The marine environment harbors a number of macro and micro organisms that have developed unique metabolic abilities to ensure their survival in diverse and hostile habitats, resulting in the biosynthesis of an array of secondary metabolites with specific activities. Several of these metabolites are high-value commercial products for the pharmaceutical and cosmeceutical industries. The aim of this review is to outline the paths of marine natural products discovery and development, with a special focus on the compounds that successfully reached the market and particularly looking at the approaches tackled by the pharmaceutical and cosmetic companies that succeeded in marketing those products. The main challenges faced during marine bioactives discovery and development programs were analyzed and grouped in three categories: biodiversity (accessibility to marine resources and efficient screening), supply and technical (sustainable production of the bioactives and knowledge of the mechanism of action) and market (processes, costs, partnerships and marketing). Tips to surpass these challenges are given in order to improve the market entry success rates of highly promising marine bioactives in the current pipelines, highlighting what can be learned from the successful and unsuccessful stories that can be applied to novel and/or ongoing marine natural products discovery and development programs.

Cationic mononuclear Ni(II) complexes of the chelating N-heterocyclic carbenes tBuCCmeth and tBuCCeth (where tBuCCmeth = 1,1‘-methylene-3,3‘-di-tert-butyldiimidazole-2,2‘-diylidene (1) and tBuCCeth = 1,2-ethylene-3,3‘-di-tert-butyldiimidazole-2,2‘-diylidene (2)) have been prepared and structurally characterized. Reaction between NiCl2(PMe3)2 and 1 equiv of 1 or 2 gives the monocationic salts [(tBuCCmeth)NiCl(PMe3)]Cl (3a) and [(tBuCCeth)NiCl(PMe3)]Cl (4a), which undergo salt metathesis with TlBPh4 to give [(tBuCCmeth)NiCl(PMe3)][BPh4] (3b) and [(tBuCCeth)NiCl(PMe3)][BPh4] (4b). A comparison of the X-ray structures of 3a and 4b shows that the bite angles at the nickel atoms, 84.92(18) and 88.4(4)°, respectively, are comparable to Ni(II) complexes of two-carbon-atom bridging chelating bis-phosphines. Reaction between NiCl2(PMe3)2 or NiBr2(DME) and 2 equiv of 1 gives the Ni(II) dicationic salts [Ni(tBuCCmeth)2][X]2 (X = Cl- (5a), X = Br- (5b)). The X-ray structure of 5b reveals a square-planar geometry at the nickel atom, and the dication adopts a trans double-boat like conformation. An analogous reaction between NiCl2(PMe3)2 and 2 equiv of 2 gives 4a and does not yield the dication [Ni(tBuCCeth)2][Cl]2. Reaction between 4a and 2 equiv of 1 gives 5a, whereas no reaction under analogous conditions occurs between 3a and 2. The influence of steric factors which determine the relative thermodynamic stability toward dicarbene substitution of complexes 3a and 4a is also discussed.

Several drug delivery systems have been investigated to reduce the side effects of chemotherapy by encapsulating the therapeutic agent in a nanosized carrier until it reaches the tumor site. Many of these particles are designed to be responsive to the mechanical and thermal perturbations delivered by ultrasound. Once the nanoparticle reaches the desired location, ultrasound is applied to release the chemotherapy drug only in the vicinity of the targeted (cancer) site, thus avoiding any detrimental interaction with healthy cells in the body. Studies using liposomes and micelles have shown promising results in this area, as these nanoparticles with simple, yet effective structures, showed high efficiency as drug delivery vehicles both in vitro and in vivo. This article reviews the design and application of two novel nanosized chemotherapeutic carriers (i.e. micelles and liposomes) intended to be actuated by ultrasound.

Methylglyoxal metabolism was studied during Saccharomyces cerevisiae grown with D-glucose as the sole carbon and energy source. Using for the first time a specific assay for methylglyoxal in yeast, metabolic fluxes of its formation and D-lactate production were determined. D-Glucose consumption and ethanol production were determined during growth. Metabolic fluxes were also determined in situ, at the glycolytic triose phosphate levels and glyoxalase pathway. Maximum fluxes of ethanol production and glucose consumption correspond to maxima of methylglyoxal and D-lactate formation fluxes during growth. Methylglyoxal formation is quantitatively related to glycolysis, representing 0.3% of the total glycolytic flux in S. cerevisiae. ß

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