We report a concise asymmetric synthesis of rakicidin A, a macrocyclic depsipeptide that selectively inhibits the growth of hypoxic cancer cells and stem-like leukemia cells. Key transformations include a diastereoselective organocatalytic cross-aldol reaction to build the polyketide portion of the molecule, a highly hindered ester fragment coupling reaction, an efficient Helquist-type Horner-Wadsworth-Emmons (HWE) macrocyclization, and a new DSC-mediated elimination reaction to construct the sensitive APD portion of rakicidin A. We further report the preparation of a simplified structural analogue (WY1) with dramatically enhanced hypoxia-selective activity.
The preparation of heteroatom-substituted p-quinones is ideally performed by direct addition of a nucleophile followed by in situ reoxidation. Albeit an appealing strategy, the reactivity of the p-quinone moiety is not easily tamed and no broadly applicable method for heteroatom functionalization exists. Shown herein is that Co(OAc) and Mn(OAc) ⋅2 H O act as powerful catalysts for oxidative p-quinone functionalization with a collection of O, N, and S nucleophiles, using oxygen as the terminal oxidant. Preliminary mechanistic observations and the first synthesis of the cytotoxic natural product strongylophorine-26 is presented.
A novel and traceless strategy has been devised that allows a coupling of thioacids and dithiocarbamateterminal amines. This strategy had been assumed to be dependent on the attachment of a functional equivalent of a cysteine side chain in earlier native chemical ligation approaches. This approach enables the traceless removal of CS 2 to directly generate the desired amide bond and is compatible with a range of unprotected side chains of amino acid. The ability to produce amide or peptides by a traceless removal of the auxiliary is a significant virtue of the method. Meanwhile, the application of this new peptide-bond-forming reaction to the synthesis of novel endomorphin (EM) derivatives with various binding potencies was realized.
We developed a habitat suitability index (HSI) model to evaluate the variability of suitable habitat for neon flying squid (Ommastrephes bartramii) under anomalous environments in the Northwest Pacific Ocean. Commercial fisheries data from the Chinese squid-jigging vessels on the traditional fishing ground bounded by 35°-45°N and 150°-175°E from July to November during 1998-2009 were used for analyses, as well as the environmental variables including sea surface temperature (SST), chlorophyll-a (Chl-a) concentration, sea surface height anomaly (SSHA) and sea surface salinity (SSS). Two empirical HSI models (arithmetic mean model, AMM; geometric mean model, GMM) were established according to the frequency distribution of fishing efforts. The AMM model was found to perform better than the GMM model. The AMM-based HSI model was further validated by the fishery and environmental data in 2010. The predicted HSI values in 1998 (high catch), 2008 (average catch) and 2009 (low catch) indicated that the squid habitat quality was strongly associated with the ENSO-induced variability in the oceanic conditions on the fishing ground. The La Niña events in 1998 tended to yield warm SST and favorable range of Chl-a concentration and SSHA, resulting in high-quality habitats for O. bartramii. While the fishing ground in the El Niño year of 2009 experienced anomalous cool waters and unfavorable range of Chl-a concentration and SSHA, leading to relatively low-quality squid habitats. Our findings suggest that the La Niña event in 1998 tended to result in more favorable habitats for O. bartramii in the Northwest Pacific with the gravity centers of fishing efforts falling within the defined suitable habitat and yielding high squid catch; whereas the El Niño event in 2009 yielded less favorable habitat areas with the fishing effort distribution mismatching the suitable habitat and a dramatic decline of the catch of O. bartramii. This study might provide some potentially valuable insights into exploring the relationship between the underlying squid habitat and the inter-annual environmental change.
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