A set of four non-heme iron(II) and 2-oxoglutarate-dependent enzymes catalyze the post-translational modification of a transcription factor, hypoxia inducible factor (HIF), that mediates the hypoxic response in animals. Hydroxylation of HIF both causes its degradation and limits its activity. We describe how the use of structural data coupled to solid-phase synthesis led to the discovery of a selective inhibitor of one of the HIF hydroxylases. The inhibitor N-oxalyl-d-phenylalanine was shown to inhibit the HIF asparaginyl hydroxylase (FIH) but not a HIF prolyl hydroxylase. A crystal structure of the inhibitor complexed to FIH reveals that it binds in the 2OG and, likely, in the dioxygen binding site. The results will help to enable the modulation of the hypoxic response for the up-regulation of specific genes of biomedical importance, such as erythropoietin and vascular endothelial growth factor.

Palmerolide A is a recently disclosed marine natural product possessing striking biological properties, including potent and selective activity against the melanoma cancer cell line UACC-62. The total syntheses of five palmerolide A stereoisomers, including the originally proposed (1) and the revised [ent-(19-epi-20-epi-1)] structures, have been accomplished. The highly convergent and flexible strategy developed for these syntheses involved the construction of key building blocks 2, 19-epi-2, 20-epi-2, ent-2, 3, ent-3, 4, and ent-4, and their assembly and elaboration to the target compounds. For the union of the building blocks, the Stille coupling reaction, Yamaguchi esterification, Horner-Wadsworth-Emmons olefination, and ring-closing metathesis reaction were employed, the latter being crucial for the stereoselective formation of the macrocycle of the palmerolide structure. The Horner-Wadsworth-Emmons olefination and the Yamaguchi lactonization were also investigated and found successful as a means to construct the palmerolide macrocycle. The syntheses were completed by attachment of the enamide moiety through a copper-catalyzed coupling process.

Cyclic beta-oxocarboxylic acids inhibit factor inhibiting hypoxia-inducible factor via ligation to the active site iron.

Palmerolide A (Figure 1) is a recently reported polyketide secondary metabolite with an impressive molecular architecture and biological profile.[1] This marine natural product was isolated from the circumpolar tunicate Synoicum adareanum, which is commonly found in the shallow waters around Anvers Island on the Antarctic Peninsula, and exhibits unusual selectivity against a number of cell lines in the 60 cell panel of the National Cancer Institute (NCI). Specifically, palmerolide A was found to exhibit potent activity against the melanoma cell line UACC-62 (LC 50 = 18 nm), only modest cytotoxicity against the colon cancer cell line HCC-2998 (LC 50 = 6.5 mm) and the renal cancer cell line RXF 393 (LC 50 = 6.5 mm), and virtually no effect (LC 50 > 10 mm) against other cell lines, thus demonstrating a selectivity index of 10 3 among the cell lines tested. Interestingly, palmerolide A displayed an activity profile in the NCI 60 cell line panel that correlated with that of vacuolar ATPase inhibitors. [2] Palmerolide A was shown to inhibit V-ATPase with an IC 50 value of 2 nm and to be active in the NCIs hollow fiber assay. The intriguing biological properties of palmerolide A, along with its relative scarcity, prompted us to undertake its chemical synthesis.Inspection of the proposed structure of palmerolide A (1 a) reveals a 20-membered macrolide, an enamide-containing side chain, 7 olefinic bonds (3 of which are trisubstituted), and a carbamate moiety. Based on detailed NMR spectroscopic analysis, the relative and absolute configuration of this natural product was put forward as that shown in structure 1 a (Figure 1), although the structural assignments at C19 and C20 were not error proof. Specifically, while the NOE interactions and coupling constants exhibited by palmerolide A may exclude the two anti C19/C20 diastereomers, both syn structures could be possible. Furthermore, while Mosher ester studies suggested the absolute stereochemistry at the C7, C10, and C11 positions, the low optical rotation of the natural product [1] did not bode well for its diagnostic value as a means to confirm its absolute stereochemistry. Most recently, these suspicions were confirmed by an elegant study by De Brabander and co-workers (which culminated in the total synthesis of the unnatural enantiomer of palmerolide A), [3] with the structural revision of not only the relative stereochemistry between the C7-C11 and C19-C20 domains, but also of the absolute configuration of the molecule. Herein, we report our own efforts in this area that culminated in total syntheses of, among several isomers, the originally proposed structure 1 a and the revised structure 1 b (Figure 1) of palmerolide A by a modular and flexible strategy that allows access to variants of the palmerolide A molecule as depicted retrosynthetically in Scheme 1.It was envisioned that a Stille coupling reaction, a Yamaguchi esterification, a ring-closing metathesis, and an enamide coupling reaction would serve to assemble and

A series of triazole-substituted quinazoline hybrid compounds were designed and synthesized for anticancer activity targeting epidermal growth factor receptor (EGFR) tyrosine kinase. Most of the compounds showed moderate to good antiproliferative activity against four cancer cell lines (HepG2, HCT116, MCF-7, and PC-3). Compound 5b showed good antiproliferative activity (IC50 = 20.71 μM) against MCF-7 cell lines. Molecular docking results showed that compound 5b formed hydrogen bond with Met 769 and Lys 721 and π–sulfur interaction with Met 742 of EGFR tyrosine kinase (PDB ID: 1M17). Compound 5b decreases the expression of EGFR and p-EGFR. It also induces apoptosis through reactive oxygen species generation, followed by the change in mitochondrial membrane potential.

A 'green' methodology for the convenient synthesis of specific regioisomers of polysubstituted oxazoles through iodine catalyzed, water-mediated, aerobic oxidative C(sp 3 )À H functionalization of primary amines has been developed. This mild and regioselective domino procedure does not require toxic peroxides, transition metals and organic solvents. The versatility of this methodology was demonstrated by preparing a natural product, texaline. It is also scalable and has a wide substrate scope. This methodology opens up a simple avenue for the synthesis of polyarylated oxazoles from various readily available amines as well as 1,2-diketones and acyloins (α-hydroxyl ketones) in moderate to excellent yields. Furthermore, these highly substituted oxazole molecules showed excellent fluorescence properties and thus have enormous potential to be a new type of fluorescent probe for use in medicinal applications and materials science.

An easy synthesis of magnetic nanoparticles (Fe 3 O 4 ) is described. Transmission electron microscopy (TEM), atomic force microscopy (AFM), dynamic light scattering (DLS) and X-ray diffraction (XRD) have been used to study the well dispersed and uniformly spherical nanoparticles. 5-Fluorouracil (5-FU) has been successfully loaded onto the nanoparticles and cytotoxicity studies were performed using a standard MTT assay. The results indicate that 5-fluorouracil-loaded iron nanoparticles are a more potent anticancer drug versus 5-fluorouracil alone.

Palmerolide A (Figure 1) is a recently reported polyketide secondary metabolite with an impressive molecular architecture and biological profile.[1] This marine natural product was isolated from the circumpolar tunicate Synoicum adareanum, which is commonly found in the shallow waters around Anvers Island on the Antarctic Peninsula, and exhibits unusual selectivity against a number of cell lines in the 60 cell panel of the National Cancer Institute (NCI). Specifically, palmerolide A was found to exhibit potent activity against the melanoma cell line UACC-62 (LC 50 = 18 nm), only modest cytotoxicity against the colon cancer cell line HCC-2998 (LC 50 = 6.5 mm) and the renal cancer cell line RXF 393 (LC 50 = 6.5 mm), and virtually no effect (LC 50 > 10 mm) against other cell lines, thus demonstrating a selectivity index of 10 3 among the cell lines tested. Interestingly, palmerolide A displayed an activity profile in the NCI 60 cell line panel that correlated with that of vacuolar ATPase inhibitors. [2] Palmerolide A was shown to inhibit V-ATPase with an IC 50 value of 2 nm and to be active in the NCIs hollow fiber assay. The intriguing biological properties of palmerolide A, along with its relative scarcity, prompted us to undertake its chemical synthesis.Inspection of the proposed structure of palmerolide A (1 a) reveals a 20-membered macrolide, an enamide-containing side chain, 7 olefinic bonds (3 of which are trisubstituted), and a carbamate moiety. Based on detailed NMR spectroscopic analysis, the relative and absolute configuration of this natural product was put forward as that shown in structure 1 a (Figure 1), although the structural assignments at C19 and C20 were not error proof. Specifically, while the NOE interactions and coupling constants exhibited by palmerolide A may exclude the two anti C19/C20 diastereomers, both syn structures could be possible. Furthermore, while Mosher ester studies suggested the absolute stereochemistry at the C7, C10, and C11 positions, the low optical rotation of the natural product [1] did not bode well for its diagnostic value as a means to confirm its absolute stereochemistry. Most recently, these suspicions were confirmed by an elegant study by De Brabander and co-workers (which culminated in the total synthesis of the unnatural enantiomer of palmerolide A), [3] with the structural revision of not only the relative stereochemistry between the C7-C11 and C19-C20 domains, but also of the absolute configuration of the molecule. Herein, we report our own efforts in this area that culminated in total syntheses of, among several isomers, the originally proposed structure 1 a and the revised structure 1 b (Figure 1) of palmerolide A by a modular and flexible strategy that allows access to variants of the palmerolide A molecule as depicted retrosynthetically in Scheme 1.It was envisioned that a Stille coupling reaction, a Yamaguchi esterification, a ring-closing metathesis, and an enamide coupling reaction would serve to assemble and