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Novel Strategies in the Development of New Therapies, Drug Substances and Drug Carriers 2.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (15 December 2022) | Viewed by 49445

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Special Issue Editors


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Guest Editor
Department of Bioanalysis and Drug Analysis, Pharmacy Department, Medical University of Warsaw, 02-097 Warsaw, 1 Banacha, Poland
Interests: medicinal chemistry; structure-activity relationship; synthetic strategies of pharmaceutical substances; design and synthesis of vitamin A and D anticancer analogs; structure analysis of nuclear receptor ligands
Special Issues, Collections and Topics in MDPI journals

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Guest Editor
School of Biomedical Sciences, Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
Interests: the use of synthetic retinoids and vitamins D as drug substances; cancer and normal stem cells; anticancer therapies; blood cell development; abnormalities in cancer stem cells
Special Issues, Collections and Topics in MDPI journals

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Guest Editor
Department of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology & Immunology, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria
Interests: to understand and unveil biochemical and molecular mechanisms of the anti-tumourigenic effects of vitamin D and dietary calcium for colon cancer prevention; to examine the role of the calcium sensing receptor (CaSR) and of its natural and pharmacologic modulators in colon carcinogenesis and inflammation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Currently, the need for the rapid development of effective and safe therapies for widespread diseases is stronger than ever. In developing new therapies, areas of current interest are the efficacy of drug development-related strategies, entirely new therapeutic molecules, new drug delivery systems, and personalized and digital medicine. There is also a need to integrate the various scientific disciplines and industrial activities that focus on these different aspects of drug research.

Volume 1.0 of the Special Issue “Novel Strategies in the Development of New Therapies, Drug Substances and Drug Carriers” (https://www.mdpi.com/journal/ijms/special_issues/ACCORD2021)has been highly successful, publishing 21 papers. We therefore aim to reopen this topic as volume 2.0 in the International Journal of Molecular Sciences (https://www.mdpi.com/journal/ijms, ISSN 1422-0067, IF 5.924, JCR Category Q1). This second Special Issue aims to promote synergy between research and activities in fields that contribute to conceiving and developing a new drug. This Special Issue is not limited to any specific aspect of drug development. On the contrary, it aims to cover the entire process at the molecular level to conform with the aims and scope of the journal. Topics include the identification of the molecular target of new drugs, studies of drug–protein interactions, studies of the modeling and optimization of functional activity, pre-formulation studies, new pharmaceutical carrier development, and preclinical development to clinical trials.

We would also like to draw your attention to the Interdisciplinary Conference on Drug Sciences, ACCORD 2022 (https://accord.wum.edu.pl/). All the participants of the ACCORD 2022  Conference will have the opportunity to publish a conference paper in this Special Issue. Manuscripts will go through the regular peer-review process of the journal.

All interested researchers are invited to submit review articles or original papers related to the topic of this Special Issue, guided by the “Aims and Scope”, “Instructions for Authors”, and the below keywords.

Prof. Dr. Andrzej Kutner
Dr. Geoffrey Brown
Dr. Enikö Kallay
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • drug design and discovery, drug lead, drug-protein interactions, drug response, drug solubility
  • antimicrobial drugs, antiviral drugs, antibiotics, anticancer drugs, cancer prevention
  • molecular modeling, molecular mechanisms, spectroscopic imaging, crystallography, anti-crystal engineering
  • preclinical study, pharmacokinetics, pharmacodynamics, pharmacognosy
  • nuclear receptors, receptor agonist and antagonist, stem cells, activity profiling, viral proteases, vaccines, markers, and diagnostics
  • drug carriers, dosage form, nanoparticles, 3D printing, dissolution testing

Published Papers (25 papers)

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Editorial

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8 pages, 233 KiB  
Editorial
Novel Strategies in the Development of New Therapies, Drug Substances, and Drug Carriers Volume II
by Andrzej Kutner, Geoffrey Brown and Enikö Kallay
Int. J. Mol. Sci. 2023, 24(6), 5621; https://doi.org/10.3390/ijms24065621 - 15 Mar 2023
Viewed by 1001
Abstract
The highly successful previous Volume 1 [...] Full article

Research

Jump to: Editorial, Review

15 pages, 7768 KiB  
Article
Understanding Passive Membrane Permeation of Peptides: Physical Models and Sampling Methods Compared
by Liuba Mazzanti and Tâp Ha-Duong
Int. J. Mol. Sci. 2023, 24(5), 5021; https://doi.org/10.3390/ijms24055021 - 06 Mar 2023
Cited by 1 | Viewed by 1418
Abstract
The early characterization of drug membrane permeability is an important step in pharmaceutical developments to limit possible late failures in preclinical studies. This is particularly crucial for therapeutic peptides whose size generally prevents them from passively entering cells. However, a sequence-structure-dynamics-permeability relationship for [...] Read more.
The early characterization of drug membrane permeability is an important step in pharmaceutical developments to limit possible late failures in preclinical studies. This is particularly crucial for therapeutic peptides whose size generally prevents them from passively entering cells. However, a sequence-structure-dynamics-permeability relationship for peptides still needs further insight to help efficient therapeutic peptide design. In this perspective, we conducted here a computational study for estimating the permeability coefficient of a benchmark peptide by considering and comparing two different physical models: on the one hand, the inhomogeneous solubility–diffusion model, which requires umbrella–sampling simulations, and on the other hand, a chemical kinetics model which necessitates multiple unconstrained simulations. Notably, we assessed the accuracy of the two approaches in relation to their computational cost. Full article
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11 pages, 2361 KiB  
Article
Identifying Drug Candidates for COVID-19 with Large-Scale Drug Screening
by Yifei Wu, Scott D. Pegan, David Crich, Lei Lou, Lauren Nicole Mullininx, Edward B. Starling, Carson Booth, Andrew Edward Chishom, Kuan Y. Chang and Zhong-Ru Xie
Int. J. Mol. Sci. 2023, 24(5), 4397; https://doi.org/10.3390/ijms24054397 - 23 Feb 2023
Cited by 1 | Viewed by 1469
Abstract
Papain-like protease (PLpro) is critical to COVID-19 infection. Therefore, it is a significant target protein for drug development. We virtually screened a 26,193 compound library against the PLpro of SARS-CoV-2 and identified several drug candidates with convincing binding affinities. The [...] Read more.
Papain-like protease (PLpro) is critical to COVID-19 infection. Therefore, it is a significant target protein for drug development. We virtually screened a 26,193 compound library against the PLpro of SARS-CoV-2 and identified several drug candidates with convincing binding affinities. The three best compounds all had better estimated binding energy than those of the drug candidates proposed in previous studies. By analyzing the docking results for the drug candidates identified in this and previous studies, we demonstrate that the critical interactions between the compounds and PLpro proposed by the computational approaches are consistent with those proposed by the biological experiments. In addition, the predicted binding energies of the compounds in the dataset showed a similar trend as their IC50 values. The predicted ADME and drug-likeness properties also suggested that these identified compounds can be used for COVID-19 treatment. Full article
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29 pages, 4857 KiB  
Article
In Vitro/In Vivo Translation of Synergistic Combination of MDM2 and MEK Inhibitors in Melanoma Using PBPK/PD Modelling: Part III
by Jakub Witkowski, Sebastian Polak, Dariusz Pawelec and Zbigniew Rogulski
Int. J. Mol. Sci. 2023, 24(3), 2239; https://doi.org/10.3390/ijms24032239 - 23 Jan 2023
Cited by 1 | Viewed by 1654
Abstract
The development of in vitro/in vivo translational methods and a clinical trial framework for synergistically acting drug combinations are needed to identify optimal therapeutic conditions with the most effective therapeutic strategies. We performed physiologically based pharmacokinetic–pharmacodynamic (PBPK/PD) modelling and virtual clinical trial simulations [...] Read more.
The development of in vitro/in vivo translational methods and a clinical trial framework for synergistically acting drug combinations are needed to identify optimal therapeutic conditions with the most effective therapeutic strategies. We performed physiologically based pharmacokinetic–pharmacodynamic (PBPK/PD) modelling and virtual clinical trial simulations for siremadlin, trametinib, and their combination in a virtual representation of melanoma patients. In this study, we built PBPK/PD models based on data from in vitro absorption, distribution, metabolism, and excretion (ADME), and in vivo animals’ pharmacokinetic–pharmacodynamic (PK/PD) and clinical data determined from the literature or estimated by the Simcyp simulator (version V21). The developed PBPK/PD models account for interactions between siremadlin and trametinib at the PK and PD levels. Interaction at the PK level was predicted at the absorption level based on findings from animal studies, whereas PD interaction was based on the in vitro cytotoxicity results. This approach, combined with virtual clinical trials, allowed for the estimation of PK/PD profiles, as well as melanoma patient characteristics in which this therapy may be noninferior to the dabrafenib and trametinib drug combination. PBPK/PD modelling, combined with virtual clinical trial simulation, can be a powerful tool that allows for proper estimation of the clinical effect of the above-mentioned anticancer drug combination based on the results of in vitro studies. This approach based on in vitro/in vivo extrapolation may help in the design of potential clinical trials using siremadlin and trametinib and provide a rationale for their use in patients with melanoma. Full article
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22 pages, 8717 KiB  
Article
An Isochroman Analog of CD3254 and Allyl-, Isochroman-Analogs of NEt-TMN Prove to Be More Potent Retinoid-X-Receptor (RXR) Selective Agonists Than Bexarotene
by Peter W. Jurutka, Orsola di Martino, Sabeeha Reshi, Sanchita Mallick, Michael A. Sausedo, Grant A. Moen, Isaac J. Lee, Dominic J. Ivan, Tyler D. Krall, Samuel J. Peoples, Anthony Perez, Lucas Tromba, Anh Le, Iraj Khadka, Ryan Petros, Brianna M. Savage, Eleine Salama, Jakline Salama, Joseph W. Ziller, Youngbin Noh, Ming-Yue Lee, Wei Liu, John S. Welch, Pamela A. Marshall and Carl E. Wagneradd Show full author list remove Hide full author list
Int. J. Mol. Sci. 2022, 23(24), 16213; https://doi.org/10.3390/ijms232416213 - 19 Dec 2022
Cited by 2 | Viewed by 1984
Abstract
Bexarotene is an FDA-approved drug for the treatment of cutaneous T-cell lymphoma (CTCL); however, its use provokes or disrupts other retinoid-X-receptor (RXR)-dependent nuclear receptor pathways and thereby incites side effects including hypothyroidism and raised triglycerides. Two novel bexarotene analogs, as well as three [...] Read more.
Bexarotene is an FDA-approved drug for the treatment of cutaneous T-cell lymphoma (CTCL); however, its use provokes or disrupts other retinoid-X-receptor (RXR)-dependent nuclear receptor pathways and thereby incites side effects including hypothyroidism and raised triglycerides. Two novel bexarotene analogs, as well as three unique CD3254 analogs and thirteen novel NEt-TMN analogs, were synthesized and characterized for their ability to induce RXR agonism in comparison to bexarotene (1). Several analogs in all three groups possessed an isochroman ring substitution for the bexarotene aliphatic group. Analogs were modeled for RXR binding affinity, and EC50 as well as IC50 values were established for all analogs in a KMT2A-MLLT3 leukemia cell line. All analogs were assessed for liver-X-receptor (LXR) activity in an LXRE system to gauge the potential for the compounds to provoke raised triglycerides by increasing LXR activity, as well as to drive LXRE-mediated transcription of brain ApoE expression as a marker for potential therapeutic use in neurodegenerative disorders. Preliminary results suggest these compounds display a broad spectrum of off-target activities. However, many of the novel compounds were observed to be more potent than 1. While some RXR agonists cross-signal the retinoic acid receptor (RAR), many of the rexinoids in this work displayed reduced RAR activity. The isochroman group did not appear to substantially reduce RXR activity on its own. The results of this study reveal that modifying potent, selective rexinoids like bexarotene, CD3254, and NEt-TMN can provide rexinoids with increased RXR selectivity, decreased potential for cross-signaling, and improved anti-proliferative characteristics in leukemia models compared to 1. Full article
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16 pages, 4009 KiB  
Article
In Vitro/In Vivo Translation of Synergistic Combination of MDM2 and MEK Inhibitors in Melanoma Using PBPK/PD Modelling: Part I
by Jakub Witkowski, Sebastian Polak, Zbigniew Rogulski and Dariusz Pawelec
Int. J. Mol. Sci. 2022, 23(21), 12984; https://doi.org/10.3390/ijms232112984 - 26 Oct 2022
Cited by 3 | Viewed by 1757
Abstract
Translation of the synergy between the Siremadlin (MDM2 inhibitor) and Trametinib (MEK inhibitor) combination observed in vitro into in vivo synergistic efficacy in melanoma requires estimation of the interaction between these molecules at the pharmacokinetic (PK) and pharmacodynamic (PD) levels. The cytotoxicity of [...] Read more.
Translation of the synergy between the Siremadlin (MDM2 inhibitor) and Trametinib (MEK inhibitor) combination observed in vitro into in vivo synergistic efficacy in melanoma requires estimation of the interaction between these molecules at the pharmacokinetic (PK) and pharmacodynamic (PD) levels. The cytotoxicity of the Siremadlin and Trametinib combination was evaluated in vitro in melanoma A375 cells with MTS and RealTime-Glo assays. Analysis of the drug combination matrix was performed using Synergy and Synergyfinder packages. Calculated drug interaction metrics showed high synergy between Siremadlin and Trametinib: 23.12%, or a 7.48% increase of combined drug efficacy (concentration-independent parameter β from Synergy package analysis and concentration-dependent δ parameter from Synergyfinder analysis, respectively). In order to select the optimal PD interaction parameter which may translate observed in vitro synergy metrics into the in vivo setting, further PK/PD studies on cancer xenograft animal models coupled with PBPK/PD modelling are needed. Full article
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11 pages, 2602 KiB  
Article
The Effects of Genistein at Different Concentrations on MCF-7 Breast Cancer Cells and BJ Dermal Fibroblasts
by Magda Aleksandra Pawlicka, Szymon Zmorzyński, Sylwia Popek-Marciniec and Agata Anna Filip
Int. J. Mol. Sci. 2022, 23(20), 12360; https://doi.org/10.3390/ijms232012360 - 15 Oct 2022
Cited by 6 | Viewed by 1786
Abstract
This study aimed to evaluate the safety and potential use of soy isoflavones in the treatment of skin problems, difficult-to-heal wounds and postoperative scars in women after the oncological treatment of breast cancer. The effects of different concentrations of genistein as a representative [...] Read more.
This study aimed to evaluate the safety and potential use of soy isoflavones in the treatment of skin problems, difficult-to-heal wounds and postoperative scars in women after the oncological treatment of breast cancer. The effects of different concentrations of genistein as a representative of soy isoflavonoids on MCF-7 tumor cells and BJ skin fibroblasts cultured in vitro were assessed. Genistein affects both healthy dermal BJ fibroblasts and cancerous MCF-7 cells. The effect of the tested isoflavonoid is closely related to its concentration. High concentrations of genistein destroy MCF-7 cancer cells, regardless of the exposure time, with a much greater effect on reducing cancer cell numbers at longer times (48 h). Lower concentrations of genistein (10 and 20 μM) increase the abundance of dermal fibroblasts. However, higher concentrations of genistein (50 μM and higher) are detrimental to fibroblasts at longer exposure times (48 h). Our studies indicate that although genistein shows high potential for use in the treatment of skin problems, wounds and surgical scars in women during and after breast cancer treatment, it is not completely safe. Introducing isoflavonoids to treatment requires further research into their mechanisms of action at the molecular level, taking into account genetic and immunological aspects. It is also necessary to conduct research in in vivo models, which will allow for eliminating adverse side effects of therapy. Full article
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11 pages, 1293 KiB  
Article
Development of a Sensitive Screening Method for Simultaneous Determination of Nine Genotoxic Nitrosamines in Active Pharmaceutical Ingredients by GC-MS
by Anna B. Witkowska, Joanna Giebułtowicz, Magdalena Dąbrowska and Elżbieta U. Stolarczyk
Int. J. Mol. Sci. 2022, 23(20), 12125; https://doi.org/10.3390/ijms232012125 - 12 Oct 2022
Cited by 7 | Viewed by 1858
Abstract
A worldwide crisis with nitrosamine contamination in medical products began in 2018. Therefore, trace-level analysis of nitrosamines is becoming an emerging topic of interest in the field of quality control. A novel GC-MS method with electron ionization and microextraction was developed and validated [...] Read more.
A worldwide crisis with nitrosamine contamination in medical products began in 2018. Therefore, trace-level analysis of nitrosamines is becoming an emerging topic of interest in the field of quality control. A novel GC-MS method with electron ionization and microextraction was developed and validated for simultaneous determination of nine carcinogenic nitrosamines (NDMA, NMEA, NDEA, NDBA, NMOR, NPYR, NPIP, NDPA, and N-methyl-npz) in active pharmaceutical ingredients (APIs): cilostazol, sunitinib malate, and olmesartan medoxomil. The method was validated according to the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines, demonstrating good linearity in the range of LOQ up to 21.6 ng/mL (120% of specification limit). The limits of detection for the nine nitrosamines were determined to be in the range 0.15–1.00 ng/mL. The developed trace level GC-MS method turned out to be specific, accurate, and precise. The accuracy of all the tested APIs ranged from 94.09% to 111.22% and the precision evaluated by repeatability, intermediate precision, and system precision was RSD ≤ 7.65%. Nitrosamines were not detected in cilostazol and sunitinib, whereas in olmesartan medoxomil NDEA was detected at the level of LOQ. The novel protocol was successfully applied for nitrosamines determination in selected APIs and can be used for the routine quality control of APIs under Good Manufacturing Practices rules, ensuring the safety and effectiveness of pharmaceutical products. Full article
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21 pages, 8492 KiB  
Article
In Vitro/In Vivo Translation of Synergistic Combination of MDM2 and MEK Inhibitors in Melanoma Using PBPK/PD Modelling: Part II
by Jakub Witkowski, Sebastian Polak, Zbigniew Rogulski and Dariusz Pawelec
Int. J. Mol. Sci. 2022, 23(19), 11939; https://doi.org/10.3390/ijms231911939 - 08 Oct 2022
Cited by 5 | Viewed by 2252
Abstract
The development of in vitro/in vivo translational methods for synergistically acting drug combinations is needed to identify the most effective therapeutic strategies. We performed PBPK/PD modelling for siremadlin, trametinib, and their combination at various dose levels and dosing schedules in an A375 xenografted [...] Read more.
The development of in vitro/in vivo translational methods for synergistically acting drug combinations is needed to identify the most effective therapeutic strategies. We performed PBPK/PD modelling for siremadlin, trametinib, and their combination at various dose levels and dosing schedules in an A375 xenografted mouse model (melanoma cells). In this study, we built models based on in vitro ADME and in vivo PK/PD data determined from the literature or estimated by the Simcyp Animal simulator (V21). The developed PBPK/PD models allowed us to account for the interactions between siremadlin and trametinib at PK and PD levels. The interaction at the PK level was described by an interplay between absorption and tumour disposition levels, whereas the PD interaction was based on the in vitro results. This approach allowed us to reasonably estimate the most synergistic and efficacious dosing schedules and dose levels for combinations of siremadlin and trametinib in mice. PBPK/PD modelling is a powerful tool that allows researchers to properly estimate the in vivo efficacy of the anticancer drug combination based on the results of in vitro studies. Such an approach based on in vitro and in vivo extrapolation may help researchers determine the most efficacious dosing strategies and will allow for the extrapolation of animal PBPK/PD models into clinical settings. Full article
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14 pages, 1948 KiB  
Article
Improved Trimethylangelicin Analogs for Cystic Fibrosis: Design, Synthesis and Preliminary Screening
by Christian Vaccarin, Daniela Gabbia, Erica Franceschinis, Sara De Martin, Marco Roverso, Sara Bogialli, Gianni Sacchetti, Chiara Tupini, Ilaria Lampronti, Roberto Gambari, Giulio Cabrini, Maria Cristina Dechecchi, Anna Tamanini, Giovanni Marzaro and Adriana Chilin
Int. J. Mol. Sci. 2022, 23(19), 11528; https://doi.org/10.3390/ijms231911528 - 29 Sep 2022
Cited by 2 | Viewed by 1538
Abstract
A small library of new angelicin derivatives was designed and synthesized with the aim of bypassing the side effects of trimethylangelicin (TMA), a promising agent for the treatment of cystic fibrosis. To prevent photoreactions with DNA, hindered substituents were inserted at the 4 [...] Read more.
A small library of new angelicin derivatives was designed and synthesized with the aim of bypassing the side effects of trimethylangelicin (TMA), a promising agent for the treatment of cystic fibrosis. To prevent photoreactions with DNA, hindered substituents were inserted at the 4 and/or 6 positions. Unlike the parent TMA, none of the new derivatives exhibited significant cytotoxicity or mutagenic effects. Among the synthesized compounds, the 4-phenylderivative 12 and the 6-phenylderivative 25 exerted a promising F508del CFTR rescue ability. On these compounds, preliminary in vivo pharmacokinetic (PK) studies were carried out, evidencing a favorable PK profile per se or after incorporation into lipid formulations. Therefore, the selected compounds are good candidates for future extensive investigation to evaluate and develop novel CFTR correctors based on the angelicin structure. Full article
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18 pages, 3901 KiB  
Article
Novel Strategies against Cancer: Dexibuprofen-Loaded Nanostructured Lipid Carriers
by Vaikunthavasan Thiruchenthooran, Marta Świtalska, Lorena Bonilla, Marta Espina, Maria Luisa García, Joanna Wietrzyk, Elena Sánchez-López and Anna Gliszczyńska
Int. J. Mol. Sci. 2022, 23(19), 11310; https://doi.org/10.3390/ijms231911310 - 25 Sep 2022
Cited by 10 | Viewed by 1744
Abstract
The aim of this work was to design innovative nanostructured lipid carriers (NLCs) for the delivery of dexibuprofen (DXI) as an antiproliferative therapy against tumoral processes, and overcome its side effects. DXI-NLC samples were prepared with beeswax, Miglyol 812 and Tween 80 using [...] Read more.
The aim of this work was to design innovative nanostructured lipid carriers (NLCs) for the delivery of dexibuprofen (DXI) as an antiproliferative therapy against tumoral processes, and overcome its side effects. DXI-NLC samples were prepared with beeswax, Miglyol 812 and Tween 80 using high-pressure homogenization. A two-level factorial design 24 was applied to optimize the formulation, and physicochemical properties such as particle size, zeta potential, polydispersity index and entrapment efficiency were measured. Optimized parameters of DXI-NLCs exhibited a mean particle size of 152.3 nm, a polydispersity index below 0.2, and high DXI entrapment efficiency (higher than 99%). Moreover, DXI-NLCs provided a prolonged drug release, slower than the free DXI. DXI-NLCs were stable for 2 months and their morphology revealed that they possess a spherical shape. In vitro cytotoxicity and anticancer potential studies were performed towards prostate (PC-3) and breast (MDA-MB-468) cancer cell lines. The highest activity of DXI-NLCs was observed towards breast cancer cells, which were effectively inhibited at 3.4 μM. Therefore, DXI-NLCs constitute a promising antiproliferative therapy that has proven to be especially effective against breast cancer. Full article
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14 pages, 8221 KiB  
Article
Comparative Study of Chemical Stability of a PK20 Opioid–Neurotensin Hybrid Peptide and Its Analogue [Ile9]PK20—The Effect of Isomerism of a Single Amino Acid
by Barbara Żyżyńska-Granica, Adriano Mollica, Azzurra Stefanucci, Sebastian Granica and Patrycja Kleczkowska
Int. J. Mol. Sci. 2022, 23(18), 10839; https://doi.org/10.3390/ijms231810839 - 16 Sep 2022
Cited by 3 | Viewed by 1339
Abstract
Chemical stability is one of the main problems during the discovery and development of potent drugs. When ignored, it may lead to unreliable biological and pharmacokinetics data, especially regarding the degradation of products’ possible toxicity. Recently, two biologically active drug candidates were presented [...] Read more.
Chemical stability is one of the main problems during the discovery and development of potent drugs. When ignored, it may lead to unreliable biological and pharmacokinetics data, especially regarding the degradation of products’ possible toxicity. Recently, two biologically active drug candidates were presented that combine both opioid and neurotensin pharmacophores in one entity, thus generating a hybrid compound. Importantly, these chimeras are structurally similar except for an amino acid change at position 9 of the peptide chain. In fact, isoleucine (C6H13NO2) was replaced with its isomer tert-leucine. These may further lead to various differences in hybrids’ behavior under specific conditions (temperature, UV, oxidative, acid/base environment). Therefore, the purpose of the study is to assess and compare the chemical stability of two hybrid peptides that differ in nature by way of one amino acid (tert-leucine vs. isoleucine). The obtained results indicate that, opposite to biological activity, the substitution of tert-leucine into isoleucine did not substantially influence the compound’s chemical stability. In fact, neither hydrolysis under alkaline and acidic conditions nor oxidative degradation resulted in spectacular differences between the two compounds—although the number of potential degradation products increased, particularly under acidic pH. However, such a modification significantly reduced the compound’s half-life from 204.4 h (for PK20 exposed to 1M HCl) to 117.7 h for [Ile9]PK20. Full article
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23 pages, 5004 KiB  
Article
Implementation of QbD Approach to the Development of Chromatographic Methods for the Determination of Complete Impurity Profile of Substance on the Preclinical and Clinical Step of Drug Discovery Studies
by Lidia Gurba-Bryśkiewicz, Urszula Dawid, Damian A. Smuga, Wioleta Maruszak, Monika Delis, Krzysztof Szymczak, Bartosz Stypik, Aleksandra Moroz, Aleksandra Błocka, Michał Mroczkiewicz, Krzysztof Dubiel and Maciej Wieczorek
Int. J. Mol. Sci. 2022, 23(18), 10720; https://doi.org/10.3390/ijms231810720 - 14 Sep 2022
Cited by 6 | Viewed by 2061
Abstract
The purpose of this work was to demonstrate the use of the AQbD with the DOE approach to the methodical step-by-step development of a UHPLC method for the quantitative determination of the impurity profile of new CPL409116 substance (JAK/ROCK inhibitor) on the preclinical [...] Read more.
The purpose of this work was to demonstrate the use of the AQbD with the DOE approach to the methodical step-by-step development of a UHPLC method for the quantitative determination of the impurity profile of new CPL409116 substance (JAK/ROCK inhibitor) on the preclinical and clinical step of drug discovery studies. The critical method parameters (CMPs) have been tested extensively: the kind of stationary phase (8 different columns), pH of the aqueous mobile phase (2.6, 3.2, 4.0, 6.8), and start (20–25%) and stop (85–90%) percentage of organic mobile phase (ACN). The critical method attributes (CMAs) are the resolution between the peaks (≥2.0) and peak symmetry of analytes (≥0.8 and ≤1.8). In the screening step, the effects of different levels of CMPs on the CMAs were evaluated based on a full fractional design 22. The robustness tests were established from the knowledge space of the screening step and performed by application fractional factorial design 2(4−1). Method operable design region (MODR) was generated. The probability of meeting the specifications for the CMAs was calculated by Monte-Carlo simulations. In relation to literature such a complete AQbD approach including screening, optimization, and validation steps for the development of a new method for the quantitative determination of the full profile of nine impurities of an innovative pharmaceutical substance with the structure-based pre-development pointed out the novelty of our work. The final working conditions were as follows: column Zorbax Eclipse Plus C18, aqueous mobile phase 10 mM ± 1 mM aqueous solution of HCOOH, pH 2.6, 20% ± 1% of ACN at the start and 85% ± 1% of ACN at the end of the gradient, and column temperature 30 °C ± 2 °C. The method was validated in compliance with ICH guideline Q2(R1). The optimized method is specified, linear, precise, and robust. LOQ is on the reporting threshold level of 0.05% and LOD at 0.02% for all impurities. Full article
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15 pages, 2970 KiB  
Article
Affinities to Oxaliplatin: Vitamins from B Group vs. Nucleobases
by Beata Szefler, Przemysław Czeleń, Kamil Wojtkowiak and Aneta Jezierska
Int. J. Mol. Sci. 2022, 23(18), 10567; https://doi.org/10.3390/ijms231810567 - 12 Sep 2022
Cited by 2 | Viewed by 1688
Abstract
Oxaliplatin, similar to Cisplatin, exhibits anticancer activity by interacting with DNA and inducing programmed cell death. It is biotransformed through a number of spontaneous and non-enzymatic processes. In this way, several transient reactive species are formed, including dichloro-, monochloro-, and diaqua-DACH platin, which [...] Read more.
Oxaliplatin, similar to Cisplatin, exhibits anticancer activity by interacting with DNA and inducing programmed cell death. It is biotransformed through a number of spontaneous and non-enzymatic processes. In this way, several transient reactive species are formed, including dichloro-, monochloro-, and diaqua-DACH platin, which can complex with DNA and other macromolecules. The molecular level suggests that such interactions can also take place with vitamins containing aromatic rings with lone pair orbitals. Theoretical and experimental studies were performed to investigate interactions of vitamins from the B group with Oxaliplatin, and the results were compared with values characterizing native purines. Quantum-chemical simulations were carried out at the B3LYP/6-31G(d,p) level, with the LANL2DZ basis set representing atomic orbitals of platinum atom, and at the MN15/def2-TZVP levels of theory with the use of Polarizable Continuum Model (IEF-PCM formulation) and water as a solvent. Additionally, time-dependent density functional theory (TD-DFT) was employed to study molecular properties in the electronic excited state. Interactions of vitamins and Oxaliplatin were investigated using UV-Vis spectroscopy. Values of the free energy (ΔGr) indicate spontaneous reactions with monoaqua [PtH2OClDACH]+ and diaqua [Pt(H2O)2DACH]2+ derivatives of Oxaliplatin. However, diaqua derivatives were found to be preferable. The free energy (ΔGr) values obtained for vitamins from the B group indicate lower affinity of Oxaliplatin compared with values characterizing complexes formed by guanine, adenine, and cytosine. The exception is the monoaqua form of vitamin B1 (thiamine) at the MN15/def2-TZVP levels of calculations. An application of atoms in molecules (AIM) theory revealed non-covalent interactions present in the complexes studied. The comparison of computed and experimental spectroscopic properties showed a good agreement. Full article
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18 pages, 3065 KiB  
Article
Designing and Synthesis of New Isatin Derivatives as Potential CDK2 Inhibitors
by Przemysław Czeleń, Agnieszka Skotnicka and Beata Szefler
Int. J. Mol. Sci. 2022, 23(14), 8046; https://doi.org/10.3390/ijms23148046 - 21 Jul 2022
Cited by 9 | Viewed by 1802
Abstract
Tumors are still one of the main causes of death; therefore, the search for new therapeutic agents that will enable the implementation of effective treatment is a significant challenge for modern pharmacy. One of the important factors contributing to the development of neoplastic [...] Read more.
Tumors are still one of the main causes of death; therefore, the search for new therapeutic agents that will enable the implementation of effective treatment is a significant challenge for modern pharmacy. One of the important factors contributing to the development of neoplastic diseases is the overexpression of enzymes responsible for the regulation of cell division processes such as cyclin-dependent kinases. Numerous studies and examples of already-developed drugs confirm that isatin is a convenient basis for the development of new groups of inhibitors for this class of enzyme. Therefore, in this work, a new group of potential inhibitors of the CDK2 enzyme, utilizing isatin derivatives and substituted benzoylhydrazines, has been designed based on the application of computational chemistry methods, such as docking and molecular dynamics, and their inhibiting ability was assessed. In the cases of the selected compounds, a synthesis method was developed, and the selected physicochemical properties of the newly synthesized derivatives were estimated. As part of the completed project, new compounds are developed which are potential inhibitors of the CDK2 enzyme. Full article
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14 pages, 3291 KiB  
Article
In Silico Prediction of the Metabolic Resistance of Vitamin D Analogs against CYP3A4 Metabolizing Enzyme
by Teresa Żołek, Kaori Yasuda, Geoffrey Brown, Toshiyuki Sakaki and Andrzej Kutner
Int. J. Mol. Sci. 2022, 23(14), 7845; https://doi.org/10.3390/ijms23147845 - 16 Jul 2022
Cited by 2 | Viewed by 1311
Abstract
The microsomal cytochrome P450 3A4 (CYP3A4) and mitochondrial cytochrome P450 24A1 (CYP24A1) hydroxylating enzymes both metabolize vitamin D and its analogs. The three-dimensional (3D) structure of the full-length native human CYP3A4 has been solved, but the respective structure of the main vitamin D [...] Read more.
The microsomal cytochrome P450 3A4 (CYP3A4) and mitochondrial cytochrome P450 24A1 (CYP24A1) hydroxylating enzymes both metabolize vitamin D and its analogs. The three-dimensional (3D) structure of the full-length native human CYP3A4 has been solved, but the respective structure of the main vitamin D hydroxylating CYP24A1 enzyme is unknown. The structures of recombinant CYP24A1 enzymes have been solved; however, from studies of the vitamin D receptor, the use of a truncated protein for docking studies of ligands led to incorrect results. As the structure of the native CYP3A4 protein is known, we performed rigid docking supported by molecular dynamic simulation using CYP3A4 to predict the metabolic conversion of analogs of 1,25-dihydroxyvitamin D2 (1,25D2). This is highly important to the design of novel vitamin D-based drug candidates of reasonable metabolic stability as CYP3A4 metabolizes ca. 50% of the drug substances. The use of the 3D structure data of human CYP3A4 has allowed us to explain the substantial differences in the metabolic conversion of the side-chain geometric analogs of 1,25D2. The calculated free enthalpy of the binding of an analog of 1,25D2 to CYP3A4 agreed with the experimentally observed conversion of the analog by CYP24A1. The metabolic conversion of an analog of 1,25D2 to the main vitamin D hydroxylating enzyme CYP24A1, of unknown 3D structure, can be explained by the binding strength of the analog to the known 3D structure of the CYP3A4 enzyme. Full article
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33 pages, 8864 KiB  
Article
Thiogenistein—Antioxidant Chemistry, Antitumor Activity, and Structure Elucidation of New Oxidation Products
by Elżbieta U. Stolarczyk, Weronika Strzempek, Marta Łaszcz, Andrzej Leś, Elżbieta Menaszek and Krzysztof Stolarczyk
Int. J. Mol. Sci. 2022, 23(14), 7816; https://doi.org/10.3390/ijms23147816 - 15 Jul 2022
Cited by 2 | Viewed by 1575
Abstract
Isoflavonoids such as genistein (GE) are well known antioxidants. The predictive biological activity of structurally new compounds such as thiogenistein (TGE)–a new analogue of GE–becomes an interesting way to design new drug candidates with promising properties. Two oxidation strategies were used to characterize [...] Read more.
Isoflavonoids such as genistein (GE) are well known antioxidants. The predictive biological activity of structurally new compounds such as thiogenistein (TGE)–a new analogue of GE–becomes an interesting way to design new drug candidates with promising properties. Two oxidation strategies were used to characterize TGE oxidation products: the first in solution and the second on the 2D surface of the Au electrode as a self-assembling TGE monolayer. The structure elucidation of products generated by different oxidation strategies was performed. The electrospray ionization mass spectrometry (ESI-MS) was used for identifying the product of electrochemical and hydrogen peroxide oxidation in the solution. Fourier transform infrared spectroscopy (FT-IR) with the ATR mode was used to identify a product after hydrogen peroxide treatment of TGE on the 2D surface. The density functional theory was used to support the experimental results for the estimation of antioxidant activity of TGE as well as for the molecular modeling of oxidation products. The biological studies were performed simultaneously to assess the suitability of TGE for antioxidant and antitumor properties. It was found that TGE was characterized by a high cytotoxic activity toward human breast cancer cells. The research was also carried out on mice macrophages, disclosing that TGE neutralized the production of the LPS-induced reactive oxygen species (ROS) and exhibits ABTS (2,2′-azino-bis-3-(ethylbenzothiazoline-6-sulphonic acid) radical scavenging ability. In the presented study, we identified the main oxidation products of TGE generated under different environmental conditions. The electroactive centers of TGE were identified and its oxidation mechanisms were proposed. TGE redox properties can be related to its various pharmacological activities. Our new thiolated analogue of genistein neutralizes the LPS-induced ROS production better than GE. Additionally, TGE shows a high cytotoxic activity against human breast cancer cells. The viability of MCF-7 (estrogen-positive cells) drops two times after a 72-h incubation with 12.5 μM TGE (viability 53.86%) compared to genistein (viability 94.46%). Full article
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24 pages, 5788 KiB  
Article
Dialdehyde Starch Nanocrystals as a Novel Cross-Linker for Biomaterials Able to Interact with Human Serum Proteins
by Katarzyna Wegrzynowska-Drzymalska, Kinga Mylkie, Pawel Nowak, Dariusz T. Mlynarczyk, Dorota Chelminiak-Dudkiewicz, Halina Kaczmarek, Tomasz Goslinski and Marta Ziegler-Borowska
Int. J. Mol. Sci. 2022, 23(14), 7652; https://doi.org/10.3390/ijms23147652 - 11 Jul 2022
Cited by 10 | Viewed by 2228
Abstract
In recent years, new cross-linkers from renewable resources have been sought to replace toxic synthetic compounds of this type. One of the most popular synthetic cross-linking agents used for biomedical applications is glutaraldehyde. However, the unreacted cross-linker can be released from the materials [...] Read more.
In recent years, new cross-linkers from renewable resources have been sought to replace toxic synthetic compounds of this type. One of the most popular synthetic cross-linking agents used for biomedical applications is glutaraldehyde. However, the unreacted cross-linker can be released from the materials and cause cytotoxic effects. In the present work, dialdehyde starch nanocrystals (NDASs) were obtained from this polysaccharide nanocrystal form as an alternative to commonly used cross-linking agents. Then, 5–15% NDASs were used for chemical cross-linking of native chitosan (CS), gelatin (Gel), and a mixture of these two biopolymers (CS-Gel) via Schiff base reaction. The obtained materials, forming thin films, were characterized by ATR-FTIR, SEM, and XRD analysis. Thermal and mechanical properties were determined by TGA analysis and tensile testing. Moreover, all cross-linked biopolymers were also characterized by hydrophilic character, swelling ability, and protein absorption. The toxicity of obtained materials was tested using the Microtox test. Dialdehyde starch nanocrystals appear as a beneficial plant-derived cross-linking agent that allows obtaining cross-linked biopolymer materials with properties desirable for biomedical applications. Full article
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21 pages, 4164 KiB  
Article
Discovery of New 3,3-Diethylazetidine-2,4-dione Based Thiazoles as Nanomolar Human Neutrophil Elastase Inhibitors with Broad-Spectrum Antiproliferative Activity
by Beata Donarska, Marta Świtalska, Joanna Wietrzyk, Wojciech Płaziński, Magdalena Mizerska-Kowalska, Barbara Zdzisińska and Krzysztof Z. Łączkowski
Int. J. Mol. Sci. 2022, 23(14), 7566; https://doi.org/10.3390/ijms23147566 - 08 Jul 2022
Cited by 5 | Viewed by 1753
Abstract
A series of 3,3-diethylazetidine-2,4-dione based thiazoles 3a3j were designed and synthesized as new human neutrophil elastase (HNE) inhibitors in nanomolar range. The representative compounds 3c, 3e, and 3h exhibit high HNE inhibitory activity with IC50 values of 35.02–44.59 [...] Read more.
A series of 3,3-diethylazetidine-2,4-dione based thiazoles 3a3j were designed and synthesized as new human neutrophil elastase (HNE) inhibitors in nanomolar range. The representative compounds 3c, 3e, and 3h exhibit high HNE inhibitory activity with IC50 values of 35.02–44.59 nM, with mixed mechanism of action. Additionally, the most active compounds 3c and 3e demonstrate high stability under physiological conditions. The molecular docking study showed good correlation of the binding energies with the IC50 values, suggesting that the inhibition properties are largely dependent on the stage of ligand alignment in the binding cavity. The inhibition properties are correlated with the energy level of substrates of the reaction of ligand with Ser195. Moreover, most compounds showed high and broad-spectrum antiproliferative activity against human leukemia (MV4-11), human lung carcinoma (A549), human breast adenocarcinoma (MDA-MB-231), and urinary bladder carcinoma (UMUC-3), with IC50 values of 4.59–9.86 μM. Additionally, compounds 3c and 3e can induce cell cycle arrest at the G2/M phase and apoptosis via caspase-3 activation, leading to inhibition of A549 cell proliferation. These findings suggest that these new types of drugs could be used to treat cancer and other diseases in which immunoreactive HNE is produced. Full article
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20 pages, 6111 KiB  
Article
Antibacterial and Cytotoxicity Evaluation of New Hydroxyapatite-Based Granules Containing Silver or Gallium Ions with Potential Use as Bone Substitutes
by Kamil Pajor, Anna Michalicha, Anna Belcarz, Lukasz Pajchel, Anna Zgadzaj, Filip Wojas and Joanna Kolmas
Int. J. Mol. Sci. 2022, 23(13), 7102; https://doi.org/10.3390/ijms23137102 - 26 Jun 2022
Cited by 9 | Viewed by 2120
Abstract
The aim of the current work was to study the physicochemical properties and biological activity of different types of porous granules containing silver or gallium ions. Firstly, hydroxyapatites powders doped with Ga3+ or Ag+ were synthesized by the standard wet method. [...] Read more.
The aim of the current work was to study the physicochemical properties and biological activity of different types of porous granules containing silver or gallium ions. Firstly, hydroxyapatites powders doped with Ga3+ or Ag+ were synthesized by the standard wet method. Then, the obtained powders were used to fabricate ceramic microgranules (AgM and GaM) and alginate/hydroxyapatite composite granules (AgT and GaT). The ceramic microgranules were also used to prepare a third type of granules (AgMT and GaMT) containing silver or gallium, respectively. All the granules turned out to be porous, except that the AgT and GaT granules were characterized by higher porosity and a better developed specific surface, whereas the microgranules had very fine, numerous micropores. The granules revealed a slow release of the substituted ions. All the granules except AgT were classified as non-cytotoxic according to the neutral red uptake (NRU) test and the MTT assay. The obtained powders and granules were subjected to various antibacterial test towards the following four different bacterial strains: Staphylococcus aureus, Staphylococcus epidermidis, Pseudomonas aeruginosa and Escherichia coli. The Ag-containing materials revealed high antibacterial activity. Full article
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22 pages, 5477 KiB  
Article
Micro-RNAs in Response to Active Forms of Vitamin D3 in Human Leukemia and Lymphoma Cells
by Justyna Joanna Gleba, Dagmara Kłopotowska, Joanna Banach, Karolina Anna Mielko, Eliza Turlej, Magdalena Maciejewska, Andrzej Kutner and Joanna Wietrzyk
Int. J. Mol. Sci. 2022, 23(9), 5019; https://doi.org/10.3390/ijms23095019 - 30 Apr 2022
Cited by 5 | Viewed by 1944
Abstract
Non-coding micro-RNA (miRNAs) regulate the protein expression responsible for cell growth and proliferation. miRNAs also play a role in a cancer cells’ response to drug treatment. Knowing that leukemia and lymphoma cells show different responses to active forms of vitamin D3, [...] Read more.
Non-coding micro-RNA (miRNAs) regulate the protein expression responsible for cell growth and proliferation. miRNAs also play a role in a cancer cells’ response to drug treatment. Knowing that leukemia and lymphoma cells show different responses to active forms of vitamin D3, we decided to investigate the role of selected miRNA molecules and regulated proteins, analyzing if there is a correlation between the selected miRNAs and regulated proteins in response to two active forms of vitamin D3, calcitriol and tacalcitol. A total of nine human cell lines were analyzed: five leukemias: MV-4-1, Thp-1, HL-60, K562, and KG-1; and four lymphomas: Raji, Daudi, Jurkat, and U2932. We selected five miRNA molecules—miR-27b, miR-32, miR-125b, miR-181a, and miR-181b—and the proteins regulated by these molecules, namely, CYP24A1, Bak1, Bim, p21, p27, p53, and NF-kB. The results showed that the level of selected miRNAs correlates with the level of proteins, especially p27, Bak1, NFκB, and CYP24A1, and miR-27b and miR-125b could be responsible for the anticancer activity of active forms of vitamin D3 in human leukemia and lymphoma. Full article
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Review

Jump to: Editorial, Research

19 pages, 6674 KiB  
Review
Will the Interactions of Some Platinum (II)-Based Drugs with B-Vitamins Reduce Their Therapeutic Effect in Cancer Patients? Comparison of Chemotherapeutic Agents such as Cisplatin, Carboplatin and Oxaliplatin—A Review
by Beata Szefler and Przemysław Czeleń
Int. J. Mol. Sci. 2023, 24(2), 1548; https://doi.org/10.3390/ijms24021548 - 12 Jan 2023
Cited by 9 | Viewed by 1869
Abstract
Pt (II) derivatives show anti-cancer activity by interacting with nucleobases of DNA, thus causing some spontaneous and non-spontaneous reactions. As a result, mono- and diaqua products are formed which further undergo complexation with guanine or adenine. Consequently, many processes are triggered, which lead [...] Read more.
Pt (II) derivatives show anti-cancer activity by interacting with nucleobases of DNA, thus causing some spontaneous and non-spontaneous reactions. As a result, mono- and diaqua products are formed which further undergo complexation with guanine or adenine. Consequently, many processes are triggered, which lead to the death of the cancer cell. The theoretical and experimental studies confirm that such types of interactions can also occur with other chemical compounds. The vitamins from B group have a similar structure to the nucleobases of DNA and have aromatic rings with single-pair orbitals. Theoretical and experimental studies were performed to describe the interactions of B vitamins with Pt (II) derivatives such as cisplatin, oxaliplatin and carboplatin. The obtained results were compared with the values for guanine. Two levels of simulations were implemented at the theoretical level, namely, B3LYP/6-31G(d,p) with LANL2DZ bases set for platinum atoms and MN15/def2-TZVP. The polarizable continuum model (IEF–PCM preparation) and water as a solvent were used. UV-Vis spectroscopy was used to describe the drug–nucleobase and drug–B vitamin interactions. Values of the free energy (ΔGr) show spontaneous reactions with mono- and diaqua derivatives of cisplatin and oxaliplatin; however, interactions with diaqua derivatives are more preferable. The strength of these interactions was also compared. Carboplatin products have the weakest interaction with the studied structures. The presence of non-covalent interactions was demonstrated in the tested complexes. A good agreement between theory and experiment was also demonstrated. Full article
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28 pages, 613 KiB  
Review
Current Knowledge on Interactions of Plant Materials Traditionally Used in Skin Diseases in Poland and Ukraine with Human Skin Microbiota
by Natalia Melnyk, Inna Vlasova, Weronika Skowrońska, Agnieszka Bazylko, Jakub P. Piwowarski and Sebastian Granica
Int. J. Mol. Sci. 2022, 23(17), 9644; https://doi.org/10.3390/ijms23179644 - 25 Aug 2022
Cited by 8 | Viewed by 3112
Abstract
Skin disorders of different etiology, such as dermatitis, atopic dermatitis, eczema, psoriasis, wounds, burns, and others, are widely spread in the population. In severe cases, they require the topical application of drugs, such as antibiotics, steroids, and calcineurin inhibitors. With milder symptoms, which [...] Read more.
Skin disorders of different etiology, such as dermatitis, atopic dermatitis, eczema, psoriasis, wounds, burns, and others, are widely spread in the population. In severe cases, they require the topical application of drugs, such as antibiotics, steroids, and calcineurin inhibitors. With milder symptoms, which do not require acute pharmacological interventions, medications, dietary supplements, and cosmetic products of plant material origin are gaining greater popularity among professionals and patients. They are applied in various pharmaceutical forms, such as raw infusions, tinctures, creams, and ointments. Although plant-based formulations have been used by humankind since ancient times, it is often unclear what the mechanisms of the observed beneficial effects are. Recent advances in the contribution of the skin microbiota in maintaining skin homeostasis can shed new light on understanding the activity of topically applied plant-based products. Although the influence of various plants on skin-related ailments are well documented in vivo and in vitro, little is known about the interaction with the network of the skin microbial ecosystem. The review aims to summarize the hitherto scientific data on plant-based topical preparations used in Poland and Ukraine and indicate future directions of the studies respecting recent developments in understanding the etiology of skin diseases. The current knowledge on investigations of interactions of plant materials/extracts with skin microbiome was reviewed for the first time. Full article
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29 pages, 38741 KiB  
Review
The Relevance of Crystal Forms in the Pharmaceutical Field: Sword of Damocles or Innovation Tools?
by Dario Braga, Lucia Casali and Fabrizia Grepioni
Int. J. Mol. Sci. 2022, 23(16), 9013; https://doi.org/10.3390/ijms23169013 - 12 Aug 2022
Cited by 21 | Viewed by 3641
Abstract
This review is aimed to provide to an “educated but non-expert” readership and an overview of the scientific, commercial, and ethical importance of investigating the crystalline forms (polymorphs, hydrates, and co-crystals) of active pharmaceutical ingredients (API). The existence of multiple crystal forms of [...] Read more.
This review is aimed to provide to an “educated but non-expert” readership and an overview of the scientific, commercial, and ethical importance of investigating the crystalline forms (polymorphs, hydrates, and co-crystals) of active pharmaceutical ingredients (API). The existence of multiple crystal forms of an API is relevant not only for the selection of the best solid material to carry through the various stages of drug development, including the choice of dosage and of excipients suitable for drug development and marketing, but also in terms of intellectual property protection and/or extension. This is because the physico-chemical properties, such as solubility, dissolution rate, thermal stability, processability, etc., of the solid API may depend, sometimes dramatically, on the crystal form, with important implications on the drug’s ultimate efficacy. This review will recount how the scientific community and the pharmaceutical industry learned from the catastrophic consequences of the appearance of new, more stable, and unsuspected crystal forms. The relevant aspects of hydrates, the most common pharmaceutical solid solvates, and of co-crystals, the association of two or more solid components in the same crystalline materials, will also be discussed. Examples will be provided of how to tackle multiple crystal forms with screening protocols and theoretical approaches, and ultimately how to turn into discovery and innovation the purposed preparation of new crystalline forms of an API. Full article
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12 pages, 1231 KiB  
Review
Antagonizing RARγ Drives Necroptosis of Cancer Stem Cells
by Geoffrey Brown
Int. J. Mol. Sci. 2022, 23(9), 4814; https://doi.org/10.3390/ijms23094814 - 27 Apr 2022
Cited by 5 | Viewed by 2579
Abstract
There is a need for agents that eliminate cancer stem cells, which sustain cancer and are also largely responsible for disease relapse and metastasis. Conventional chemotherapeutics and radiotherapy are often highly effective against the bulk of cancer cells, which are proliferating, but spare [...] Read more.
There is a need for agents that eliminate cancer stem cells, which sustain cancer and are also largely responsible for disease relapse and metastasis. Conventional chemotherapeutics and radiotherapy are often highly effective against the bulk of cancer cells, which are proliferating, but spare cancer stem cells. Therapeutics that target cancer stem cells may also provide a bona fide cure for cancer. There are two rationales for targeting the retinoic acid receptor (RAR)γ. First, RARγ is expressed selectively within primitive cells. Second, RARγ is a putative oncogene for a number of human cancers, including cases of acute myeloid leukemia, cholangiocarcinoma, and colorectal, renal and hepatocellular carcinomas. Prostate cancer cells depend on active RARγ for their survival. Antagonizing all RARs caused necroptosis of prostate and breast cancer stem cell-like cells, and the cancer stem cells that gave rise to neurospheres from pediatric patients’ primitive neuroectodermal tumors and an astrocytoma. As tested for prostate cancer, antagonizing RARγ was sufficient to drive necroptosis. Achieving cancer-selectively is a longstanding paradigm for developing new treatments. The normal prostate epithelium was less sensitive to the RARγ antagonist and pan-RAR antagonist than prostate cancer cells, and fibroblasts and blood mononuclear cells were insensitive. The RARγ antagonist and pan-RAR antagonist are promising new cancer therapeutics. Full article
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