The synthesis and evaluation of a refined series of α-ketoheterocycles based on the oxazole 2 (OL-135) incorporating systematic changes in the central heterocycle bearing a key set of added ...substituents are described. The nature of the central heterocycle, even within the systematic and minor perturbations explored herein, significantly influenced the inhibitor activity: 1,3,4-oxadiazoles and 1,2,4-oxadiazoles 9 > tetrazoles, the isomeric 1,2,4-oxadiazoles 10, 1,3,4-thiadiazoles > oxazoles including 2 > 1,2-diazines > thiazoles > 1,3,4-triazoles. Most evident in these trends is the observation that introduction of an additional heteroatom at position 4 (oxazole numbering, N > O > CH) substantially increases activity that may be attributed to a reduced destabilizing steric interaction at the FAAH active site. Added heterocycle substituents displaying well-defined trends may be utilized to enhance the inhibitor potency and, more significantly, to enhance the inhibitor selectivity. These trends, exemplified herein, emerge from both enhancements in the FAAH activity and simultaneous disruption of binding affinity for competitive off-target enzymes.
Using various chromatographic techniques, a total of 15 compounds, including one novel megastigmane named tiliaceic acid A (1) and 14 known compounds, were isolated from the traditional medicinal ...Vietnamese mangrove Hibiscus tiliaceus. Their structures were confirmed based on spectroscopic experiments including, UV, 1 D- and 2 D-NMR, HR-ESI-MS, and ECD analysis. The antioxidant and α-glucosidase inhibitory activities of the isolated compounds from H. tiliaceus were evaluated for the first time. Compound 2 showed strong α-glucosidase inhibitory activity with an IC
50
of 77.78 ± 1.00 μM compared with the positive control acarbose at 105.71 ± 2.29 μM.
Full text
Available for:
BFBNIB, GIS, IJS, KISLJ, NUK, PNG, UL, UM, UPUK
The stability of peptide-MHC complex (pMHC) is an important factor to shape the fate of peptide-specific T cell immune response, but how it influences on T cell activation process is poorly ...understood. To better understand that, we investigated various T cell activation events driven by L
MHCI loaded with graded concentrations of P2Ca and QL9 peptides, respectively, with 2C TCR Tg T cells; the binding strength of P2Ca for L
is measurably weaker than that of QL9, but either peptides in the context of L
interact with 2C TCR with a similar strength. When their concentrations required for early T cell activation events, which occur within several minutes to an hour, were concerned, EC50s of QL9 were about 100 folds lower than those of P2Ca, which was expected from their association constants for L
. When EC
s for late activation events, which takes over several hours to occur, were concerned, the differences grew even larger (> 300 folds), suggesting that, due to weak binding, L
/P2Ca dissociate from each other more easily to lose its antigenicity in a short time. Accordingly, fixation of L
/P2Ca with paraformaldehyde resulted in a significant improvement in its immunogenicity. These results imply that binding strength of a peptide for a MHC is a critical factor to determine the duration of pMHC-mediated T cell activation and thus the attainment of productive T cell activation. It is also suggested that paraformaldehyde fixation should be an effective tool to ameliorate the immunogenicity of pMHC with a poor stability.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Proliferation of memory-phenotype (CD44
hi) CD8
+ cells induced by infectious agents can be mimicked by injection of type I interferon (IFN I) and by IFN I–inducing agents such as lipopolysaccharide ...and Poly I:C; such proliferation does not affect naive T cells and appears to be TCR independent. Since IFN I inhibits proliferation in vitro, IFN I–induced proliferation of CD8
+ cells in vivo presumably occurs indirectly through production of secondary cytokines, e.g., interleukin-2 (IL-2) or IL-15. We show here that, unlike IL-2, IL-15 closely mimics the effects of IFN I in causing strong and selective stimulation of memory-phenotype CD44
hi CD8
+ (but not CD4
+) cells in vivo; similar specificity applies to purified T cells in vitro and correlates with much higher expression of IL-2Rβ on CD8
+ cells than on CD4
+ cells.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The synthesis and evaluation of analogues and key derivatives of 10-CF3CO-DDACTHF as inhibitors of glycinamide ribonucleotide transformylase (GAR Tfase) and aminoimidazole carboxamide transformylase ...(AICAR Tfase) are reported. Polyglutamate analogues of 1 were evaluated as inhibitors of Escherichia coli and recombinant human (rh) GAR Tfase, and AICAR Tfase. Although the pentaglutamate 6 was found to be the most active inhibitor of the series tested against rhGAR Tfase (Ki=0.004 microM), little distinction between the mono-pentaglutamate derivatives was observed (Ki=0.02-0.004 microM), suggesting that the principal role of the required polyglutamation of 1 is intracellular retention. In contrast, 1 and its defined polyglutamates 3-6 were much less inactive when tested against rhAICAR Tfase (Ki=65-0.120 microM) and very selective (> or =100-fold) for rh versus E. coli GAR Tfase. Additional key analogues of 1 were examined (7 and 8) and found to be much less active (1000-fold) highlighting the exceptional characteristics of 1.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
48.
Total Synthesis of Ningalin D Hamasaki, Akiyuki; Zimpleman, Jeffrey M; Hwang, Inkyu ...
Journal of the American Chemical Society,
08/2005, Volume:
127, Issue:
30
Journal Article
Peer reviewed
Open access
A concise (nine-step) and effective (19% overall yield) total synthesis of ningalin D (1a) is disclosed and is based on a key 1,2,4,5-tetrazine → 1,2-diazine → pyrrole Diels−Alder strategy to ...assemble a fully substituted pyrrole core central to its structure. Additional highlights of the synthesis include a double Dieckmann condensation to introduce the C and D aryl rings enlisting substituents judiciously placed on the dienophile and intrinsic to the widely used tetrazine 2, a highly effective Suzuki coupling of the resulting C and D phenol triflates for introduction of the sterically demanding F and G aryl rings, and an unusually effective formal oxidative decarboxylation reaction cascade initiated by a Curtius rearrangement to directly provide the biphenylene quinone methide found imbedded in the structure of ningalin D. The cytotoxic and multidrug resistance (MDR) reversal activity of ningalin D, its derivatives, and the key synthetic intermediates are detailed.
Full text
Available for:
IJS, KILJ, NUK, PNG, UL, UM
Using various chromatographic separations, sixteen compounds, including one new triterpene saponin named aegicoroside A (1), were isolated from the leaves of the Vietnamese mangrove Aegiceras ...corniculatum. Their structures were determined by spectroscopic methods such as 1D and 2D NMR and HR-ESI-MS. The cytotoxic activities of the isolated compounds against MCF7 (breast), HCT116 (colon), B16F10 (melanoma), and A549 (adenocarcinoma) cancer cell lines were also evaluated. Strong cytotoxicity was observed for sakurasosaponin (2) against all four cancer cell lines and for sakurasosaponin methyl ester (3) against MCF7, A549, and HCT116 cell lines with IC
50
values ranging from 2.89 ± 0.02 to 9.86 ± 0.21 μM.
Full text
Available for:
BFBNIB, GIS, IJS, KISLJ, NUK, PNG, UL, UM, UPUK
Fatty acid amide hydrolase (FAAH) degrades neuromodulating fatty acid amides including anandamide (endogenous cannabinoid agonist) and oleamide (sleep-inducing lipid) at their sites of action and is ...intimately involved in their regulation. Herein we report the discovery of a potent, selective, and efficacious class of reversible FAAH inhibitors that produce analgesia in animal models validating a new therapeutic target for pain intervention. Key to the useful inhibitor discovery was the routine implementation of a proteomics-wide selectivity screen against the serine hydrolase superfamily ensuring selectivity for FAAH coupled with systematic in vivo examinations of candidate inhibitors.
PDF
