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Cancer metabolism has emerged as an important area of research in recent years. Elucidation of the metabolic differences between cancer and normal cells and the underlying mechanisms will not only advance our understanding of fundamental cancer cell biology but also provide an important basis for the development of new therapeutic strategies and novel compounds to selectively eliminate cancer cells by targeting their unique metabolism. This article reviews several important metabolic alterations in cancer cells, with an emphasis on increased aerobic glycolysis (the Warburg effect) and glutamine addiction, and discusses the mechanisms that may contribute to such metabolic changes. In addition, metabolic alterations in cancer stem cells, mitochondrial metabolism and its influence on drug sensitivity, and potential therapeutic strategies and agents that target cancer metabolism are also discussed.

Background:The mechanistic action of antitumor agent OSW-1 is not clearly understood. Results: OSW-1 triggers a calcium-dependent cell death through inhibition of sodium-calcium exchanger 1 (NCX1) and mitochondrial calcium overload. Conclusion: Potency and efficacy of OSW-1 in eliminating leukemia cells are dependent on homeostatic calcium disruption. Significance: New insights on the role of calcium in the mechanism of OSW-1 reveal potential in therapeutics.

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Many polymeric medical device materials contain color additives which could lead to adverse health effects. The potential health risk of color additives may be assessed by comparing the amount of color additive released over time to levels deemed to be safe based on available toxicity data. We propose a conservative model for exposure that requires only the diffusion coefficient of the additive in the polymer matrix, D, to be specified. The model is applied here using a model polymer (poly(ether-block-amide), PEBAX 2533) and color additive (quinizarin blue) system. Sorption experiments performed in an aqueous dispersion of quinizarin blue (QB) into neat PEBAX yielded a diffusivity D 5 4.8 3 10 210 cm 2 s 21 , and solubility S 5 0.32 wt %. On the basis of these measurements, we validated the model by comparing predictions to the leaching profile of QB from a PEBAX matrix into physiologically representative media. Toxicity data are not available to estimate a safe level of exposure to QB, as a result, we used a Threshold of Toxicological Concern (TTC) value for QB of 90 mg/adult/day. Because only 30% of the QB is released in the first day of leaching for our film thickness and calculated D, we demonstrate that a device may contain significantly more color additive than the TTC value without giving rise to a toxicological concern. The findings suggest that an initial screening-level risk assessment of color additives and other potentially toxic compounds found in device polymers can be improved.

By design: A truncated superstolide A, a simplified analogue of the potent anticancer marine macrolide superstolide A, was designed and successfully synthesized by a highly efficient and convergent approach. The biological evaluation showed that this compound maintains the potent anticancer activity of the original natural product superstolide A.

OSW-1 is a highly potent anticancer natural saponin with an unknown mode of action. To determine its cellular target(s) biotinylated OSW-1 was successfully synthesized in 9 steps.

Keywordsanticancer agent; superstolide A analogue; macrolide; drug design; asymmetric synthesis Marine macrolides are well known for their fascinating molecular structure and potent anticancer activity. [1] Superstolides A (1) and B (2) (Figure 1), two marine macrolides, were isolated in minute amounts from the deep-water marine sponge Neosiphonia superstes. [2] Their absolute structures were determined by extensive spectroscopic methods. The structural novelty of these two molecules is characterized by a unique 16-membered macrolactone attached to a functionalized cis-decalin.Both superstolides A and B exhibit potent antiproliferative effect against several tumor cell lines with IC 50 values ranging from 4.8 to 64 nM. [2] Their novel and unprecedented structures suggest they might have a unique cellular target(s) and a novel mechanism of action. Unfortunately, the isolation yields for both superstolides A and B are only 0.003% and 0.0003%, respectively. In addition, the marine sponge Neosiphonia superstes live at 500-515 meters deep in the ocean off New Caledonia, which makes collecting of a large amount of the marine sponge very difficult and dangerous and has the potential to cause significant damage to the marine habitat. Furthermore, sponges are notorious for being extremely difficult animals to cultivate in controlled systems. [3] The lack of adequate compound supply severely impedes research into a thorough understanding of their The potent anticancer activities coupled with their challenging molecular structures have attracted a great deal of attention from the synthetic organic chemistry community. [4,5] So far the only completed total synthesis of superstolide A was accomplished by Roush and his coworkers. [5h] Several years ago, we initiated a program directed toward the total synthesis of superstolides A and B. [4] While working on the total synthesis, it became apparent to us that because of the structural complexity of the target molecules, it would be extremely challenging to develop a practical total synthesis that is capable of providing an adequate amount of material for biological investiga-tion, therapeutic evaluation and possible future clinical trials.The lack of a sufficient amount of natural products coupled with the overwhelming difficulty in the development of a practical total synthesis approach entails designing of simplified superstolide A analogue that contains the basic pharmacophore and can be easily synthesized in a much shorter reaction sequence. Herein, we report for the first time the design and synthesis of a truncated superstolide A (3) in which the cis-fused functionalized decalin is simplified to a cyclohexene ring whereas the 16-membered macrolactone remains intact ( Figure 2).This design is based on our hypothesis that the 16-membered macrolactone may be the key pharmacophore that interacts with cellular target(s) while the cis-fused decalin may lock the macrolide into an advantageous conformation. This modification would simplify the synthesis substantially, a...