Quinazolines. VII. Synthesis of 1,3-Diamino-5,6-dihydrobenzo[f]quinazolines

Eighteen new 1,3-diamino-5,6-dihydrobenzo[f] quinazolines ( 6 , R. = alkyl, Cl, MeO) were synthesized via the condensation of appropriate 2-tetralones with cyanoguanidine under fusion conditions. Methods were developed for the preparation of a number of heretofore undescribed 2-tetralones as precursors. The final products can be viewed as conformationally rigid analogs of pyrimethamine ( 2 ), and are of interest as inhibitors of dihydrofolate reductase and as potential antimalarial and antitumor agents.     

Gold(I)-Catalyzed Intermolecular Hydroamination of Allenes with Arylamines

A mixture of (3)AuCl [3 = P(t-Bu)(2)o-biphenyl] and AgOTf catalyzes the intermolecular hydroamination of monosubstituted and 1,1- and 1,3-disubstituted allenes with primary and secondary arylamines.     

Cyclodextrin catalysis of the smiles rearrangement of 4-nitrophenyl salicylate

α- and β-Cyclodextrins accelerate the Smiles rearrangement of 4-nitrophenyl salicylate which proceeds through the mechanism of intramolecular aromatic nucleophilic substitution. The binding and catalytic rate constants were calculated from the dependences of the observed pseudo-first-order rate constants of the rearrangement reaction on cyclodextrin concentration obtained at various pH values. The catalysis was interpreted in terms of a tighter binding of the anionic, highly delocalized δ-complex intermediate than that of the substrate to cyclodextrins.     

Rapid synthesis of pomalidomide-conjugates for the development of protein degrader libraries

Current methods for the preparation of heterobifunctional pomalidomide-conjugates rely on methods that are often low yielding and produce intractable byproducts. Herein we describe our strategy for the reliable and succinct preparation of pomalidomide-linkers which is essential to the formation of these conjugates. We present the preparation of 18 pomalidomide-linkers in high yield compared to current literature methods. Our findings show that secondary amines consistently afford greater yields than their primary counterparts, a trend that we were able to exploit in the synthesis of several new pomalidomide homo-dimers in enhanced yields compared to similar literature syntheses. This trend was further utilised to develop the first one-pot synthesis of JQ1-pomalidomide conjugates in yields up to 62%, providing a method that is suited to rapid preparation of conjugate libraries as is frequently required for the development of new protein degraders.

Current methods for the preparation of heterobifunctional pomalidomide-conjugates rely on methods that are often low yielding and produce intractable byproducts. Herein we describe our strategy for the succinct preparation of pomalidomide-linkers.     

A data-driven,high-throughput methodology to determine tissue-specific differentially methylated regions able to discriminate body fluids

Tissue-specific differentially methylated regions (tDMRs) are regions of the genome with methylation patterns that modulate gene expression in those tissue types. The detection of tDMRs in forensic evidence can permit the identification of body fluids at trace levels. In this report, we have performed a bioinformatic analysis of an existing array dataset to determine if new tDMRs could be identified for use in body fluid identification from forensic evidence. Once these sites were identified, primers were designed and bisulfite modification was performed. The relative methylation level for each body fluid at a given locus was then determined using qPCR with high-resolution melt analysis (HRM). After screening 127 tDMR's in multiple body fluids, we were able to identify four new markers able to discriminate blood (2 markers), vaginal epithelia (1 marker) and buccal cells (1 marker). One marker for each target body fluid was also tested with pyrosequencing showing results consistent with those obtained by HRM. This work successfully demonstrates the ability of in silico analysis to develop a novel set of tDMRs capable of being differentiated by real time PCR/HRM. The method can rapidly determine the body fluids left at crime scenes, assisting the triers of fact in forensic casework.     

The Effect of Auxiliary Nitrogenated Linkers on the Design of New Cadmium-Based Coordination Polymers as Sensors for the Detection of Explosive Materials

Three new cadmium-based coordination polymers, denoted [Cd(hfipbb)(4,4’-bipy)] ( CdPF-1 ), [Cd(hfipbb)(2,2’-bipy)] ( CdPF-2 ), and [Cd(hfipbb)(1,10-phen)] ( CdPF-3 ), have been hydrothermally synthesized by using the well-known V-shaped organic linker 4,4’-(hexafluoroisopropylidene)bis(benzoic acid) (H₂hfipbb), together with different nitrogenated auxiliary linkers. Considering the d¹⁰ configuration of the transition metal selected, the luminescent properties for these CdPF-n materials were explored, finding that materials CdPF-2 and CdPF-3 act as excellent sensors in the detection of explosive nitro aromatic compounds. The photoluminescence properties of CdPF-2 and CdPF-3 revealed that significant and sensitive fluorescence quenching was observed toward NP (nitrophenol) for CdPF-2 and PA (picric acid) for CdPF-3 in MeOH suspensions.     

Inherent Ethyl Acetate Selectivity in a Trianglimine Molecular Solid

Ethyl acetate is an important chemical raw material and solvent. It is also a key volatile organic compound in the brewing industry and a marker for lung cancer. Materials that are highly selective toward ethyl acetate are needed for its separation and detection. Here, we report a trianglimine macrocycle ( TAMC ) that selectively adsorbs ethyl acetate by forming a solvate. Crystal structure prediction showed this to be the lowest energy solvate structure available. This solvate leaves a metastable, “templated” cavity after solvent removal. Adsorption and breakthrough experiments confirmed that TAMC has adequate adsorption kinetics to separate ethyl acetate from azeotropic mixtures with ethanol, which is a challenging and energy-intensive industrial separation.     

Stimuli-responsive temporary adhesives: enabling debonding on demand through strategic molecular design

Stimuli-responsive temporary adhesives constitute a rapidly developing class of materials defined by the modulation of adhesion upon exposure to an external stimulus or stimuli. Engineering these materials to shift between two characteristic properties, strong adhesion and facile debonding, can be achieved through design strategies that target molecular functionalities. This perspective reviews the recent design and development of these materials, with a focus on the different stimuli that may initiate debonding. These stimuli include UV light, thermal energy, chemical triggers, and other potential triggers, such as mechanical force, sublimation, electromagnetism. The conclusion discusses the fundamental value of systematic investigations of the structure–property relationships within these materials and opportunities for unlocking novel functionalities in future versions of adhesives.

Stimuli-responsive temporary adhesives emerge as next-generation multifunctional materials with advantages that include strong temporary adhesion, debonding on demand, and tunable reactivity.     

Human Group IIA Phospholipase A2—Three Decades on from Its Discovery

Phospholipase A₂ (PLA₂) enzymes were first recognized as an enzyme activity class in 1961. The secreted (sPLA₂) enzymes were the first of the five major classes of human PLA₂s to be identified and now number nine catalytically-active structurally homologous proteins. The best-studied of these, group IIA sPLA₂, has a clear role in the physiological response to infection and minor injury and acts as an amplifier of pathological inflammation. The enzyme has been a target for anti-inflammatory drug development in multiple disorders where chronic inflammation is a driver of pathology since its cloning in 1989. Despite intensive effort, no clinically approved medicines targeting the enzyme activity have yet been developed. This review catalogues the major discoveries in the human group IIA sPLA₂ field, focusing on features of enzyme function that may explain this lack of success and discusses future research that may assist in realizing the potential benefit of targeting this enzyme. Functionally-selective inhibitors together with isoform-selective inhibitors are necessary to limit the apparent toxicity of previous drugs. There is also a need to define the relevance of the catalytic function of hGIIA to human inflammatory pathology relative to its recently-discovered catalysis-independent function.