeleton. The complete 1 H and 13 C NMR assignments and the connectivities were determined from analysis of a combination of COSY, HMQC, and HMBC data. Three mutually coupled methylene groups were revealed by the cross peaks observed in the COSY spectrum. In the HMBC spectrum, H-1 (δ H 2.41) showed correlations with C-2 (δ C 33.0), C-3 (δ C 30.6), C-1' (δ C 140.2), and with C-2' and C-6', both of which had the same chemical shifts (δ C 108.7). The A 2 substitution pattern of the A ring of 1 was established by HMBC correlations from the signal at δ H 6.18 (H-2' and H-6') to C-1 (δ C 36.5), C-1' (δ C 140.2), C-3' (δ C 151.3), C-4' (δ C 134.7) and C-6' and C-2' (δ C 108.7), as well as the correlation from one OCH 3 group at δ H 3.75 to C-4' (δ C 134.7). The proton substitutions on the B ring were assigned based on the 3 J HMBC correlations between H-3 (δ H 2.52) and C-6" (δ C 120.5), and between H-5" (δ H 6.38) and C-1" (δ C 123.4). Moreover, the H-5" proton showed HMBC correlations to C-6" (δ C 120.5), C-4" (δ C 147.8) and C-3" ...
The vast majority of intracellular protein targets are refractory toward small-molecule therapeutic engagement, and additional therapeutic modalities are needed to overcome this deficiency. Here, the identification and characterization of a natural product, WDB002, reveals a therapeutic modality that dramatically expands the currently accepted limits of druggability. WDB002, in complex with the FK506-binding protein (FKBP12), potently and selectively binds the human centrosomal protein 250 (CEP250), resulting in disruption of CEP250 function in cells. The recognition mode is unprecedented in that the targeted domain of CEP250 is a coiled coil and is topologically featureless, embodying both a structural motif and surface topology previously considered on the extreme limits of “undruggability” for an intracellular target. Structural studies reveal extensive protein–WDB002 and protein–protein contacts, with the latter being distinct from those seen in FKBP12 ternary complexes formed by FK506 and rapamycin. Outward-facing structural changes in a bound small molecule can thus reprogram FKBP12 to engage diverse, otherwise “undruggable” targets. The flat-targeting modality demonstrated here has the potential to expand the druggable target range of small-molecule therapeutics. As CEP250 was recently found to be an interaction partner with the Nsp13 protein of the SARS-CoV-2 virus that causes COVID-19 disease, it is possible that WDB002 or an analog may exert useful antiviral activity through its ability to form high-affinity ternary complexes containing CEP250 and FKBP12.
Ammosamide D (1), an oxidized analog of the ammosamide family, was isolated from a marine-derived Streptomyces variabilis. Pyrroloquinoline containing alkaloids are a growing class of natural products, with 1 being the first example of an oxidized analog resulting in a 5,6-dioxo-5,6-dihydroquinoline ring system. Attempts at chemical conversion of ammosamide B to ammosamide D revealed that a strong chemical oxidant is required. Ammosamide D has modest cytotoxicity to the MIA PaCa-2 pancreatic cancer cell line.
Investigation of the endemic Madagascar plant Leptadenia madagascariensis Decne. (Apocynaceae) for antiproliferative activity against the A2780 ovarian cancer cell line led to the isolation of the four new cardenolides 1-4. The structure elucidations of these compounds were based on analyses of their 1D and 2D NMR spectra and mass spectrometric data. The cardenolides were strongly antiproliferative to the A2780 ovarian cancer cell line, with IC 50 values of 0.18, 0.21, 0.17 and 0.29 μM line, and to the H460 human lung cancer cell line, with IC 50 values of 0.16, 0.68, 0.37 and 0.48 μM respectively.
Investigation of the Madagascan endemic plant Ambavia gerrardii (Baill.) Le Thomas (Annonaceae) for antiproliferative activity against the A2780 ovarian cancer cell line led to the isolation of the three new alkaloids 8-hydroxyeupolauridine (1), 9-methoxyeupolauridine 1-oxide (2) and 11-methoxysampangine (3), and the three known alkaloids 4–6. The structures of 1 and 2 were confirmed by synthesis. Compounds 3, 4, and 6 showed moderate to good antiproliferative activities, with IC50 values of 10.3, 3.5, and 0.60 µM, respectively, against the A2780 human ovarian cancer cell line, and with IC50 values of 0.57, 1.77, and 0.58 µM, respectively, against the H460 human lung cancer cell line.
Investigation of extracts from the plant Athroisma proteiforme (Humbert) Mattf. (Asteraceae) for antimalarial activity led to the isolation of the five new sesquiterpene lactones 1–5 together with centaureidin (6). The structures of the new compounds were deduced from analyses of physical and spectroscopic data, and the absolute configuration of compound 1 was confirmed by an X-ray crystallographic study. Athrolides C (3) and D (4) both showed antiplasmodial activities with IC50 values of 6.6 (3) and 7.2 μM (4) against the HB3 strain and 5.5 (3) and 4.2 μM (4) against the Dd2 strain of the malarial parasite Plasmodium falciparum. The isolates 1–6 also showed antiproliferative activity against A2780 human ovarian cancer cells, with IC50 values ranging from 0.4 to 2.5 μM.
Total synthesis enabled the assignment of relative and absolute stereochemistry of nigricanoside A, which was reported to show potent cytotoxicity.
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