Wyniki wyszukiwania dla: Peter M. Blumberg

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Chiral 2‐phenyl‐3‐hydroxypropyl esters as PKC‐alpha modulators: HPLC enantioseparation, NMR absolute configuration assignment, and molecular docking studies

Pasquale Linciano, Rita Nasti, Roberta Listro, Marialaura Amadio, więcej

Chirality > 34 > 3 > 498 - 513

Protein kinase C (PKC) isoforms play a pivotal role in the regulation of numerous cellular functions, making them extensively studied and highly attractive drug targets. In our previous work, we identified in racemate 1–2, based on the 2‐benzyl‐3‐hydroxypropyl ester scaffold, two new potent and promising PKCα and PKCδ ligands, targeting the C1 domain of these two kinases. Herein, we report the resolution...

artykuł

Discovery of 2-(3,5-difluoro-4-methylsulfonaminophenyl)propanamides as potent TRPV1 antagonists

Changhoon Kim, Jihyae Ann, Sunho Lee, Wei Sun, więcej

Bioorganic & Medicinal Chemistry Letters > 2018 > 28 > 14 > 2539-2542

A series of A-region analogues of 2-(3-fluoro-4-methylsufonamidophenyl) propanamide 1 were investigated as TRPV1 antagonists. The analysis of structure-activity relationship indicated that a fluoro group at the 3- (or/and) 5-position and a methylsulfonamido group at the 4-position were optimal for antagonism of TRPV1 activation by capsaicin. The most potent antagonist 6 not only exhibited potent antagonism...

artykuł

Importance of the REM (Ras exchange) domain for membrane interactions by RasGRP3

Agnes Czikora, Noemi Kedei, Heather Kalish, Peter M. Blumberg

Biochimica et Biophysica Acta (BBA) - Biomembranes > 2017 > 1859 > 12 > 2350-2360

RasGRP comprises a family of guanine nucleotide exchange factors, regulating the dissociation of GDP from Ras GTPases to enhance the formation of the active GTP-bound form. RasGRP1 possesses REM (Ras exchange), GEF (catalytic), EF-hand, C1, SuPT (suppressor of PT), and PT (plasma membrane-targeting) domains, among which the C1 domain drives membrane localization in response to diacylglycerol or phorbol...

artykuł

The C1 domain of Vav3, a novel potential therapeutic target

Jessica S. Kelsey, Tamás Géczy, Christopher J. Kaler, Peter M. Blumberg

Cellular Signalling > 2017 > 40 > C > 133-142

Vav1/2/3 comprise a protein family with guanyl nucleotide exchange activity for Rho and Rac as well as with motifs conferring adapter activity. Biologically, Vav1 plays a critical role in hematologic cell signaling, whereas Vav2/3 have a wider tissue distribution, but all 3 Vav proteins are implicated in cancer development. A structural feature of Vav1/2/3 is the presence of an atypical C1 domain,...

artykuł

Pyrazole C-region analogues of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides as potent TRPV1 antagonists

Sunho Lee, Changhoon Kim, Jihyae Ann, Shivaji A. Thorat, więcej

Bioorganic & Medicinal Chemistry Letters > 2017 > 27 > 18 > 4383-4388

A series of 1-substituted 3-(t-butyl/trifluoromethyl)pyrazole C-region analogues of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides were investigated for hTRPV1 antagonism. The structure activity relationship indicated that the 3-chlorophenyl group at the 1-position of pyrazole was the optimized hydrophobic group for antagonistic potency and the activity was stereospecific to the S-configuration,...

artykuł

Exploring the influence of indololactone structure on selectivity for binding to the C1 domains of PKCα, PKCε, and RasGRP

Eleonora Elhalem, Lucía Gandolfi Donadío, Xiaoling Zhou, Nancy E. Lewin, więcej

Bioorganic & Medicinal Chemistry > 2017 > 25 > 12 > 2971-2980

C1 domain-containing proteins, such as protein kinase C (PKC), have a central role in cellular signal transduction. Their involvement in many diseases, including cancer, cardiovascular disease, and immunological and neurological disorders has been extensively demonstrated and has prompted a search for small molecules to modulate their activity. By employing a diacylglycerol (DAG)-lactone template,...

artykuł

t-Butyl pyridine and phenyl C-region analogues of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides as potent TRPV1 antagonists

Sunho Lee, Dong Wook Kang, HyungChul Ryu, Changhoon Kim, więcej

Bioorganic & Medicinal Chemistry > 2017 > 25 > 8 > 2451-2462

A series of 2-substituted 6-t-butylpyridine and 4-t-butylphenyl C-region analogues of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides were investigated for hTRPV1 antagonism. The analysis of structure activity relationships indicated that the pyridine derivatives generally exhibited a little better antagonism than did the corresponding phenyl surrogates for most of the series. Among the compounds,...

artykuł

Biological activity of the bryostatin analog Merle 23 on mouse epidermal cells and mouse skin

Jessica S. Kelsey, Christophe Cataisson, Jinqiu Chen, Michelle A. Herrmann, więcej

Molecular Carcinogenesis > 55 > 12 > 2183 - 2195

Bryostatin 1, a complex macrocyclic lactone, is the subject of multiple clinical trials for cancer chemotherapy. Although bryostatin 1 biochemically functions like the classic mouse skin tumor promoter phorbol 12‐myristate 13‐acetate (PMA) to bind to and activate protein kinase C, paradoxically, it fails to induce many of the typical phorbol ester responses, including tumor promotion. Intense synthetic...

artykuł

Replacement of the bryostatin A- and B-pyran rings with phenyl rings leads to loss of high affinity binding with PKC

Mark E. Petersen, Noemi Kedei, Nancy E. Lewin, Peter M. Blumberg, więcej

Tetrahedron Letters > 2016 > 57 > 42 > 4749-4753

We describe a convergent synthesis of a bryostatin analogue in which the natural A- and B-ring pyrans have been replaced by phenyl rings. The new analogue exhibited PMA like behavior in cell assays, but failed to maintain high affinity binding for PKC, despite retaining an unaltered C-ring ‘binding domain’

artykuł

Discovery of N-(3-fluoro-4-methylsulfonamidomethylphenyl)urea as a potent TRPV1 antagonistic template

Jihyae Ann, Wei Sun, Xing Zhou, Aeran Jung, więcej

Bioorganic & Medicinal Chemistry Letters > 2016 > 26 > 15 > 3603-3607

A series of homologous analogues of prototype antagonist 1 and its urea surrogate were investigated as hTRPV1 ligands. Through one-carbon elongation in the respective pharmacophoric regions, N-(3-fluoro-4-methylsulfonamidomethylphenyl)urea was identified as a novel and potent TRPV1 antagonistic template. Its representative compound 27 showed a potency comparable to that of lead compound 1. Docking...

rozdział

Insights into TRPV1 pharmacology provided by non-capsaicin ligands

Peter M. Blumberg, Derek C. Braun, Noemi Kedei, Jozsef Lazar, więcej

Progress in Inflammation Research > Turning up the Heat on Pain: TRPV1 Receptors in Pain and Inflammation > Pharmacology and physiology of vanilloid receptors > 55-69

artykuł

2-Sulfonamidopyridine C-region analogs of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides as potent TRPV1 antagonists

Jihyae Ann, Yooran Ki, Suyoung Yoon, Myeong Seop Kim, więcej

Bioorganic & Medicinal Chemistry > 2016 > 24 > 6 > 1231-1240

A series of 2-sulfonamidopyridine C-region derivatives of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamide were investigated as hTRPV1 ligands. Systematic modification on the 2-sulfonamido group provided highly potent TRPV1 antagonists. The N-benzyl phenylsulfonamide derivatives 12 and 23 in particular showed higher affinities than that of lead compound 1. Compound 12 exhibited strong analgesic activity...

artykuł

Engineering Vanilloid-Sensitivity into the TRPV2 Channel

Feng Zhang, Sonya M. Hanson, Larry Pearce, Dmitriy Krepkiy, więcej

Biophysical Journal > 2016 > 110 > 3 Supplement 1 > 286a

rozdział

Phorbol Esters and Diacylglycerol: The PKC Activators

Peter M. Blumberg, Noemi Kedei, Nancy E. Lewin, Dazhi Yang, więcej

Current Cancer Research > Protein Kinase C in Cancer Signaling and Therapy > Regulation of PKC Isozyme Function: From Genes to Biochemistry > 25-53

Protein kinase C (PKC) represents the most prominent of the families of signaling proteins integrating response to the ubiquitous lipophilic second messenger sn-1,2-diacylglycerol and to its ultrapotent analogs, the tumor-promoting phorbol esters. Response is mediated through twin conserved zinc finger structures, the C1 domains. The C1 domains function as hydrophobic switches, for which ligand binding...

artykuł

Multi-Functional Diarylurea Small Molecule Inhibitors of TRPV1 with Therapeutic Potential for Neuroinflammation

Zhiwei Feng, Larry V. Pearce, Yu Zhang, Changrui Xing, więcej

The AAPS Journal > 2016 > 18 > 4 > 898-913

Transient receptor potential vanilloid type 1 (TRPV1), a heat-sensitive calcium channel protein, contributes to inflammation as well as to acute and persistent pain. Since TRPV1 occupies a central position in pathways of neuronal inflammatory signaling, it represents a highly attractive potential therapeutic target for neuroinflammation. In the present work, we have in silico identified a series of...

artykuł

Structure activity relationships of benzyl C-region analogs of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides as potent TRPV1 antagonists

Jihyae Ann, Aeran Jung, Mi-Yeon Kim, Hyuk-Min Kim, więcej

Bioorganic & Medicinal Chemistry > 2015 > 23 > 21 > 6844-6854

A series of 2-substituted 4-(trifluoromethyl)benzyl C-region analogs of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides were investigated for hTRPV1 antagonism. The analysis indicated that the phenyl C-region derivatives exhibited better antagonism than those of the corresponding pyridine surrogates for most of the series examined. Among the phenyl C-region derivatives, the two best compounds 43...

artykuł

α-Substituted 2-(3-fluoro-4-methylsulfonamidophenyl)acetamides as potent TRPV1 antagonists

Phuong-Thao Tran, Ho Shin Kim, Jihyae Ann, Sung-Eun Kim, więcej

Bioorganic & Medicinal Chemistry Letters > 2015 > 25 > 11 > 2326-2330

A series of α-substituted acetamide derivatives of previously reported 2-(3-fluoro-4-methylsulfonamidophenyl)propanamide leads (1, 2) were investigated for antagonism of hTRPV1 activation by capsaicin. Compound 34, which possesses an α-m-tolyl substituent, showed highly potent and selective antagonism of capsaicin with K _i(CAP) =0.1nM. It thus reflected a 3-fold improvement in potency over...

artykuł

Pyridine C-region analogs of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides as potent TRPV1 antagonists

HyungChul Ryu, Sejin Seo, Jee-Young Lee, Tae-Hwan Ha, więcej

European Journal of Medicinal Chemistry > 2015 > 93 > Complete > 101-108

A series of pyridine derivatives in the C-region of N-((6-trifluoromethyl-pyridin-3-yl)methyl) 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides were investigated as hTRPV1 antagonists. The SAR analysis indicated that 6-difluorochloromethyl pyridine derivatives were the best surrogates of the C-region for previous leads. Among them, compound 31 showed excellent antagonism to capsaicin as well as...

artykuł

6,6-Fused heterocyclic ureas as highly potent TRPV1 antagonists

Wei Sun, Hyo-Shin Kim, Sunho Lee, Aeran Jung, więcej

Bioorganic & Medicinal Chemistry Letters > 2015 > 25 > 4 > 803-806

A series of N-[{2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)-pyridin-3-yl}methyl] N′-(6,6-fused heterocyclic) ureas have been investigated as hTRPV1 antagonists. Among them, compound 15 showed highly potent TRPV1 antagonism to capsaicin, with K _i(ant) =0.2nM, as well as antagonism to other activators, and it was efficacious in a pain model. A docking study of 15 with our hTRPV1 homology...

artykuł

Design and synthesis of protein kinase C epsilon selective diacylglycerol lactones (DAG-lactones)

Jihyae Ann, Suyoung Yoon, Jisoo Baek, Da Hye Kim, więcej

European Journal of Medicinal Chemistry > 2015 > 90 > Complete > 332-341

DAG-lactones afford a synthetically accessible, high affinity platform for probing structure activity relationships at the C1 regulatory domain of protein kinase C (PKC). Given the central role of PKC isoforms in cellular signaling, along with their differential biological activities, a critical objective is the design of isoform selective ligands. Here, we report the synthesis of a series of DAG-lactones...

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