Facial Amphiphile-Modified Lipids Highly Sensitize Liposomes toward Secretory Phospholipase A.

Upregulated secretory phospholipase A (sPLA) in tumors has been proposed as a stimulus to trigger drug release from liposomes for therapeutic effects. However, the current strategy for developing sPLA-responsive liposomes merely considering substrate preference suffers from limited membrane disruptive effects induced by enzymatic hydrolysis and safety issues resulting from the overuse of sPLA-preferred lipids. Here, a membrane-destabilizing mechanism based on enzymatic extraction and the transition of facial amphiphiles (FAs) within lipid membranes was introduced.

-Methylation of carboxylic acids with streptozotocin.

The clinically used DNA-alkylating drug streptozotocin (STZ) was investigated using a simple work-up as an -methylating agent to transform various carboxylic acids, sulfonic acids and phosphorous acids into corresponding methyl esters, and did so with yields of up to 97% in 4 h at room temperature. Good substrate tolerance was observed, and benefited from the mild conditions and compatibility of the reaction with water.

A synthetic resveratrol analog termed Q205 reactivates latent HIV-1 through activation of P-TEFb.

The persistence of HIV-1 latent reservoir creates the major obstacle toward an HIV-1 cure. The "shock and kill" strategy aims to reverse HIV-1 proviral latency using latency-reversing agents (LRAs), thus boosting immune recognition and clearance to residual infected cells. Unfortunately, to date, none of these tested LRA candidates has been demonstrated effectiveness and/or safety in reactivation HIV-1 latency.

A New Small-Molecule Compound, Q308, Silences Latent HIV-1 Provirus by Suppressing Tat- and FACT-Mediated Transcription.

Eliminating the latent HIV reservoir remains a difficult problem for creating an HIV functional cure or achieving remission. The "block-and-lock" strategy aims to steadily suppress transcription of the viral reservoir and lock the HIV promoter in deep latency using latency-promoting agents (LPAs). However, to date, most of the investigated LPA candidates are not available for clinical trials, and some of them exhibit immune-related adverse reactions.

The one-pot synthesis of butyl-1H-indol-3-alkylcarboxylic acid derivatives in ionic liquid as potent dual-acting agent for management of BPH.

Based on the SAR of both α-AR antagonists and 5α-reductase (5AR) inhibitors, the dual-acting agent 4-(1-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-1H-indol-3-yl)butanoic acid 4aaa was designed against BPH and synthesized by two steps of N-alkylation. One-pot protocol towards 4aaa was newly developed. With IL [Cmin]Br as solvent, the yield of 4aaa was increased to 75.

Diastereoselective Synthesis of 3,4-Dihydropyran-3-carboxamides with in Vitro Anti-inflammatory Activity.

A versatile and economical reaction of diketene (), aryl amines , cyclic 1,3-diketones , primary amines , and aryl aldehydes was explored to synthesize 3,4-dihydropyran-3-carboxamide derivatives under mild conditions. Three stereogenic centers are generated in the products, and the structure of the major diastereomer of {,,,} was identified by X-ray diffraction and 2D NMR spectroscopy. The scope and limitation investigation provided two series of (2,3,4)-chromene-3-carboxamides in good to excellent yields with high diastereoselectivity.

"On-Water" Synthesis of Quinazolinones and Dihydroquinazolinones Starting from -Bromobenzonitrile.

A versatile and practical "on-water" protocol was newly developed to synthesize quinazolinones using -bromobenzonitrile as a novel starting material. Studies have found that air as well as water plays an important role in synthesis of quinazolinones. Further investigation indicated that dihydroquinazolinones can be prepared with this protocol under the protection of N₂.

The BET bromodomain inhibitor apabetalone induces apoptosis of latent HIV-1 reservoir cells following viral reactivation.

The persistence of latent HIV-1 reservoirs throughout combination antiretroviral therapy (cART) is a major barrier on the path to achieving a cure for AIDS. It has been shown that bromodomain and extra-terminal (BET) inhibitors could reactivate HIV-1 latency, but restrained from clinical application due to their toxicity and side effects. Thus, identifying a new type of BET inhibitor with high degrees of selectivity and safety is urgently needed.

Identification and characterization of a potent and selective inhibitor of human urate transporter 1.

Background: Selective inhibitors of human urate transporter 1 (hURAT1) are considered to be effective treatment for hyperuricemia and gout, which can reduce the reabsorption of more than 90% of uric acid in the proximal tubule of the kidney. We aimed to design and synthesize a more potent hURAT1 based on the structure of Lesinurad (LU), which was reported to lower uric acid levels with IC50 value of hURAT1 (about 60μM).

Methods: A cell model was conducted and characterized via Real-time qRCR and Western blot.

Catalytic Site-Selective Acylation of Carbohydrates Directed by Cation-n Interaction.

Site-selective functionalization of hydroxyl groups in carbohydrates is one of the long-standing challenges in chemistry. Using a pair of chiral catalysts, we now can differentiate the most prevalent trans-1,2-diols in pyranoses systematically and predictably. Density functional theory (DFT) calculations indicate that the key determining factor for the selectivity is the presence or absence of a cation-n interaction between the cation in the acylated catalyst and an appropriate lone pair in the substrate.

Rhodium(I)-Catalyzed Benzannulation of Heteroaryl Propargylic Esters: Synthesis of Indoles and Related Heterocycles.

A de novo synthesis of a benzene ring allows for the preparation of a diverse range of heterocycles including indoles, benzofurans, benzothiophenes, carbazoles, and dibenzofurans from simple heteroaryl propargylic esters using a unified carbonylative benzannulation strategy. Multiple substituents can be easily introduced to the C4-C7 positions of indoles and related heterocycles.

Synthesis of Carbazoles and Carbazole-Containing Heterocycles via Rhodium-Catalyzed Tandem Carbonylative Benzannulations.

Polycyclic aromatic compounds are important constituents of pharmaceuticals and other materials. We have developed a series of Rh-catalyzed tandem carbonylative benzannulations for the synthesis of tri-, tetra-, and pentacyclic heterocycles from different types of aryl propargylic alcohols. These tandem reactions provide efficient access to highly substituted carbazoles, furocarbazoles, pyrrolocarbazoles, thiophenocarbazoles, and indolocarbazoles.

Synthesis of Substituted Tropones by Sequential Rh-Catalyzed [5+2] Cycloaddition and Elimination.

Highly substituted tropones are prepared from cycloheptatrienes derived from Rh-catalyzed intermolecular [5+2] cycloaddition of 3-acyloxy-1,4-enynes and propargylic alcohols. The intermolecular [5+2] cycloaddition is highly regioselective for a variety of propargylic alcohols. Elimination of the cycloaddition products afforded various substituted tropones.

Synthesis and potent inhibitory activities of carboxybenzyl-substituted 8-(3-(R)-aminopiperidin-1-yl)-7-(2-chloro/cyanobenzyl)-3-methyl-3,7-dihydro-purine-2,6-diones as dipeptidyl peptidase IV (DPP-IV) inhibitors.

Fourteen 3-methyl-3,7-dihydro-purine-2,6-dione derivatives 1-14 bearing carboxybenzyl and 2-chloro/cyanobenzyl groups at the N-1 and N-7 positions, respectively, were synthesized as dipeptidyl peptidase IV (DPP-IV) inhibitors. These compounds were characterized on the basis of NMR ((1)H and (13)C) and ESI MS data. In vitro bioassay indicates that most of these compounds showed moderate to good inhibitory activities against DPP-IV.

[Design, synthesis and biological activity assessment of phenoxybutyric acid derivatives as nonsteroidal 5α-reductase inhibitors].

Objevtive: To synthesize phenoxybutyric acid derivatives as 5α-reductase inhibitors and test their biological activities in vitro.

Methods: Eight analogues as nonsteroidal 5α-reductase inhibitors were designed and synthesized by substitution reaction of 6-(4-phenyl-piperazine-1-yl)-3(2H)-pyridazinone with phenoxybutyric acid derivatives.

Results And Conclusion: The structures of the compounds were characterized by 1H-NMR and MS.

[Design, synthesis and characterization of cyanopyrrolidine-bearing compounds as DPP-4 inhibitors].

Objective: To synthesize novel cyanopyrrolidine-bearing compounds as dipeptidyl peptidase 4 (DPP4) inhibitors and characterize their biological activities in vitro.

Methods: Eleven analogues of carbonitrilpyrrolidine were designed and synthesized by substitution reaction of (S)-2-(2-cyanopyrrolidin-1-yl)acetyl bromide with substituted phenyl piperazine pyridazinones.

Results: The structures of the compounds were characterized by (1)H-NMR and MS spectra.

Drug metabolism-based design, synthesis, and bioactivities of 1-(2,6-dimethylphenoxy)-2-(3,4-dimethoxyphenylethylamino)propane hydrochloride (DDPH) analogs as α₁-adrenoceptors antagonists.

1-(2,6-dimethylphenoxy)-2-(3,4-dimethoxyphenylethylamino)propane hydrochloride (DDPH) is a potent α₁-adrenoceptor antagonist that is currently under Phase II clinic trials. However, the fast metabolism has restricted its further use. In this paper, 11 DDPH analogs were designed according to the probable metabolism pathways of DDPH, and featured the structures of halogen, methyl, and cyano groups at the 3-, or 4-position of aromatic ring A to block the hydroxylation, and one hydroxyl group at the 3-, or 4-position of aromatic ring B to extend the duration time.

Synthesis and blocking activities of isoindolinone- and isobenzofuranone-containing phenoxylalkylamines as potent α(1)-adrenoceptor antagonists.

This paper describes the synthesis and blocking activities of twelve new isoindolinone- and isobenzofuranone-containing phenoxylalkylamines as potent α(1)-Adrenoceptor antagonists. These compounds were synthesized in moderate to good yields starting from 3,4-dimethylphenol, and characterized with (1)H-NMR, MS, IR and elemental analysis. Their blocking activities toward α(1)-Adrenoceptors were evaluated on isolated rat anococcygeus muscles.

Synthesis and blocking activities of a new class of α₁-adrenoceptor antagonists.

Finding effective chemotherapeutic agents for clinical use is a long-lasting goal in medicinal chemistry. In this study, we report a new class of α₁-adrenoceptor (α₁-AR) antagonists. Specifically, we describe the synthesis and the blocking activities toward α₁-AR of 7-(2-hydroxypropoxy)-3,4-dihydroisoquinolin-1(2H)-one 1 and its structurally perturbed analogs 2-11 that were designed according to the principle of bioisosterism.

2-(5-Bromo-pent-yl)-4-chloro-5-[2-(4-meth-oxy-phen-yl)ethyl-amino]-pyridazin-3(2H)-one.

The asymmetric unit of the title compound, C(18)H(23)BrClN(3)O(2), consists of two mol-ecules which exhibit different conformations of the pentyl chains [C-C-C-C torsion angles of -60.4 (4) and 175.8 (3)°].

4-[2-(3,4-Dimethoxy-phenethyl-amino)prop-oxy]-2-methoxy-benzamide.

The title compound, C(21)H(28)N(2)O(5), has two intra-molecular N-H⋯O hydrogen bonds. Inter-molecular N-H⋯O hydrogen bonds [graph-set motif R(2) (2)(8)] give rise to a dimer. Weak N-H⋯N hydrogen bonds between neighboring dimers further extend the crystal structure, which exhibits an infinite chain motif.