Structure-Permeability Relationship of Semipeptidic Macrocycles-Understanding and Optimizing Passive Permeability and Efflux Ratio.

We herein report the first thorough analysis of the structure-permeability relationship of semipeptidic macrocycles. In total, 47 macrocycles were synthesized using a hybrid solid-phase/solution strategy, and then their passive and cellular permeability was assessed using the parallel artificial membrane permeability assay (PAMPA) and Caco-2 assay, respectively. The results indicate that semipeptidic macrocycles generally possess high passive permeability based on the PAMPA, yet their cellular permeability is governed by efflux, as reported in the Caco-2 assay. Structural variations led to tractable structure-permeability and structure-efflux relationships, wherein the linker length, stereoinversion, N-methylation, and peptoids site-specifically impact the permeability and efflux. Extensive nuclear magnetic resonance, molecular dynamics, and ensemble-based three-dimensional polar surface area (3D-PSA) studies showed that ensemble-based 3D-PSA is a good predictor of passive permeability.

Purine analogs targeting the guanine riboswitch as potential antibiotics against Clostridioides difficile.

Riboswitches recently emerged as possible targets for the development of alternative antimicrobial approaches. Guanine-sensing riboswitches in the bacterial pathogen Clostridioides difficile (formerly known as Clostridium difficile) constitute potential targets based on their involvement in the regulation of basal metabolic control of purine compounds. In this study, we deciphered the structure-activity relationship of several guanine derivatives on the guanine riboswitch and determined their antimicrobial activity. We describe the synthesis of purine analogs modified in ring B as well as positions 2 and 6. Their biological activity was determined by measuring their affinity for the C. difficile guanine riboswitch and their inhibitory effect on bacterial growth, including a counter-screen to discriminate against riboswitch-independent antibacterial effects. Altogether, our results suggest that improvements in riboswitch binding affinity in vitro do not necessarily translate into improved antibacterial activity in bacteria, despite the fact that some structure-activity relationship was observed at least with respect to binding affinity.

Design and synthesis of new antioxidants predicted by the model developed on a set of pulvinic acid derivatives.

Antioxidative activity expressed as protection of thymidine has been investigated for a set of 30 pulvinic acid derivatives. A combination of in vitro testing and in silico modeling was used for synthesis of new potential antioxidants. Experimental data obtained from a primary screening test based on oxidation under Fenton conditions and by an UV exposure followed by back-titration of the amount of thymidine remaining intact have been used to develop a computer model for prediction of antioxidant activity. Structural descriptors of 30 compounds tested for their thymidine protection activity were calculated in order to define the structure-property relationship and to construct predictive models. Due to the potential nonlinearity, the counter-propagation artificial neural networks were assessed for modeling of the antioxidant activity of these compounds. The optimized model was challenged with 80 new molecules not present in the initial training set. The compounds with the highest predicted antioxidant activity were considered for synthesis. Among the predicted structures, some coumarine derivatives appeared to be especially interesting. One of them was synthesized and tested on in vitro assays and showed some antioxidant and radioprotective activities, which turned out as a promising lead toward more potent antioxidants.

Synthesis and radioprotective properties of pulvinic acid derivatives.

A high-throughput screening method has highlighted the marked antioxidant activity of some pulvinic acid derivatives (PADs) towards oxidation of thymidine, under γ and UV irradiation, and Fenton-like conditions. Here, we report the synthesis of a series of new hydrophilic PADs and the evaluation of their radioprotective efficacy in cell culture. Using a cell-based fluorescent assay, we show that some of these compounds have a pronounced ability to prevent cell death caused by radiation and to allow the subsequent resumption of proliferation. Thus, PADs may be considered as a novel class of radioprotective agents.

Synthesis and antioxidant properties of pulvinic acids analogues.

The synthesis of three types of pulvinic acid analogues, using a diversity-oriented strategy starting from a single compound, dimethyl l-tartrate, is described. Lacey-Dieckmann condensation, alcohol dehydration and Suzuki-Miyaura cross-couplings were employed in the course of the analogues syntheses. The evaluation of the antioxidant properties of the 28 synthesized analogues was carried out using antioxidant capacity assays (protection of thymidine and ß-carotene) and free radical scavenging assays (DPPH radical and ABTS radical cation). This allowed to assess the relative influence of the groups bonded to the tetronic ring and to the exocyclic double bond on the activity, as well as the importance of this exocyclic double bond. It was shown that the presence of an electron-donating group on the 3-position of the tetronic ring had a beneficial effect. It was shown in several assays that the presence of the exocyclic bond was not crucial to the activity.

Radiation countermeasure agents: an update.

IMPORTANCE OF THE FIELD: Ionizing radiation (IR) can produce deleterious effects in living tissues, leading to significant morbidity and a potentially fatal illness affecting various organs dose-dependently. As people may be exposed to IR during cancer radiotherapy or as a result of a radiological/nuclear incident or act of terrorism, the danger of irradiation represents a serious public health problem. At present, however, this problem remains largely impervious to medical management. There is, therefore, a pressing need to develop safe and effective radiation countermeasure (RC) agents to prevent, mitigate or treat the harmful consequences of IR exposure. AREAS COVERED IN THIS REVIEW: Recent advances in the search for RC agents as reflected by the relevant patent literature of the past five years along with peer-reviewed publications are surveyed. WHAT THE READER WILL GAIN: A total of 43 patents, describing approximately 38 chemically diverse compounds with RC potential are analyzed. These include antioxidants capable of scavenging IR-induced free radicals, modulators of cell death signaling or cell cycle progression, cytokines or growth factors promoting tissue repair and inhibitors of inflammatory cytokines. TAKE HOME MESSAGE: Several of these RC candidates appear promising, including at least two that are undergoing evaluation for fast-track clinical development.

Synthesis of pulvinic derivatives via TBAF-mediated regioselective opening of an unsymmetrical monoaromatic pulvinic dilactone.

The synthesis of the monoaromatic pulvinic dilactone 1 from a tetronic acid derivative is reported. The reaction of 1 with various amines was found to provide the two pulvinamides regioisomers 2a and 2b. Using tetrabutylammonium fluoride (TBAF) as an activator, pulvinamides 2a could be obtained with excellent regioselectivities and good yields. Additions of alcohols to 1 are also studied, leading to similar observations.