New Halogen-Containing Drugs Approved by FDA in 2021: An Overview on Their Syntheses and Pharmaceutical Use

Tiz, Davide Benedetto; Bagnoli, Luana; Rosati, Ornelio; Marini, Francesca; Sancineto, Luca; Santi, Claudio

doi:10.3390/molecules27051643

Cited by 87 publications

(56 citation statements)

References 63 publications

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“…This indicates that to study low enrichments and/or for early time points experiments, iodine (Figure D) or bromine should be the first choice as labels. Fluorine is another interesting halogen label that might be used especially since an increasing number of new therapeutics already natively contain one or more fluorine atoms as it plays a role in biological activity and/or chemical synthesis, including oligonucleotide therapeutics like siRNA , …”

Section: Resultsmentioning

confidence: 99%

“…This indicates that to study low enrichments and/or for early time points experiments, iodine (Figure 1D) or bromine 7 should be the first choice as labels. Fluorine is another interesting halogen label that might be used especially since an increasing number of new therapeutics already natively contain one or more fluorine atoms as it plays a role in biological activity and/or chemical synthesis, 43 including oligonucleotide therapeutics like siRNA 44,45 Prior to NanoSIMS analysis, the cell sections were imaged by SEM. Similarly to naked ASOs, the SEM micrographs (Figure S5) reveal that 34 S 15 -ASO enrichments overlap with electron dense structures identified as lysosomes, correlating with previous studies.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

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Intracellular Absolute Quantification of Oligonucleotide Therapeutics by NanoSIMS

Becquart

Stulz

Thomen³

et al. 2022

Anal. Chem.

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Antisense oligonucleotide (ASO)-based therapeutics hold great potential for the treatment of a variety of diseases. Therefore, a better understanding of cellular delivery, uptake, and trafficking mechanisms of ASOs is highly important for early-stage drug discovery. In particular, understanding the biodistribution and quantifying the abundance of ASOs at the subcellular level are needed to fully characterize their activity. Here, we used a combination of electron microscopy and NanoSIMS to assess the subcellular concentrations of a 34 S-labeled GalNAc-ASO and a naked ASO in the organelles of primary human hepatocytes. We first cross-validated the method by including a 127 I-labeled ASO, finding that the absolute concentration of the lysosomal ASO using two independent labeling strategies gave matching results, demonstrating the strength of our approach. This work also describes the preparation of external standards for absolute quantification by NanoSIMS. For both the 34 S and 127 I approaches used for our quantification methodology, we established the limit of detection (5 and 2 μM, respectively) and the lower limit of quantification (14 and 5 μM, respectively).

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Section: Resultsmentioning

confidence: 99%

Section: ■ Results and Discussionmentioning

confidence: 99%

Intracellular Absolute Quantification of Oligonucleotide Therapeutics by NanoSIMS

Becquart

Stulz

Thomen³

et al. 2022

Anal. Chem.

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“…They are characterized by a 4-nitrophenyl substituent instead of the hydroxyl group of RSV and, in the case of compound 6, by a chlorine in 3 -position (Figure 1). In the literature, it is reported that the increase in lipophilicity due to the introduction of a halogen atom to one or more specific positions of a biologically active molecule leads to a higher partitioning of the halogenated compound into the lipophilic portion of a cell membrane or lipophilic domains of a target [50,51]. Moreover, the electronic property of the nitro group could affect biological activity [38].…”

Section: Discussionmentioning

confidence: 99%

Nitrostilbenes: Synthesis and Biological Evaluation as Potential Anti-Influenza Virus Agents

et al. 2022

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Resveratrol (RSV) is a natural stilbene polyphenolic compound found in several plant species. It is characterized by antioxidant properties, and its role in controlling viral replication has been demonstrated for different viral infections. Despite its promising antiviral properties, RSV biological activity is limited by its low bioavailability and high metabolic rate. In this study, we optimized its structure by synthesizing new RSV derivatives that maintained the phenolic scaffold and contained different substitution patterns and evaluated their potential anti-influenza virus activity. The results showed that viral protein synthesis decreased 24 h post infection; particularly, the nitro-containing compounds strongly reduced viral replication. The molecules did not exert their antioxidant properties during infection; in fact, they were not able to rescue the virus-induced drop in GSH content or improve the antioxidant response mediated by the Nrf2 transcription factor and G6PD enzyme. Similar to what has already been reported for RSV, they interfered with the nuclear-cytoplasmic traffic of viral nucleoprotein, probably inhibiting cellular kinases involved in the regulation of specific steps of the virus life cycle. Overall, the data indicate that more lipophilic RSV derivatives have improved antiviral efficacy compared with RSV and open the way for new cell-targeted antiviral strategies.

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“…Furthermore, Hays et al showed shorter Br-O contacts at the Holliday junction [32], which kindle our curiosity to substitute halogens in these inhibitors to tune their inhibition activity. Several halogen-based drugs have been approved to treat human diseases over the years [33][34][35]. In spite of several experimental and computational approaches, a detailed systematic computational investigation is clearly lacking, and explaining the binding modes, binding affinity and their respective interactions between the estrogenrelated receptor protein and inhibitor will be highly beneficial to understand the biological phenomenon better [36].…”

Section: Introductionmentioning

confidence: 99%

Halogen-Based 17β-HSD1 Inhibitors: Insights from DFT, Docking, and Molecular Dynamics Simulation Studies

Kulandaisamy

Panneerselvam²,

Solomon³

et al. 2022

Molecules

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The high expression of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) mRNA has been found in breast cancer tissues and endometriosis. The current research focuses on preparing a range of organic molecules as 17β-HSD1 inhibitors. Among them, the derivatives of hydroxyphenyl naphthol steroidomimetics are reported as one of the potential groups of inhibitors for treating estrogen-dependent disorders. Looking at the recent trends in drug design, many halogen-based drugs have been approved by the FDA in the last few years. Here, we propose sixteen potential hydroxyphenyl naphthol steroidomimetics-based inhibitors through halogen substitution. Our Frontier Molecular Orbitals (FMO) analysis reveals that the halogen atom significantly lowers the Lowest Unoccupied Molecular Orbital (LUMO) level, and iodine shows an excellent capability to reduce the LUMO in particular. Tri-halogen substitution shows more chemical reactivity via a reduced HOMO–LUMO gap. Furthermore, the computed DFT descriptors highlight the structure–property relationship towards their binding ability to the 17β-HSD1 protein. We analyze the nature of different noncovalent interactions between these molecules and the 17β-HSD1 using molecular docking analysis. The halogen-derived molecules showed binding energy ranging from −10.26 to −11.94 kcal/mol. Furthermore, the molecular dynamics (MD) simulations show that the newly proposed compounds provide good stability with 17β-HSD1. The information obtained from this investigation will advance our knowledge of the 17β-HSD1 inhibitors and offer clues to developing new 17β-HSD1 inhibitors for future applications.

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New Halogen-Containing Drugs Approved by FDA in 2021: An Overview on Their Syntheses and Pharmaceutical Use

Cited by 87 publications

References 63 publications

Intracellular Absolute Quantification of Oligonucleotide Therapeutics by NanoSIMS

Intracellular Absolute Quantification of Oligonucleotide Therapeutics by NanoSIMS

Nitrostilbenes: Synthesis and Biological Evaluation as Potential Anti-Influenza Virus Agents

Halogen-Based 17β-HSD1 Inhibitors: Insights from DFT, Docking, and Molecular Dynamics Simulation Studies

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