Amanda Skoumbourdis | Penn State University (original) (raw)

Papers by Amanda Skoumbourdis

Bioorganic & Medicinal Chemistry Letters, 2008

A series of substituted 3,6-diphenyl-7H- triazolo [3,4-b] thiadiazines were prepared and analyzed... more A series of substituted 3,6-diphenyl-7H- triazolo [3,4-b] thiadiazines were prepared and analyzed as inhibitors of phosphodiesterase 4 (PDE4). Synthesis, structure activity relationships and the selectivity of a highly potent analogue against related phosphodiesterase isoforms are presented.

Organic Process Research & Development, 2000

... Praveen Kumar Suryadevara, Srinivas Olepu, Jeffrey W. Lockman, Junko Ohkanda, Mandana Karimi,... more ... Praveen Kumar Suryadevara, Srinivas Olepu, Jeffrey W. Lockman, Junko Ohkanda, Mandana Karimi, Christophe LMJ Verlinde, James M. Kraus, Jan Schoepe, Wesley C. Van Voorhis, Andrew D. Hamilton, Frederick S. Buckner and Michael H. Gelb. ...

ChemInform, 2000

A New Facile Method for the Synthesis of 1-Arylimidazole-5carboxylates.

International journal of biological sciences, 2006

BRCA1 and BRCA2 mutations are responsible for most familial breast carcinomas. Recent reports car... more BRCA1 and BRCA2 mutations are responsible for most familial breast carcinomas. Recent reports carried out in non-cancerous mouse BRCA1- or BRCA2-deficient embryonic stem (ES) cells, and hamster BRCA2-deficient cells have demonstrated that the targeted inhibition of poly(ADP-ribose) polymerase (PARP-1) kills BRCA mutant cells with high specificity. Although these studies bring hope for BRCA mutation carriers, the effectiveness of PARP-1 inhibitors for breast cancer remains elusive. Here we present the first in vivo demonstration of PARP-1 activity in BRCA1-deficient mammary tumors and describe the effects of PARP-1 inhibitors (AG14361, NU1025, and 3-aminobenzamide) on BRCA1-deficient ES cells, mouse and human breast cancer cells. AG14361 was highly selective for BRCA1-/- ES cells; however, NU1025 and 3-aminobenzamide were relatively non-selective. In allografts of naïve ES BRCA1-/- cells there was either partial or complete remission of tumors. However, in allografts of mouse, BRCA1-...

ChemInform, 2001

Efficient Molar-Scale Synthesis of 1-Methyl-5-acylimidazole Triflic Acid Salts.

Tetrahedron Letters, 2007

Substitutions on the 2-position of the imidizole ring of histamine have proven useful in a number... more Substitutions on the 2-position of the imidizole ring of histamine have proven useful in a number of biochemical settings. Current art for the synthesis of these constructs relies upon a cumbersome and low-yielding condensation reaction. Here-in we report a new procedure for the synthesis of a series of substituted 2-phenylhistamines utilizing a microwave-promoted Suzuki coupling.

The expression of human pyruvate kinase M2 (hPK-M2) in cancer cells appears to be critical for tu... more The expression of human pyruvate kinase M2 (hPK-M2) in cancer cells appears to be critical for tumor cell growth and proliferation in vivo. Because the PK-M2 isoform is expressed in all cancer cells studied, it represents a target for drug development that could potentially ...

Tetrahedron Letters, 2000

A new facile method for the preparation of 1-arylimidazole-5-carboxylates was developed. The new ... more A new facile method for the preparation of 1-arylimidazole-5-carboxylates was developed. The new method involved reaction of anilines and ethyl glyoxylate in methanol to give a-anilino-a-methoxyacetates followed by cyclization with TosMIC, aording 1-arylimidazole-5-carboxylates in two steps in 40±94% overall yields. #

Pharmacology Biochemistry and Behavior, 2011

Pleasure-seeking deficits, including lack of libido, are a core feature of depression. Animal and... more Pleasure-seeking deficits, including lack of libido, are a core feature of depression. Animal and preliminary clinical studies both suggest that phosphodiesterase 4 (PDE4) is a target for developing novel antidepressants. This study examined the potential involvement of PDE4 in the pathology of depression in both animal models and human postmortem brains. In humans, PDE4B and PDE4D levels were elevated in cingulate cortical tissue from individuals with major depressive disorder (MDD) compared to controls. Using the female urine smelling test (FUST), a recently refined method for monitoring sexual pleasure-seeking activity in mice, we found that icv infusion of selective potent PDE4 inhibitors enhanced sexual pleasure-seeking activity in male mice that underwent the learned helplessness or serotonin depletion paradigms. The infusion also increased sexual pleasure-seeking activity in naïve male mice. The results suggest that PDE4 may be a plausible contributor to the sexual pleasure-seeking deficits seen in depressed patients; inhibiting PDE4 may restore these deficits.

Molecular Pharmaceutics, 2011

Tasigna (Nilotinib) is a BCR-ABL kinase inhibitor recently approved by the Food and Drug Administ... more Tasigna (Nilotinib) is a BCR-ABL kinase inhibitor recently approved by the Food and Drug Administration, which is indicated for the treatment of drug-resistant chronic myelogenous leukemia (CML). The efflux of tyrosine kinase inhibitors by ATP-binding cassette (ABC) drug transporters, which actively pump these drugs out of cells utilizing ATP as an energy source, has been linked to the development of drug resistance in CML patients. We report here the synthesis and characterization of a fluorescent derivative of Tasigna to study its interaction with two major ABC transporters, P-glycoprotein (Pgp) and ABCG2, in in vitro and ex vivo assays. A fluorescent derivative of Tasigna, BODIPY FL Tasigna, inhibited the BCR-ABL kinase activity in K562 cells and was also effluxed by Pgp-and ABCG2-expressing cells in both cultured cells and rat brain capillaries expressing Pgp and ABCG2. In addition, [ 3 H]-Tasigna was found to be transported by Pgp-expressing polarized LLC-PK1 cells in a transepithelial transport assay. Consistent with these results, both Tasigna and BODIPY FL Tasigna were less effective at inhibiting the phosphorylation of Crkl (a substrate of BCR-ABL kinase) in Pgp-and ABCG2-expressing K562 cells due to their reduced intracellular concentration. Taken together, these data provide evidence that BODIPY FL Tasigna is transported by Pgp and ABCG2, and Tasigna is transported by Pgp. Further, we propose that BODIPY FL Tasigna can potentially be used as a probe for functional analysis of Pgp and ABCG2 in cancer cells and in other preclinical studies.

Leukemia, 2014

bone marrow blasts, 2 with splenomegaly, 7 with diploid cytogenetics and 1 with JAK2-V617F mutati... more bone marrow blasts, 2 with splenomegaly, 7 with diploid cytogenetics and 1 with JAK2-V617F mutation. Whether these patients share a specific genetic phenotype is conceivable, and molecular characterization of this subgroup is ongoing.

Journal of the American Chemical Society, 2008

Virtual screening has become a major focus of bioactive small molecule lead identification, and r... more Virtual screening has become a major focus of bioactive small molecule lead identification, and reports of agonists and antagonists discovered via virtual methods are becoming more frequent. G protein-coupled receptors (GPCRs) are the one class of protein targets for which success with this approach has been limited. This is likely due to the paucity of detailed experimental information describing GPCR structure and the intrinsic function-associated structural flexibility of GPCRs which present major challenges in the application of receptor-based virtual screening. Here we describe an in silico methodology that diminishes the effects of structural uncertainty, allowing for more inclusive representation of a potential docking interaction with exogenous ligands. Using this approach, we screened one million compounds from a virtual database, and a diverse subgroup of 100 compounds was selected, leading to experimental identification of five structurally diverse antagonists of the thyrotropin-releasing hormone receptors (TRH-R1 and TRH-R2). The chirality of the most potent chemotype was demonstrated to be important in its binding affinity to TRH receptors; the most potent stereoisomer was noted to have a 13-fold selectivity for TRH-R1 over TRH-R2. A comprehensive mutational analysis of key amino acid residues that form the putative binding pocket of TRH receptors further verified the binding modality of these small molecule antagonists. The described virtual screening approach may prove applicable in the search for novel small molecule agonists and antagonists of other GPCRs.

The Journal of Organic Chemistry, 2007

The syntheses of (+/-)-dibromophakellstatin and, from this species, (+/-)-dibromophakellin are de... more The syntheses of (+/-)-dibromophakellstatin and, from this species, (+/-)-dibromophakellin are described. Oxidative cyclization of a phenylthiolated dihydrooroidin derivative triggered by a Pummerer reaction constitutes the key step in this biomimetic approach to this family of marine alkaloids.

The Journal of Organic Chemistry, 1999

Methyl N-unprotected α-amino esters are important intermediates in organic synthesis. 1 They can ... more Methyl N-unprotected α-amino esters are important intermediates in organic synthesis. 1 They can be conveniently prepared by a Fisher-type esterification of the corresponding free α-amino acids in methanol using gaseous HCl, 1a SOCl 2 , 1b or TMSCl. 1c In addition, an ...

Journal of Natural Products, 2012

We report herein that the oroidin-derived alkaloids palau'amine (1), dibromophakellin (2), and di... more We report herein that the oroidin-derived alkaloids palau'amine (1), dibromophakellin (2), and dibromophakellstatin (3) inhibit the proteolytic activity of the human 20S proteasome as well as the i 20S immunoproteasome catalytic core. Palau'amine is found to prevent the degradation of ubiquitinylated proteins, including IκBα, in cell culture, which may be indicative of the potential mechanism by which these agents exhibit their exciting cytotoxic and immunosuppressive properties.