Ana R. Díaz-Marrero

Bafilomycins produced in culture by Streptomyces spp. isolated from marine habitats are potent inhibitors of autophagy

Five new bafilomycins, F (1) to J (5), have been isolated from laboratory cultures of two Streptomyces spp. obtained from marine sediments collected in British Columbia, and their structures have been elucidated by detailed analysis of spectroscopic data and the synthesis of model compounds. The new bafilomycins F (1), G (2), H (3), and J (5) along with several co-occurring known analogues showed potent inhibition of autophagy in microscopy and biochemical assays. The thiomorpholinone fragment present in bafilomycin F (1) has not previously been found in a natural product.

Abrogation of ionizing radiation-induced G2 checkpoint and inhibition of nuclear export by Cryptocarya pyrones.

G2 checkpoint inhibitors can force cells arrested in G2 phase by DNA damage to enter mitosis. In this manner, several G2 checkpoint inhibitors can enhance killing of cancer cells by ionizing radiation and DNA-damaging chemotherapeutic agents, particularly in cells lacking p53 function. All G2 checkpoint inhibitors identified to date target protein phosphorylation by inhibiting checkpoint kinases or phosphatases. Using a phenotypic cell-based assay for G2 checkpoint inhibitors, we have screened a large collection of plant extracts and identified Z-Cryptofolione and Cryptomoscatone D2 as highly efficacious inhibitors of the G2 checkpoint. These compounds and related pyrones also inhibit nuclear export. Leptomycin B, a potent inhibitor of Crm1-mediated nuclear export, is also a very potent G2 checkpoint inhibitor. These compounds possess a reactive Michael acceptor site and do not appear promising as a radiosensitizing agents because they are toxic to unirradiated cells at checkpoint inhibitory concentrations. Nevertheless, the results show that inhibition of nuclear export is an alternative to checkpoint kinase inhibition for abrogating the G2 checkpoint and they should stimulate the search for less toxic nuclear export inhibitors.

Cytotoxic Activity of Halogenated Monoterpenes from Plocamium cartilagineum

Nine halogenated monoterpenes isolated from the red alga Plocamium cartilagineum have been evaluated for their cytotoxic effects on the tumor cell lines CT26 (murine colon adenocarcinoma), SW480 (human colon adenocarcinoma), HeLa (human cervical adenocarcinoma) and SkMel28 (human malignant melanoma) with several multidrug resistance mechanisms and the mammalian non-tumor cell line CHO (Chinese hamster ovary cells). The activities of these compounds were compared with those of the insecticide γ-hexachlorocyclohexane (lindane) due to chemical structure similarities. Compounds 1, 2, 3, and 5 exhibited selective cytotoxicity against colon and cervical adenocarcinoma cells. Interestingly, the effect of compound 3 was specific and irreversible to human colon adenocarcinoma SW480 cells, which overexpress the transmembrane P-glycoprotein often related to chemoresistance. None of the anti-tumor doses of these compounds was cytotoxic against CHO cells. Furthermore, analysis of cellular extracts after incubation with the test compounds and rotenone (positive uptake control) demonstrated the intracellular accumulation of 1, 2, 3, and 5.

Pronuciferine N-Oxide, a Proaporphine N-Oxide Alkaloid from Berberis coletioides

Pronuciferine N-oxide (1), a proaporphine N-methyl-N-oxide alkaloid, along with the parent alkaloid pronuciferine (2) were isolated from Berberis coletioides. The structure of the new compound was determined by spectroscopic evidence. Compound 1 is the first naturally occurring proaporphinoid alkaloid with an N-oxide functionality.

Scalarane-based metabolites isolated from the antimitotic extract of the marine sponge Hyrtios erectus

Two novel sesterterpenes, 1 and 3, containing a scalarane-based framework, have been isolated from the sponge Hyrtios erectus collected in Papua New Guinea. Their structures and relative stereochemistry have been elucidated by analysis of their spectroscopic data.

Leptolide Improves Insulin Resistance in Diet-Induced Obese Mice

Type 2 diabetes (T2DM) is a complex disease linked to pancreatic beta-cell failure and insulin resistance. Current antidiabetic treatment regimens for T2DM include insulin sensitizers and insulin secretagogues. We have previously demonstrated that leptolide, a member of the furanocembranolides family, promotes pancreatic beta-cell proliferation in mice. Considering the beneficial effects of leptolide in diabetic mice, in this study, we aimed to address the capability of leptolide to improve insulin resistance associated with the pathology of obesity. To this end, we tested the hypothesis that leptolide should protect against fatty acid-induced insulin resistance in hepatocytes. In a time-dependent manner, leptolide (0.1 µM) augmented insulin-stimulated phosphorylation of protein kinase B (PKB) by two-fold above vehicle-treated HepG2 cells. In addition, leptolide (0.1 µM) counteracted palmitate-induced insulin resistance by augmenting by four-fold insulin-stimulated phosphorylation of PKB in HepG2 cells. In vivo, acute intraperitoneal administration of leptolide (0.1 mg/kg and 1 mg/kg) improved glucose tolerance and insulin sensitivity in lean mice. Likewise, prolonged leptolide treatment (0.1 mg/kg) in diet-induced obese mice improved insulin sensitivity. These effects were paralleled with an ~50% increased of insulin-stimulated phosphorylation of PKB in liver and skeletal muscle and reduced circulating pro-inflammatory cytokines in obese mice. We concluded that leptolide significantly improves insulin sensitivity in vitro and in obese mice, suggesting that leptolide may be another potential treatment for T2DM.

Compounds isolated from Salinispora arenicola of the Gulf of California, México

La actinobacteria marina AMS370, identificada mediante comparacion de las secuencias del gen 16S del ARNr como Salinispora arenicola, fue aislada a partir de sedimento del Golfo de California, Mexico. De su extracto semi-polar, se aislaron 8 compuestos conocidos: acido-4-Hidroxi-fenil acetico (1), 5-Metil-2-metilen-2,3-dihidro-1H-pirimidin-4-ona (2), 1H-Pirimidin-2,4-diona (3), acido-3-amino-5-hidroxi-benzoico (4), 2-(4-Amino-imidazol-[4,5-d]piridazin-1-il)-5-hidroximetil-4-metil-tetrahidro -furan-3-ol (5), Acrilato de 3-(4-Hidroxi-genil)-metilo (6), 3-Bencil-6-isobutil-piperazin-2,5-diona (7) y 5,8-epidioxi-(22E,24R)-ergosta-6,22-dien-3-ol (Peroxido de Ergosterol) (8). La identificacion quimica fue realizada mediante comparacion de sus espectros de RMN con los espectros de los compuestos originales. Esta seria la primera ocasion que el compuesto 4 se reporta como un producto natural a partir del genero Salinispora. El extracto crudo y todas sus fracciones fueron ensayadas contra Bacillus cereus, Escherichia coli, Enterococcus faecalis, Klebsiella pneumoniae, Proteus mirabilis, Staphylococcus aureus, Salmonella sp. y Candida albicans para probar su actividad antibiotica y antifungica en el caso de la ultima especie. Asimismo se evaluo su actividad citotoxica frente a las lineas celulares de cancer de mama (MCF-7), cervicouterino (HeLa) y colorectal (HCT-116). Solamente el extracto crudo semipolar y las fracciones 5.1 y 5.2 resultaron activas contra Klebsiella pneumoniae y Staphylococcus aureus.

Chloro-Furanocembranolides from Leptogorgia sp. Improve Pancreatic Beta-Cell Proliferation

Two new chloro-furanocembranolides (1, 2) and two new 1,4-diketo cembranolides (3, 4) were isolated from the crude extract of Leptogorgia sp. together with a new seco-furanocembranolide (5) and the known Z-deoxypukalide (6), rubifolide (7), scabrolide D (8) and epoxylophodione (9). Their structures were determined based on spectroscopic evidence. Four compounds: 1, 2, 7 and 8 were found to activate the proliferation of pancreatic insulin-producing (beta) cells.