Cognitive impairments in Huntington's disease (HD) are attributed to a dysfunction of the cortico-striatal pathway and significantly affect the quality of life of the patients, but this has not been a therapeutic focus in HD to date. We postulated that adenosine A(2A) receptors (A(2A)R), located at pre- and post-synaptic elements of the cortico-striatal pathways, modulate striatal neurotransmission and synaptic plasticity and cognitive behaviors. To critically evaluate the ability of A(2A)R inactivation to prevent cognitive deficits in early HD, we cross-bred A(2A)R knockout (1(0) mice with two R6/2 transgenic lines of HD (CAG120 and CAG240) to generate two double transgenic R6/2-CAG120-A(2A)R KO and R6/2-CAG240-A(2A)R KO mice and their corresponding wild-type (WT) littermates. Genetic inactivation of A(2A)R prevented working memory deficits induced by R6/2-CAG120 at post-natal week 6 and by R6/2-CAG240 at post-natal month 2 and post-natal month 3, without modifying motor deficits. Similarly the A(2A)R antagonist KW6002 selectively reverted working memory deficits in R6/2-CAG240 mice at post-natal month 3. The search for possible mechanisms indicated that the genetic inactivation of A(2A)R did not affect ubiquitin-positive neuronal inclusions, astrogliosis or Thr-75 phosphorylation of DARPP-32 in the striatum. Importantly, A(2A)R blockade preferentially controlled long-term depression at cortico-striatal synapses in R6/2-CAG240 at post-natal week 6. The reported reversal of working memory deficits in R6/2 mice by the genetic and pharmacological inactivation of A(2A)R provides a proof-of-principle for A(2A)R as novel targets to reverse cognitive deficits in HD, likely by controlling LTD deregulation. (C) 2015 Published by Elsevier Inc.

We have previously reported substituted 2-aryl-thiazolidine-4-carboxylic acid amides as potent and selective antiproliferative agents for melanoma. To understand the importance of the thiazolidine ring and to reduce potential complications associated with the two chiral centers, we designed and synthesized sets of new analogs by modifying this ring. These new analogs were tested in two melanoma cell lines and fibroblast cells (negative controls). Compared with the older analogs containing the thiazolidine ring, these new analogs have lower potency in general, but some of these analogs still have very good selectivity. These structure-activity studies indicated that the thiazolidine ring is very critical for the activity for these series of compounds. (C) 2008 Elsevier Ltd. All rights reserved.

To develop PET tracers for imaging of Alzheimer's disease, a new carbon-11-labeled AMPAR allosteric modulator 4-cyclopropyl-7-(3-[C-11] methoxyphenoxy)-3,4-dihydro-2H-benzo[e][1,2,4] thiadiazine 1,1-dioxide ([C-11] 8) has been synthesized. The reference standard 4-cyclopropyl-7-(3-methoxyphenoxy)-3,4-dihydro-2H-benzo[e][1,2,4] thiadiazine 1,1-dioxide (8) and its corresponding desmethylated precursor 4-cyclopropyl-7-(3-hydroxyphenoxy)3,4- dihydro-2H-benzo[e][1,2,4] thiadiazine 1,1-dioxide (9) were synthesized from 4-methoxyabiline and chlorosulfonyl isocyanate in eight and nine steps with 3% and 1% overall chemical yield, respectively. The target tracer [C-11] 8 was prepared from the precursor 9 with [C-11] CH3OTf through O-[C-11] methylation and isolated by HPLC combined with SPE in 10-15% radiochemical yield, based on [C-11] CO2 and decay corrected to end of bombardment (EOB). The radiochemical purity was> 99%, and the molar activity (AM) at EOB was 370-740 GBq/mu mol with a total synthesis time of 35-40-minutes from EOB.

To identify the structural features of 9H-pyrimido[4,5-b]indoles as microtubule depolymerizers, pyrimido[4,5-b]indoles 2-8 with varied substituents at the 2-, 4-and 5-positions were designed and synthesized. Nucleophilic displacement of 2,5-substituted-4-chloro-pyrimido[4,5-b]indoles with appropriate arylamines was the final step employed in the synthesis of target compounds 2-8. Compounds 2 and 6 had two-digit nanomolar potency (IC50) against MDA-MB-435, SK-OV-3 and HeLa cancer cells in vitro. Compounds 2 and 6 also depolymerized microtubules comparable to the lead compound 1. Compounds 2, 3, 6 and 8 were effective in cells expressing P-glycoprotein or the beta III isotype of tubulin, mechanisms that are associated with clinical drug resistance to microtubule targeting drugs. Proton NMR and molecular modeling studies were employed to identify the structural basis for the microtubule depolymerizing activity of pyrimido[4,5-b]indoles. (C) 2017 Elsevier Ltd. All rights reserved.

Histone H3 encoding genes, particularly H3F3A and H3F3B, the genes encoding the variant histone H3.3, are mutated at high frequency in pediatric brain and bone malignancies. Compared to the extensive studies on K27M and K36M mutations, little is known about the mechanism of G34 mutations found in pediatric glioblastoma or giant cell tumors of the bone. Here we report that unlike the K27M or K36M that affect global histone methylation, the giant cell tumors of the bone G34 mutations (G34L/W) only affect histone H3K36 and H3K27 methylation on the same mutated histone tails (in cis), a mechanism distinct from known histone mutations. (C) 2018 Elsevier Ltd. All rights reserved.

Interferon (IFN)-lambda 1 [also known as interleukiun (IL)-29] belongs to the recently discovered group of type III IFNs. All type III IFNs initiate signaling processes through formation of specific heterodimeric receptor complexes consisting of IFN-lambda R1 and IL-10R2. We have determined the structure of human IFN-lambda 1 complexed with human IFN-lambda R1, a receptor unique to type III IFNs. The overall structure of IFN-lambda 1 is topologically similar to the structure of IL-10 and other members of the IL-10 family of cytokines. IFN-lambda R1 consists of two distinct domains having fibronectin type III topology. The ligand receptor interface includes helix A, loop AB, and helix F on the IFN site, as well as loops primarily from the N-terminal domain and inter-domain hinge region of IFN-lambda R1. Composition and architecture of the interface that includes only a few direct hydrogen bonds support an idea that long-range ionic interactions between ligand and receptor govern the process of initial recognition of the molecules while hydrophobic interactions finalize it. Published by Elsevier Ltd.