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Sulindac is a non-steroidal anti-inflammatory drug (NSAID) that has shown significant anticancer activity. Sulindac sulfide amide (1) possessing greatly reduced COX-related inhibition ...relative to sulindac displayed in vivo antitumor activity that was comparable to sulindac in a human colon tumor xenograft model. Inspired by these observations, a panel of diverse sulindac amide derivatives have been synthesized and their activity probed against three cancer cell lines (prostate, colon and breast). A neutral analog, compound 79 was identified with comparable potency relative to lead 1 and activity against a panel of lymphoblastic leukemia cell lines. Several new series also show good activity relative to the parent (1), including five analogs that also possess nanomolar inhibitory potencies against acute lymphoblastic leukemia cells. Several new analogs identified may serve as anticancer lead candidates for further development.
Disruptor of Telomeric Silencing 1-Like (DOT1L), the sole histone H3 lysine 79 (H3K79) methyltransferase, is required for leukemogenic transformation in a subset of leukemias bearing chromosomal ...translocations of the Mixed Lineage Leukemia (MLL) gene, as well as other cancers. Thus, DOT1L is an attractive therapeutic target and discovery of small molecule inhibitors remain of high interest. Herein, we are presenting screening results for a unique focused library of 1200 nucleoside analogs originally produced under the aegis of the NIH Pilot Scale Library Program. The complete nucleoside set was screened virtually against DOT1L, resulting in 210 putative hits. In vitro screening of the virtual hits resulted in validation of 11 compounds as DOT1L inhibitors clustered into two distinct chemical classes, adenosine-based inhibitors and a new chemotype that lacks adenosine. Based on the developed DOT1L ligand binding model, a structure-based design strategy was applied and a second-generation of non-nucleoside DOT1L inhibitors was developed. Newly synthesized compound 25 was the most potent DOT1L inhibitor in the new series with an IC50 of 1.0 μM, showing 40-fold improvement in comparison with hit 9 and exhibiting reasonable on target effects in a DOT1L dependent murine cell line. These compounds represent novel chemical probes with a unique non-nucleoside scaffold that bind and compete with the SAM binding site of DOT1L, thus providing foundation for further medicinal chemistry efforts to develop more potent compounds.
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•Virtual screening of unique 1200 nucleoside analogs library against DOT1L.•11 compounds were confirmed and clustered into two distinct chemical classes.•A series of non-nucleoside DOT1L inhibitors was developed by structure-based design.•25 with N-aminoethyl-pyrrolopyrimidin-4-amine scaffold has 40-fold improvement.
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•Anticancer activities of 60 new α-Me analogs of sulindac sulfide amide are reported.•Several compounds (6–29 and 60) show comparable inhibition of prostate, colon, breast ...cancer.•Addition of an α-methyl group to the lead scaffold does not dramatically alter activity.•Several analogs (6, 8, 11, 14, 20, 21, 24, 29, 57) show activity against several other cell lines.•Separated isomers, 5 and epi-5, show similar activities.
Non-steroidal anti-inflammatory drugs (NSAIDs) have a variety of potential indications that include management of pain and inflammation as well as chemoprevention and/or treatment of cancer. Furthermore, a specific form of ibuprofen, dexibuprofen or the S-(+) form, shows interesting neurological activities and has been proposed for the treatment of Alzheimer’s disease. In a continuation of our work probing the anticancer activity of small sulindac libraries, we have prepared and screened a small diversity library of α-methyl substituted sulindac amides in the profen class. Several compounds of this series displayed promising activity compared with a lead sulindac analog.
TGF-β has been a target of interest for the treatment of fibrotic diseases and certain cancers. Approaches to target TGF-β include antagonists of the active ligand or TGF-β receptor kinase activity. ...These approaches have failed in clinical trials due to a lack of effectiveness and a limited therapeutic window. In this context, newer and more selective approaches to target TGF-β are needed. We previously reported that the matricellular protein, thrombospondin 1, activates the latent TGF-β complex and that antagonism of this pathway using tri/tetrapeptides in various animal models reduces fibrosis. The tripeptide, SRI-31277 (
), is effective
but has a short plasma half life (0.2 h). Herein we describe the design and synthesis SRI-31277 analogs, specifically smaller peptides that retain potency and have improved bioavailability. We identified SRI-35241 (
) with a single chiral center, which blocks TGF-β activation (pIC
= 8.12 nM) and has a plasma half life of 1.8 h (iv).
The glycolipid alpha-galactosylceramide binds with high affinity to CD1d and stimulates natural killer T cells. Here we report the crystal structure of human CD1d in complex with synthetic ...alpha-galactosylceramide at a resolution of 3.0 A. The structure shows a tightly fit lipid in the CD1d binding groove, with the sphingosine chain bound in the C' pocket and the longer acyl chain anchored in the A' pocket. We also present the CD1d structure without lipid, which has a more open conformation of the binding groove, suggesting a dual conformation of CD1d in which the 'open' conformation is more able to load lipids. These structures provide clues as to how CD1 molecules load glycolipids as well as data to guide the design of new therapeutic agents.
Modification in the function of dendritic cells (DC), such as that achieved by microbial stimuli or T cell help, plays a critical role in determining the quality and size of adaptive responses to Ag. ...NKT cells bearing an invariant TCR (iNKT cells) restricted by nonpolymorphic CD1d molecules may constitute a readily available source of help for DC. We therefore examined T cell responses to i.v. injection of soluble Ag in the presence or the absence of iNKT cell stimulation with the CD1d-binding glycolipid alpha-galactosylceramide (alpha-GalCer). Considerably enhanced CD4(+) and CD8(+) T cell responses were observed when alpha-GalCer was administered at the same time as or close to OVA injection. This enhancement was dependent on the involvement of iNKT cells and CD1d molecules and required CD40 signaling. Studies in IFN-gammaR(-/-) mice indicated that IFN-gamma was not required for the adjuvant effect of alpha-GalCer. Consistent with this result, enhanced T cell responses were observed using OCH, an analog of alpha-GalCer with a truncated sphingosine chain and a reduced capacity to induce IFN-gamma. Splenic DC from alpha-GalCer-treated animals expressed high levels of costimulatory molecules, suggesting maturation in response to iNKT cell activation. Furthermore, studies with cultured DC indicated that potentiation of T cell responses required presentation of specific peptide and alpha-GalCer by the same DC, implying conditioning of DC by iNKT cells. The iNKT-enhanced T cell responses resisted challenge with OVA-expressing tumors, whereas responses induced in the absence of iNKT stimulation did not. Thus, iNKT cells exert a significant influence on the efficacy of immune responses to soluble Ag by modulating DC function.
ALS is a rare type of progressive neurological disease with unknown etiology. It results in the gradual degeneration and death of motor neurons responsible for controlling the voluntary muscles. ...Identification of mutations in the superoxide dismutase (SOD) 1 gene has been the most significant finding in ALS research. SOD1 abnormalities have been associated with both familial as well as sporadic ALS cases. SOD2 is a highly inducible SOD that performs in concurrence with SOD1 to detoxify ROS. Induction of SOD2 can be obtained through activation of NF-ҡBs. We previously reported that SRI-22819 increases NF-ҡB expression and activation in vitro, but it has poor ADME properties in general and has no oral bioavailability. Our initial studies were focused on direct modifications of SRI-22819. There were active compounds identified but no improvement in microsomal stability was observed. In this context, we focused on making more significant structural changes in the core of the molecule. Ataluren, an oxadiazole compound that promotes read-through and expression of dystrophin in patients with Duchenne muscular dystrophy, bears some structural similarity to SRI-22819. Thus, we synthesized a series of SRI-22819 and Ataluren (PTC124) hybrid compounds. Several compounds from this series exhibited improved activity, microsomal stability and lower calculated polar surface area (PSA). This manuscript describes the synthesis and biological evaluation of SRI-22819 analogs and its hybrid combination with Ataluren.
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•Development of novel compounds for the treatment of amyotrophic lateral sclerosis.•Abnormality of Superoxide dismutase 1 function causes hyper-generation of reactive oxygen species.•Superoxide dismutase 2 works in conjunction with Superoxide dismutase 1 to detoxify reactive oxygen species.•Structure-activity relationship studies of N-(3-methylpyridin-2-yl)-4-(pyridin-2-yl)thiazol-2-amine.•Hybrid compounds based on N-(3-methylpyridin-2-yl)-4-(pyridin-2-yl)thiazol-2-amine and Ataluren.
The glycolipid alpha-galactosylceramide binds with high affinity to CD1d and stimulates natural killer T cells. Here we report the crystal structure of human CD1d in complex with synthetic ...alpha-galactosylceramide at a resolution of 3.0 A. The structure shows a tightly fit lipid in the CD1d binding groove, with the sphingosine chain bound in the C' pocket and the longer acyl chain anchored in the A' pocket. We also present the CD1d structure without lipid, which has a more open conformation of the binding groove, suggesting a dual conformation of CD1d in which the 'open' conformation is more able to load lipids. These structures provide clues as to how CD1 molecules load glycolipids as well as data to guide the design of new therapeutic agents.
Experimental and epidemiological studies and clinical trials suggest that nonsteroidal anti-inflammatory drugs possess antitumor potential. Sulindac, a widely used nonsteroidal anti-inflammatory ...drug, can prevent adenomatous colorectal polyps and colon cancer, especially in patients with familial adenomatous polyposis. Sulindac sulfide amide (SSA) is an amide-linked sulindac sulfide analog that showed in vivo antitumor activity in a human colon tumor xenograft model. Results/methodology: A new analog series with heterocyclic rings such as oxazole or thiazole at the C-2 position of sulindac was prepared and screened against prostate, colon and breast cancer cell lines to probe the effect of these novel substitutions on the activity of sulindac analogs.
In general, replacement of the amide function of SSA analogs had a negative impact on the cell lines tested. A small number of hits incorporating rigid oxazole or thiazole groups in the sulindac scaffold in place of the amide linkage show comparable activity to our lead agent SSA.
Eighteen new pyridopyrazine and pyrimidothiazine derivatives were synthesized and tested against FtsZ from Mycobacterium tuberculosis (Mtb) and in vitro antibacterial activity against Mtb H37Ra and ...Mtb H37Rv. Two compounds were studied in vivo in a murine Mtb model.
A series of pyridopyrazine and pyrimidothiazine derivatives have been synthesized and their activity against FtsZ from Mycobacterium tuberculosis (Mtb) and in vitro antibacterial activity against Mtb H37Ra and Mtb H37Rv are reported. Certain analogs described herein showed moderate to good inhibitory activity.
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