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1.
Antibiotics (Basel) ; 11(2)2022 Feb 19.
Article in English | MEDLINE | ID: mdl-35203876

ABSTRACT

Pseudomonas aeruginosa (P. aeruginosa) is an opportunistic gram-negative pathogen that can cause various infections, particularly in patients with compromised host defenses. P. aeruginosa forms biofilms and produces virulence factors through quorum sensing (QS) network, resulting in resistance to antibiotics. RhlI/RhlR, one of key QS systems in P. aeruginosa, is considered an attractive target for inhibiting biofilm formation and attenuating virulence factors. Several recent studies examined small molecules targeting the RhlI/RhlR system and their in vitro and in vivo biological activities. In this review, RhlR-targeted modulators, including agonists and antagonists, are discussed with particular focus on structure-activity relationship studies and outlook for next-generation anti-biofilm agents.

2.
J Enzyme Inhib Med Chem ; 37(1): 269-279, 2022 Dec.
Article in English | MEDLINE | ID: mdl-34894957

ABSTRACT

Inositol hexakisphosphate kinase (IP6K) is an important mammalian enzyme involved in various biological processes such as insulin signalling and blood clotting. Recent analyses on drug metabolism and pharmacokinetic properties on TNP (N2-(m-trifluorobenzyl), N6-(p-nitrobenzyl)purine), a pan-IP6K inhibitor, have suggested that it may inhibit cytochrome P450 (CYP450) enzymes and induce unwanted drug-drug interactions in the liver. In this study, we confirmed that TNP inhibits CYP3A4 in type I binding mode more selectively than the other CYP450 isoforms. In an effort to find novel purine-based IP6K inhibitors with minimal CYP3A4 inhibition, we designed and synthesised 15 TNP analogs. Structure-activity relationship and biochemical studies, including ADP-Glo kinase assay and quantification of cell-based IP7 production, showed that compound 9 dramatically reduced CYP3A4 inhibition while retaining IP6K-inhibitory activity. Compound 9 can be a tool molecule for structural optimisation of purine-based IP6K inhibitors.


Subject(s)
Cytochrome P-450 CYP3A/metabolism , Enzyme Inhibitors/pharmacology , Phosphotransferases (Phosphate Group Acceptor)/antagonists & inhibitors , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Molecular Structure , Phosphotransferases (Phosphate Group Acceptor)/metabolism , Structure-Activity Relationship
3.
Expert Opin Ther Pat ; 31(6): 525-547, 2021 Jun.
Article in English | MEDLINE | ID: mdl-33459068

ABSTRACT

INTRODUCTION: Prostate-specific membrane antigen (PSMA), also known as glutamate carboxypeptidase II, is a potential target protein for imaging and treatment of patients with prostate cancer because of its overexpression during metastasis. Various PSMA-targeted imaging and therapeutic probes have been designed and synthesized based on the Lys-urea-Glu motif. Structural modifications have been made exclusively in the linker region, while maintaining the Lys-urea-Glu structure that interacts with S1 and S1' pockets. AREA COVERED: This review includes WIPO-listed patents (from January 2017 to June 2020) reporting PSMA-targeted probes based on the Lys-urea-Glu or Glu-urea-Glu structure. EXPERT OPINION: : PSMA-targeted imaging agents labeled with radionuclides such as fluorine-18, copper-64, gallium-68, and technetium-99m have been successfully translated into clinical phase for the early diagnosis of metastatic prostate cancer. Recently, PSMA-targeted therapeutic agents labeled with iodine-131, lutetium-177, astatine-211, and lead-212 have also been developed with notable progress. Most PSMA-targeted agents are based on the Lys-urea-Glu or Glu-urea-Glu structure, demonstrate strong PSMA-binding affinity in nanomolar range, and achieve diverse structural modifications in the non-pharmacophore pocket. By exploiting the S1 accessory pocket or the tunnel region of the PSMA active site, the in vivo efficacy and pharmacokinetic profiles of the PMSA-targeted agents can be effectively modulated.


Subject(s)
Antineoplastic Agents/pharmacology , Glutamate Carboxypeptidase II/antagonists & inhibitors , Prostatic Neoplasms/drug therapy , Animals , Antigens, Surface/metabolism , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Drug Design , Glutamate Carboxypeptidase II/metabolism , Humans , Male , Molecular Targeted Therapy , Neoplasm Metastasis , Patents as Topic , Prostatic Neoplasms/diagnosis , Prostatic Neoplasms/pathology , Structure-Activity Relationship
4.
J Med Chem ; 63(15): 8388-8407, 2020 08 13.
Article in English | MEDLINE | ID: mdl-32696644

ABSTRACT

Pseudomonas aeruginosa (P. aeruginosa) is an opportunistic human pathogen that forms biofilms and produces virulence factors via quorum sensing (QS). Blocking the QS system in P. aeruginosa is an excellent strategy to reduce biofilm formation and the production of virulence factors. RhlR plays an essential role in the QS system of P. aeruginosa. We synthesized 55 analogues based on the chemical structure of 4-gingerol and evaluated their RhlR inhibitory activities using the cell-based reporter strain assay. Comprehensive structure-activity relationship studies identified the alkynyl ketone 30 as the most potent RhlR antagonist. This compound displayed selective RhlR antagonism over LasR and PqsR, strong inhibition of biofilm formation, and reduced production of virulence factors in P. aeruginosa. Furthermore, the survival rate of Tenebrio molitor larvae treated with 30 in vivo greatly improved. Therefore, compound 30, a pure RhlR antagonist, can be utilized for developing QS-modulating molecules in the control of P. aeruginosa infections.


Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Bacterial Proteins/antagonists & inhibitors , Pseudomonas Infections/drug therapy , Pseudomonas aeruginosa/drug effects , Bacterial Proteins/metabolism , Biofilms/drug effects , Catechols/chemistry , Catechols/pharmacology , Drug Discovery , Fatty Alcohols/chemistry , Fatty Alcohols/pharmacology , Humans , Pseudomonas Infections/microbiology , Pseudomonas aeruginosa/physiology , Quorum Sensing/drug effects
6.
Sci Rep ; 9(1): 8762, 2019 06 19.
Article in English | MEDLINE | ID: mdl-31217492

ABSTRACT

Thymic stromal lymphopoietin (TSLP) plays an important role in the differentiation and proliferation of Th2 cells, resulting in eosinophilic inflammation and numerous allergic diseases. Baicalein (1), a major component of Scutellaria baicalensis, was found to be the first small molecule to block TSLP signaling pathways. It inhibited effectively eosinophil infiltration in house dust mite-induced and ovalbumin-challenged mouse models. Structure-activity relationship studies identified compound 11a, a biphenyl flavanone analog, as a novel human TSLP inhibitor for the discovery and development of new anti-allergic drugs.


Subject(s)
Anti-Allergic Agents , Asthma , Cytokines , Flavanones , Animals , Anti-Allergic Agents/chemical synthesis , Anti-Allergic Agents/chemistry , Anti-Allergic Agents/pharmacology , Asthma/chemically induced , Asthma/drug therapy , Asthma/immunology , Asthma/pathology , Cell Line , Cytokines/antagonists & inhibitors , Cytokines/chemistry , Flavanones/chemical synthesis , Flavanones/chemistry , Flavanones/pharmacology , Humans , Mice , Pyroglyphidae/immunology
7.
Bioorg Chem ; 89: 102990, 2019 08.
Article in English | MEDLINE | ID: mdl-31136899

ABSTRACT

Hepsin is a type II serine protease that is highly expressed in neoplastic prostate. It is an attractive biomarker for imaging metastatic prostate cancer because of its overexpression in advanced prostate cancer and the location of its active site on the cell surface. We designed and synthesized novel hepsin-targeted imaging probes by conjugating the hepsin-binding ligand with near-infrared (NIR) optical dyes. The Leu-Arg dipeptides, attached to BODIPY or SulfoCy7, exhibited strong hepsin-inhibitory activities with Ki values of 21 and 22 nM, respectively. Compound 2 showed selective uptake and retention in hepsin-overexpressing cells. This is the first report of hepsin-targeted optical probes with strong binding affinities and high selectivity over matriptase. Compound 2 has the potential to be used for developing hepsin-based imaging probes and be as a prototype molecule in the design of new hepsin inhibitors.


Subject(s)
Drug Design , Fluorescent Dyes/chemistry , Serine Endopeptidases/chemistry , Serine Proteinase Inhibitors/chemistry , Binding Sites , Boron Compounds/chemistry , Catalytic Domain , Cell Line, Tumor , Humans , Inhibitory Concentration 50 , Ligands , Molecular Docking Simulation , Serine Endopeptidases/genetics , Serine Endopeptidases/metabolism , Serine Proteinase Inhibitors/metabolism
8.
J Speech Lang Hear Res ; 61(8): 1945-1969, 2018 08 08.
Article in English | MEDLINE | ID: mdl-30073307

ABSTRACT

Purpose: This study aimed to examine the effect of an intensive vocabulary intervention embedded in e-books on the vocabulary skills of young Spanish-English speaking English learners (ELs) from low-socioeconomic status backgrounds. Method: Children (N = 288) in kindergarten and 1st grade were randomly assigned to treatment and read-only conditions. All children received e-book readings approximately 3 times a week for 10-20 weeks using the same books. Children in the treatment condition received e-books supplemented with vocabulary instruction that included scaffolding through explanations in Spanish, repetition in English, checks for understanding, and highlighted morphology. Results: There was a main effect of the intervention on expressive labeling (g = 0.38) and vocabulary on the Peabody Picture Vocabulary Test-Fourth Edition (g = 0.14; Dunn & Dunn, 2007), with no significant moderation effect of initial Peabody Picture Vocabulary Test score. There was no significant difference between conditions on children's expressive definitions. Conclusion: Findings substantiate the effectiveness of computer-implemented embedded vocabulary intervention for increasing ELs' vocabulary knowledge. Implications: Computer-assisted vocabulary instruction with scaffolding through Spanish explanations, repetitions, and highlighted morphology is a promising approach to facilitate word learning for ELs in kindergarten and 1st grade.


Subject(s)
Child Language , Computer-Assisted Instruction , Multilingualism , Textbooks as Topic , Vocabulary , Child , Educational Measurement , Female , Humans , Male , Poverty/psychology
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