Qualitative analysis of the fluorophosphonate-based chemical probes using the serine hydrolases from mouse liver and poly-3-hydroxybutyrate depolymerase (PhaZ) from Bacillus thuringiensis.

The serine hydrolase family consists of more than 200 members and is one of the largest enzyme families in the human genome. Although up to 50 % of this family remains unannotated, there are increasing evidences that activities of certain serine hydrolases are associated with diseases like cancer neoplasia, invasiveness, etc. By now, several activity-based chemical probes have been developed and are applied to profile the global activity of serine hydrolases in diverse proteomes. In this study, two fluorophosphonate (FP)-based chemical probes were synthesized. Further examination of their abilities to label and pull down serine hydrolases was conducted. In addition, the poly-3-hydroxybutyrate depolymerase (PhaZ) from Bacillus thuringiensis was demonstrated as an appropriate standard serine hydrolase, which can be applied to measure the labeling ability and pull-down efficiency of FP-based probes. Furthermore, mass spectrometry (MS) was used to identify the serine residue that covalently bonded to the active probes. Finally, these FP-based probes were shown capable of establishing the serine hydrolase profiles in diverse mouse tissues; the serine hydrolases pulled down from mouse liver organ were further identified by MS. In summary, our study provides an adequate method to evaluate the reactivity of FP-based probes targeting serine hydrolases.

Exploring a sulfone linker utilizing trimethyl aluminum as a cleavage reagent: solid-phase synthesis of sulfonamides and ureas.

A novel and efficient cleavage reagent, trimethyl aluminum, for traceless sulfinate-functionalized resin has been developed. The synthesis of sulfonamide and urea derivatives via a traceless solid-phase sulfone linker strategy through six synthetic steps comprising utilization of trimethyl aluminum as a novel cleavage reagent was also established. An insight of the plausible mechanism of the cleavage reaction was discussed.

A Novel Mechanistic Study on Ultrasound-Assisted, One-Pot Synthesis of Functionalized Benzimidazo[2,1-b]quinazolin-1(1H)-ones.

Ultrasound-assisted synthesis of benzimidazo[2,1-b]quinazolin-1(1H)-ones was achieved via piperidine-catalyzed three-component reaction of 2-aminobenzimidazoles, an aromatic aldehyde, and 1,3-dione in aqueous isopropanol. This mechanism was first suspected following our identification of unusual reaction intermediates in a one-pot reaction. An unprecedented coupling reaction, it involved a nucleophilic attack by 2-aminobenzimidazole on in situ generated Michael adduct, followed by electrocyclic ring formation reaction. In contrast to the commonly accepted mechanism, that the direct reaction of 2-amino benzimidazole with a Knoevenagel adduct cannot deliver target compounds.

Multicomponent Synthesis of Functionalized Tetrahydroacridinones: Insights into a Mechanistic Route.

A mechanistic study of three-component reactions of various aromatic amines with a number of aldehydes and 1,3-diones was achieved. The unprecedented reaction involved a nucleophilic attack of an aromatic amine on the in situ generated Michael adduct intermediate followed by six-electron ring cyclizations. It is contrary to the common belief that advocates involvement of coupling reactions between a Knoevenagel adduct and an aromatic amine to deliver substituted tetrahydroacridinones.

Telescoped Synthesis of 2-Acyl-1-aryl-1,2-dihydroisoquinolines and Their Inhibition of the Transcription Factor NF-κB.

A sequential single-flask multicomponent reactions is highly effective for the synthesis of 1,2-dihydroisoquinolines through amidealkylation from intermediate N-acylisoquinolinium salts under mild conditions. N-Acylisoquinolinium ions and trichloromethyl-1-(1H-indol-3-yl)isoquinoline-2(1H)-carboxylate have demonstrated their reactivity toward aromatic and aliphatic π-nucleophiles. One of the 1,2-dihydroisoquinoline derivatives was found to be a potent inhibitor for transcription factor NF-κB by blocking IκBα degradation, p65 nuclear translocation, and NF-κB DNA binding in TNF-α-induced NIH 3T3 cells.

Novel cyclization of bis-Boc-guanidines: expeditive traceless synthesis of 1,3,5-oxadiazinones under microwave conditions.

A novel intramolecular cyclization was discovered during the reaction of soluble polymer supported bis-Boc-guanidines with amines under microwave irradiation, leading to an oxadiazinone skeleton. The cyclized polymer conjugates have been further utilized to generate substituted 1,3,5-oxadiazinones by a traceless synthesis.