Prodrugs that release hydrogen sulfide upon esterase-mediated cleavage of an ester group followed by lactonization are described herein. By modifying the ester group and thus its susceptibility to esterase, and structural features critical to the lactonization rate, H₂S release rates can be tuned. Such prodrugs directly release hydrogen sulfide without the involvement of perthiol species, which are commonly encountered with existing H₂S donors. Additionally, such prodrugs can easily be conjugated to another non-steroidal anti-inflammatory agent, leading to easy synthesis of hybrid prodrugs. As a biological validation of the H₂S prodrugs, the anti-inflammatory effects of one such prodrug were examined by studying its ability to inhibit LPS-induced TNF-α production in RAW 264.7 cells. This type of H₂S prodrugs shows great potential as both research tools and therapeutic agents.

Prodrugs that release hydrogen sulfide upon esterase-mediated cleavage of an ester group followed by lactonization are described herein. By modifying the ester group and thus its susceptibility to esterase, and structural features critical to the lactonization rate, H₂S release rates can be tuned. Such prodrugs directly release hydrogen sulfide without the involvement of perthiol species, which are commonly encountered with existing H₂S donors. Additionally, such prodrugs can easily be conjugated to another non-steroidal anti-inflammatory agent, leading to easy synthesis of hybrid prodrugs. As a biological validation of the H₂S prodrugs, the anti-inflammatory effects of one such prodrug were examined by studying its ability to inhibit LPS-induced TNF-α production in RAW 264.7 cells. This type of H₂S prodrugs shows great potential as both research tools and therapeutic agents.

Boronic acids are important in the organic and biological arenas. Thus, their identification and characterization are important. ESI-MS is a well-known tool for such uses. Herein we report a systematic analysis of the chemical behavior of arylboronic acids under ESI-MS conditions. Such information will be very critical to understanding the gas-phase chemistry of boronic acids in an ESI mass spectrometer ion source in general and the MS analysis of boronic acids and their macromolecular conjugates in particular.

Post-synthesis modification of DNA is an important way of functionalizing DNA molecules. Herein, we describe a method that first enzymatically incorporates a cyanobenzothiazole (CBT)-modified thymidine. The side-chain handle CBT can undergo a rapid and site-specific cyclization reaction with 1,2-aminothiols to afford DNA functionalization in aqueous solution. Another key advantage of this method is the formation of a single stereo/regioisomer in the process, which allows for precise control of DNA modification to yield a single component for aptamer selection work and other applications.

SecA, a key component of bacterial Sec-dependent secretion pathway, is an attractive target for exploring novel antimicrobials. Rose bengal (RB), a polyhalogenated fluorescein derivative, was found from our previous study as a potent SecA inhibitor. Here we describe the synthesis and structure–activity relationships (SAR) of 23 RB analogues that were designed by systematical dissection of RB. Evaluation of these analogues allowed us to establish an initial SAR in SecA inhibition. The antimicrobial effects of these SecA inhibitors are confirmed in experiments using E. coli and B. subtilis.

SecA is a central component of the general secretion system that is essential for bacterial growth and thus an ideal target for antimicrobial agents. A series of fluorescein analogues were first screened against the ATPase activity using the truncated unregulated SecA catalytic domain. Rose bengal (RB) and erythrosin B (EB) were found to be potent inhibitors SecA with IC₅₀ values of 0.5 μM and 2 μM, respectively. RB and EB inhibit the catalytic SecA ATPase more effectively than the F₁F₀-proton ATPase. We used three assays to test the effect of these compounds on full-length SecA ATPase: in solution (intrinsic ATPase), in membrane preparation, and translocation ATPase. RB and EB show the following trend in terms of IC₅₀ values: translocation ATPase<membrane ATPase<intrinsic ATPase. Very importantly, the potency of these fluorescein analogues in inhibiting the truncated SecA ATPase correlates with their ability to inhibit the biologically relevant protein translocation activity of SecA. The in vitro translocation of proOmpA precursors into membrane vesicles is strongly inhibited by RB with IC₅₀ values of approximately 0.25 μM, making RB the most potent inhibitor of SecA ATPase and SecA-dependent protein translocation reported thus far. The ability of these compounds to inhibit SecA also directly translates into antibacterial effects. Our findings show the value of fluorescein analogues as probes for mechanistic studies of SecA functions and for the potential development of new antimicrobial agents with SecA as the target.

Two series of rhein analogues were synthesized with modification at the 3-position. Their cytotoxicities were evaluated using an MTT assay. Among all the compounds synthesized, one compound showed the best potency, with an IC₅₀ value of 2.7 μM against the HeLa cell line and 0.6 μM against the MOLT4 cell line.

DNA molecules are known to be important materials in sensing, aptamer selection, nanocomputing, and construction of unique architectures. The incorporation of modified nucleobases affords unique DNA properties for applications in areas that would otherwise be difficult or not possible. Earlier, we demonstrated that the boronic acid moiety can be introduced into DNA through polymerase-catalyzed reactions. In order to study whether such incorporation by polymerase is a general phenomenon, we designed and synthesized four boronic acid-modified thymidine triphosphate (TTP) analogues. The synthesis of certain analogues was through the use of a single dialkyne tether for both the Sonogashira coupling with thymidine and the later Cu-mediated [3+2] cycloaddition for linking the boronic acid moiety. This approach is much more efficient than the previously described method, and paves the way for the preparation of a large number of boronic acid-modified TTPs with a diverse set of structural features. All analogues showed very good stability under polymerase chain reaction (PCR) conditions and were recognized as a substrate by DNA polymerase, and thus incorporated into DNA.

The boronic acid group is an important recognition moiety for sensor design. Herein, we report a series of isoquinolinylboronic acids that have extraordinarily high affinities for diol-containing compounds at physiological pH. In addition, 5- and 8-isoquinolinylboronic acids also showed fairly high binding affinities towards D-glucose (K_a=42 and 46 M⁻¹, respectively). For the first time, weak but encouraging binding of cis-cyclohexanediol was found for these boronic acids. Such binding was coupled with significant fluorescence changes. Furthermore, 4- and 6-isoquinolinylboronic acids also showed the ability to complex methyl α-D-glucopyranose (K_a=3 and 2 M⁻¹, respectively).

Bacterial quorum sensing refers to the ability of bacteria to control gene expression through the detection of a threshold concentration of certain chemicals called autoinducer(s), which are secreted by self and/or other bacteria. Quorum sensing is implicated in the regulation of pathologically relevant events such as biofilm formation, virulence, conjugation, sporulation, and swarming mobility. Inhibitors of bacterial quorum sensing are valuable research tools and potential antimicrobial agents. In this paper, we describe the discovery of several boronic acid inhibitors of bacterial quorum sensing in Vibrio harveyi with IC₅₀ values in the low to sub-micromolar range in whole cell assays.

Bacterial quorum sensing has received much attention in recent years because of its relevance to pathological events such as biofilm formation. Based on the structures of two lead inhibitors (IC₅₀: 35–55 μM) against autoinducer-2-mediated quorum sensing identified through virtual screening, we synthesized 39 analogues and examined their inhibitory activities. Twelve of these new analogues showed equal or better inhibitory activities than the lead inhibitors. The best compound showed an IC₅₀ value of ∼6 μM in a whole-cell assay using Vibrio harveyi as the model organism. The structure–activity relationship is discussed herein.

Quorum sensing has been implicated in the control of pathologically relevant bacterial behavior such as secretion of virulence factors, biofilm formation, sporulation, and swarming motility. The AI-2 quorum sensing pathway is found in both Gram-positive and Gram-negative bacteria. Therefore, antagonizing AI-2 quorum sensing is a possible approach to modifying bacterial behaviour. However, efforts in developing inhibitors of AI-2-mediated quorum sensing are especially lacking. High-throughput virtual screening using the V. harveyi LuxP crystal structure identified two compounds that were found to antagonize AI-2-mediated quorum sensing in V. harveyi without cytotoxicity. The sulfone functionality of these inhibitors was identified as critical to their ability to mimic the natural ligand in their interactions with Arg 215 and Arg 310 of the active site.

Boronic acids that change fluorescence properties upon sugar binding are very useful for the synthesis of carbohydrate sensors. Along this line, boronic acids that fluoresce beyond 500 nm are especially useful. A series of boronic acid fluorescent reporter compounds based on the 4-amino-1,8-naphthalimide structure have been synthesized (1 a–d) and evaluated under near physiological conditions. These compounds showed good water solubility and significant changes in fluorescence properties after binding with sugars, with the emission wavelength being at around 570 nm. Analogues in this series with different substitutions showed similar properties. We have also examined the mechanism of the observed fluorescence changes for these compounds.

Dopamine is an important neurotransmitter that plays important roles in various physiological and pathological processes, such as Parkinson's disease. Chemosensors for dopamine have a number of potential applications. On the basis both of the strong and reversible complexation between the boronic acid moiety and a diol functional group and computational chemistry studies, we have designed a series of four compounds for selective three-point recognition of dopamine, which include boronic acid–diol complexation, aromatic–hydrophobic interactions, and ionic interactions between a carboxylate and a protonated amino group. These compounds were synthesized in seven or eight linear steps and showed dopamine selectivity of up to tenfold over epinephrine. NMR spectroscopy experiments were conducted to probe the structures of the receptor–dopamine complexes. These receptors are the first to show such significant selectivity for dopamine over epinephrine in aqueous solution under near physiological conditions.