Cytotoxic Alkaloids from <i>Fusarium incarnatum</i> Associated with the Mangrove Tree <i>Aegiceras corniculatum</i>

Several unusual alkaloids, <i>N</i>-2-methylpropyl-2-methylbutenamide (<b>1</b>), 2-acetyl-1,2,3,4-tetrahydro-β-carboline (<b>2</b>), fusarine (<b>3</b>), fusamine (<b>4</b>), and 3-(1-aminoethylidene)-6-methyl-2<i>H</i>-pyran-2,4­(3<i>H</i>)-dione (<b>5</b>), were isolated from the culture broth of <i>Fusarium incarnatum</i> (HKI0504), an endophytic fungus of the mangrove plant <i>Aegiceras corniculatum</i>. Compounds <b>2</b>, <b>4</b>, and <b>5</b> exhibit weak antiproliferative and cytotoxic activities against HUVEC, K-562, and HeLa human cell lines, respectively

Injury-Induced Biosynthesis of Methyl-Branched Polyene Pigments in a White-Rotting Basidiomycete

A stereaceous basidiomycete was investigated with regard to its capacity to produce yellow pigments after physical injury of the mycelium. Two pigments were isolated from mycelial extracts, and their structures were elucidated by ESIMS and one- and two-dimensional NMR methods. The structures were identified as the previously undescribed polyenes (3<i>Z</i>,5<i>E</i>,7<i>E</i>,9<i>E</i>,­11<i>E</i>,13<i>Z</i>,15<i>E</i>,17<i>E</i>)-18-methyl-19-oxoicosa-3,5,7,9,11,13,15,17-octaenoic acid (<b>1</b>) and (3<i>E</i>,5<i>Z</i>,7<i>E</i>,9<i>E</i>,11<i>E</i>,­13<i>E</i>,15<i>Z</i>,17<i>E</i>,19<i>E</i>)-20-methyl-21-oxodocosa-3,5,7,9,11,13,15,17,19-nonaenoic acid (<b>2</b>). Stable-isotope feeding with [1-¹³C]­acetate and l-[methyl-¹³C]­methionine demonstrated a polyketide backbone and that the introduction of the sole methyl branch is most likely <i>S</i>-adenosyl-l-methionine-dependent. Dose-dependent inhibition of <i>Drosophila melanogaster</i> larval development was observed with both polyenes in concentrations between 12.5 and 100 μM. GI₅₀ values for <b>1</b> and <b>2</b> against HUVEC (K-562 cells) were 71.6 and 17.4 μM (15.4 and 1.1 μM), respectively, whereas CC₅₀ values for HeLa cells were virtually identical (44.1 and 45.1 μM)

Synthetic Remodeling of the Chartreusin Pathway to Tune Antiproliferative and Antibacterial Activities

Natural products of the benzonaphthopyranone class, such as chartreusin, elsamicin A, gilvocarcin, and polycarcin, represent potent leads for urgently needed anticancer therapeutics and antibiotics. Since synthetic protocols for altering their architectures are limited, we harnessed enzymatic promiscuity to generate a focused library of chartreusin derivatives. Pathway engineering of the chartreusin polyketide synthase, mutational synthesis, and molecular modeling were employed to successfully tailor the structure of chartreusin. For the synthesis of the aglycones, improved synthetic avenues to substituted coumarin building blocks were established. Using an engineered mutant, in total 11 new chartreusin analogs (desmethyl, methyl, ethyl, vinyl, ethynyl, bromo, hydroxy, methoxy, and corresponding (1→2) <i>abeo</i>-chartreusins) were generated and fully characterized. Their biological evaluation revealed an unexpected impact of the ring substituents on antiproliferative and antibacterial activities. Irradiation of vinyl- and ethynyl-substituted derivatives with blue light resulted in an improved antiproliferative potency against a colorectal cancer cell line. In contrast, the replacement of a methyl group by hydrogen caused a drastically decreased cytotoxicity but markedly enhanced antimycobacterial activity. Furthermore, mutasynthesis of bromochartreusin led to the first crystal structure of a chartreusin derivative that is not modified in the glycoside residue. Beyond showcasing the possibility of converting diverse, fully synthetic polyphenolic aglycones into the corresponding glycosides in a whole-cell approach, this work identified new chartreusins with fine-tuned properties as promising candidates for further development as therapeutics

Antitubercular and Cytotoxic Chlorinated <i>seco</i>-Cyclohexenes from <i>Uvaria alba</i>

Two new chlorine-containing polyoxygenated <i>seco</i>-cyclohexenes, albanols A (<b>1</b>) and B (<b>2</b>), along with the oxepinone metabolite grandiuvarone (<b>3</b>) were isolated from the endemic Philippine Annonaceae plant <i>Uvaria alba</i>. Both new compounds exhibited modest antitubercular activity. Compound <b>1</b> showed cytostatic activity (ranging from 1–50 μM) against HeLa cells and weak antiproliferative activity against HUVEC and K-562 cells with GI₅₀ values of 106 and 81 μM, respectively

Tetrahydroxanthene-1,3(2<i>H</i>)‑dione Derivatives from <i>Uvaria valderramensis</i>

Two tetrahydroxanthene-1,3­(2<i>H</i>)-dione metabolites, valderramenols A (<b>1</b>) and B (<b>2</b>), were isolated from the Philippine endemic Annonaceous species <i>Uvaria valderramensis</i>. Planar structures of the <i>rac</i>-xanthene-1,3-(2<i>H</i>)-diones <b>1</b> and <b>2</b> were established by MS and NMR measurements. Their enantiomers were separated by chiral HPLC, and the absolute configurations of the separated enantiomers were determined by comparison of the HPLC-ECD spectra with computed TDDFT-generated spectra. A TDDFT-ECD study of the known grandiuvarone (<b>3</b>) allowed the revision of its absolute configuration as <i>S</i>. Compound <b>1</b> showed antitubercular activity (MIC 10 μg/mL), while <b>3</b> and <b>4</b> had weaker activities (MIC 32 μg/mL). Oxepinone <b>3</b> exhibited cytotoxic activity against KB-562, a chronic myeloid leukemia cell line

Additional file 1: Figure S1. of Age-related macular degeneration associated polymorphism rs10490924 in ARMS2 results in deficiency of a complement activator

Expression vector with ARMS2 coding sequence. (PDF 268 kb