Genetically Encoded Activators of Small Molecules for Imaging and Drug Delivery

Chemical biologists have developed many tools based on genetically encoded macromolecules and small, synthetic compounds. The two different approaches are extremely useful, but they have inherent limitations. In this Minireview, we highlight examples of strategies that combine both concepts to tackle challenging problems in chemical biology. We discuss applications in imaging, with a focus on super‐resolved techniques, and in probe and drug delivery. We propose future directions in this field, hoping to inspire chemical biologists to develop new combinations of synthetic and genetically encoded probes.     

On k-dimensional graphs and their bases

Periodica Mathematica Hungarica -     

Multistep Continuous Flow Synthesis of Isolable NH2-Sulfinamidines via Nucleophilic Addition to Transient Sulfurdiimide

The growing interest in novel sulfur pharmacophores led to recent advances in the synthesis of some S(IV) and S(VI) motifs. However, preparation and isolation of uncommon primary sulfinamidines, the aza-analogues of sulfinamides, is highly desirable. Here we report a multistep continuous flow synthesis of poorly explored NH₂-sulfinamidines by nucleophilic attack of organometallic reagents to in situ prepared N-(trimethylsilyl)-N-trityl-λ⁴-sulfanediimine (Tr−N=S=N−TMS). The transformation can additionally be realized under mild conditions, at room temperature, via a highly chemoselective halogen-lithium exchange of aryl bromides and iodides with n-butyllithium. Moreover, the synthetic potential of the methodology was assessed by exploring further manipulations of the products and accessing novel S(IV) analogues of celecoxib, tasisulam, and relevant sulfinimidoylureas.     

Continuous-Flow Divergent Lithiation of 2,3-Dihalopyridines: Deprotolithiation versus Halogen Dance

We describe herein the first halogen dance (HD) in continuous flow on 2-chloro-3-bromopyridine by selectively trapping a (pyridin-4-yl)lithium species that is known to undergo the halogen-dance process. In addition, this lithiated intermediate was trapped at lower temperature before the HD occurs. The HD process was extended to fluoro-iodopyridines by using various electrophiles to afford 28 examples with yields ranging from 42 to 97 % with very short residence times. Finally, scale up of the reaction was demonstrated, affording a promising space-time yield (STY) of 4.2 kg.h⁻¹.L⁻¹.     

Biomedical applications of X-ray absorption and vibrational spectroscopic microscopies in obtaining structural information from complex systems

Protein crystallography and NMR spectroscopy took decades to emerge as routine techniques in structural biology. X-ray absorption spectroscopy now has reached a similar stage of maturity for obtaining complementary local structural information around metals in metalloproteins. However, the relatively recent emergence of X-ray and vibrational spectroscopic microprobes that build on these techniques has enabled the structural information obtained from the “mature” techniques on isolated biomolecules to be translated into in situ structural information from inhomogeneous complex systems, such as whole cells and tissues.     

Stereocontrolled synthesis of (-)-kainic acid from trans-4-hydroxy-L-proline

[reaction: see text] A highly stereoselective synthesis of (-)-kainic acid has been achieved in 14 steps and >7% overall yield starting from inexpensive trans-4-hydroxy-L-proline. The key steps are diastereoselective enolate alkylation and cuprate substitution reactions.     

Synthesis and Evaluation as Glycosidase Inhibitors of Carbasugar‐Derived Spirodiaziridines,Spirodiazirines, and Spiroaziridines

The spirodiaziridines 6 and 9 , potential inhibitors of α‐ and β‐glucosidases, were prepared from the validoxylamine A‐derived cyclohexanone 5 . The trimethylsilyl protecting groups of 5 are crucial for the formation of 6 in good yields. Oxidation of 6 gave 7 . The diaziridine 6 (pK_HA=2.6) and the diazirine 7 did not inhibit the β‐glucosidases from almonds, the β‐glucosidase from Caldocellum saccharolyticum, and the α‐glucosidase from yeast. The N‐benzyl diaziridine 9 is a very weak inhibitor of the α‐glucosidase, but did not inhibit the β‐glucosidases. To see whether the weak inhibition is due to the low basicity of the diaziridines or to geometric factors, we prepared the spiro‐aziridines 21 and 25 and 1‐epivalidamine ( 32 ). The known cyclohexanone 10 was methylenated and epoxidised to 16 and 17 . Azide opening of 16 and 17 , mesylation, LiAlH₄ reduction, and deprotection gave the aziridines 21 and 25 respectively. 1‐Epivalidamine ( 32 ) was prepared from the known carba‐glucose 29 . The aziridine 25 (pK_HA=6.8) is a weak irreversible inhibitor of the β‐glucosidase from Caldocellum saccharolyticum and a weak reversible inhibitor of the α‐glucosidase from yeast, but did not inhibit the β‐glucosidases from almonds. The poorly stable aziridine 21 weakly inhibited the three enzymes. Similarly, 1‐epivalidamine (pK_HA=8.4) proved only a weak inhibitor. The known cyclopentylamine 34 (pK_HA=7.9), however, is a micromolar inhibitor of these enzymes. The much stronger inhibition by 34 is related to the pseudoaxial orientation of its amino group.