The benz [a]anthraquinones are a class of compounds that have attracted a great deal of attention owing to their interesting biological properties.As part of our on-going screening for new antitumor compounds from marine microorganisms, we have isolated a new angucyclinone, PM070747 (1) (Figure 1), produced by the actinomycete Saccharopolyspora taberi PEM-06-F23-019B, from a marine sponge collected from near the coast of Tanzania. Additionally, traces of the known angucyclinone, PD116740 1 (2), were also found.Compound 1 is structurally closely related to 2 and TAN-1085 2 (3) (Figure 1). Compound 2 was first isolated from the unknown actinomycete, WP4669, and it was described as a compound with antitumor properties against leukemia and adenocarcinoma cell lines. 1 Recently, an epimer of 2 was isolated from a marine fungus, Penicillium sp. 3 Compound 3 and its aglycone were described as angiogenesis and aromatase inhibitors in the Japanese patent JP02289532. 2 The microbial producer of 1, Saccharopolyspora taberi PEM-06-F23-019B, was isolated by spreading the homogenized ectosome of the sponge on Bennett's agar medium 4 plates supplemented with nalidixic acid (0.02%) and cycloheximide (0.02%). The plates were incubated at 28 1C for 30 days.The strain was subjected to a phylogenetic analysis based on 16S rRNA sequences analyzed by BLAST (Basic Local Alignment Search Tool) against the NCBI (National Center for Biotechnology Information) database, 5 and showed a high identity with that of Saccharopolyspora, such as Saccharopolyspora taberi DSM 43856 (956/968, 98.8%) (sequence AF002819). 6 The seed culture was developed in two scale-up steps, first in 100-ml Erlenmeyer flasks containing 20 ml of seed medium, and then in 250-ml Erlenmeyer flasks with 50 ml of the same medium. The seed culture was grown on a medium containing dextrose (0.1%), soluble starch 2.4%, soy peptone 0.3%, yeast extract 0.5%, Tryptone 0.5%, soya flour 0.5%, NaCl 0.54%, KCl 0.02%, MgCl 2 0.24%, Na 2 SO 4 0.75% and CaCO 3 0.4% in tap water, and cultured at 28 1C on an orbital shaker for 72 h. For production, 12.5 ml of the seed medium was transferred into 2000-ml Erlenmeyer flasks containing 250 ml of fermentation medium, comprising yeast extract 0.5%, soy peptone 0.1%, dextrose 0.5%, soya flour 0.3%, Glucidex 2.0%, NaCl 0.53%, KCl 0.02%, MgCl 2 Á6H 2 O 0.24%, Na 2 SO 4 0.75%, MnSO 4 Á4H 2 O 0.00076%, CoCl 2 Á6H 2 O 0.0001%, K 2 HPO 4 0.05% and CaCO 3 0.4%. The culture was grown at 28 1C using an orbital shaker (5-cm eccentricity, 220 r.p.m.) for 5 days.The bioassay-guided isolation of 1 from the fermentation broth is depicted in Figure 2 and summarized below.The fermentation broth (6 l) was subjected to centrifugation, and the clarified broth was extracted with ethyl acetate 1 : 1 (v/v). The extract was concentrated to give a broth extract (382 mg). It was subjected to reversed-phase vacuum chromatography by a filter funnel on Polygoprep 100-50 mm C18, using a H 2 O-MeOH-CH 2 Cl 2 mixture as the eluting solvent. The cytotoxic activity was...

QM/NMR-DFT (quantum mechanics combined with nuclear magnetic resonance parameters calculated by density functional theory approximations) studies allowed us to link two stereoclusters separated by two methylene groups present in the new meroditerpenes halioxepine B (2) and halioxepine C (3) and the known halioxepine (1), isolated from two Indonesian sponges of the genus Haliclona (Reniera). DP4 and DP4+ probabilities were used to discriminate the two diastereotopic arrangements of the two stereoclusters, whose unconnected relative configurations were determined by ROESY and J-based configurational analysis. To confirm the DFT studies, the full relative configuration of 1 was deduced using a mixture of benzene-d and pyridine-d as the NMR solvent. ROESY measurements connected the two stereoclusters and demonstrated that DFT calculations accurately predict the configuration when two methylenes separate the two stereoclusters. The different arrangements of the distant stereoclusters C-1/C-2/C-7 and C-10/C-15 for compounds 2 and 3 were deduced by DFT calculations and explained the opposite optical rotations observed for the two compounds. Halioxepines B (2) and C (3) display moderate cytotoxicity against different human cancer cell lines.

Lurbinectedin is a novel and potent selective inhibitor of active transcription of proteincoding genes, triggering apoptosis of cancerous cells, which has been approved for the treatment of patients with metastatic small-cell lung cancer with disease progression on or after platinum-based chemotherapy. Different studies aimed at exploring the disposition and metabolism of lurbinectedin were performed in vitro and in vivo (by intravenous administration of lurbinectedin). Low blood cell partitioning for lurbinectedin in rat, nonhuman primate (NHP) and human was determined as 23.4%, 29.8% and 9.8%, respectively. Protein binding was very high (>95%) in total plasma (rat, NHP, human), albumin and -1-acid glycoprotein (both from human). In vitro, lurbinectedin underwent intense liver microsome-mediated metabolism (in 10 minutes, an 80% of the compound is metabolized in human), with CYP3A4 being the isoform involved in that metabolism; results also showed NHP being the nonclinical species which, metabolically, most closely resembles humans. Mass balance studies performed in rats (both genders), NHP (male only) and patients (both genders) demonstrated that the principal route of excretion of 14 C-lurbinectedin-related radioactivity was through the feces (88.7±10.1% in patients), with only a minor fraction recovered from the urine (5.6±2.0% in patients). In plasma samples, the majority of lurbinectedin-related radioactivity was attributed to unchanged compound (95±3.1% and 70.2±10.9% in NHP and human, respectively); plasma metabolic profiling demonstrated the major (% compared to unchanged compound) circulating metabolites were N-Desmethyllurbinectedin (0.4±0.2% and 10.4±2.2% in NHP and patients, respectively) and 1',3'-Desmethylene-lurbinectedin (0.9±0.7% and 14.3±10.4% in NHP and patients, respectively).

No abstract