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18 pages, 3112 KiB

Open AccessFeature PaperArticle

Natural-like Chalcones with Antitumor Activity on Human MG63 Osteosarcoma Cells

by Martina Rossi, Concettina Cappadone, Giovanna Picone, Alessandra Bisi, Giovanna Farruggia, Federica Belluti, Paolo Blasi, Silvia Gobbi and Emil Malucelli

Molecules 2022, 27(12), 3751; https://doi.org/10.3390/molecules27123751 - 11 Jun 2022

Cited by 2 | Viewed by 1735

Abstract

Osteosarcoma (OS) is a malignant disease characterized by poor prognosis due to a high incidence of metastasis and chemoresistance. Recently, Licochalcone A (Lic-A) has been reported as a promising agent against OS. Starting from chalcones selected from a wide in-house library, a new [...] Read more.

Osteosarcoma (OS) is a malignant disease characterized by poor prognosis due to a high incidence of metastasis and chemoresistance. Recently, Licochalcone A (Lic-A) has been reported as a promising agent against OS. Starting from chalcones selected from a wide in-house library, a new series was designed and synthetized. The antitumor activity of the compounds was tested on the MG63 OS cell line through the innovative Quantitative Phase Imaging technique and MTT assay. To further investigate the biological profile of active derivatives, cell cycle progression and apoptosis induction were evaluated. An earlier and more consistent arrest in the G2-M phase with respect to Lic-A was observed. Moreover, apoptosis was assessed by Annexin V staining as well as by the detection of typical morphological features of apoptotic cells. Among the selected compounds, 1e, 1q, and 1r proved to be the most promising antitumor molecules. This study pointed out that an integrated methodological approach may constitute a valuable platform for the rapid screening of large series of compounds. Full article

(This article belongs to the Special Issue Featured Papers in Medicinal Chemistry)

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16 pages, 3389 KiB

Open AccessEditor’s ChoiceArticle

Characterization of CM-398, a Novel Selective Sigma-2 Receptor Ligand, as a Potential Therapeutic for Neuropathic Pain

by Lisa L. Wilson, Amy R. Alleyne, Shainnel O. Eans, Thomas J. Cirino, Heather M. Stacy, Marco Mottinelli, Sebastiano Intagliata, Christopher R. McCurdy and Jay P. McLaughlin

Molecules 2022, 27(11), 3617; https://doi.org/10.3390/molecules27113617 - 04 Jun 2022

Cited by 11 | Viewed by 2348

Abstract

Sigma receptors modulate nociception, offering a potential therapeutic target to treat pain, but relatively little is known regarding the role of sigma-2 receptors (S2R) in nociception. The purpose of this study was to investigate the in vivo analgesic and anti-allodynic activity and liabilities [...] Read more.

Sigma receptors modulate nociception, offering a potential therapeutic target to treat pain, but relatively little is known regarding the role of sigma-2 receptors (S2R) in nociception. The purpose of this study was to investigate the in vivo analgesic and anti-allodynic activity and liabilities of a novel S2R selective ligand, 1-[4-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)butyl]-3-methyl-1,3-dihydro-1,3-benzimidazol-2-one (CM-398). The inhibition of thermal, induced chemical, or inflammatory pain as well as the allodynia resulting from chronic nerve constriction injury (CCI) model of neuropathic pain were assessed in male mice. CM-398 dose-dependently (10–45 mg/kg i.p.) reduced mechanical allodynia in the CCI neuropathic pain model, equivalent at the higher dose to the effect of the control analgesic gabapentin (50 mg/kg i.p.). Likewise, pretreatment (i.p.) with CM-398 dose-dependently produced antinociception in the acetic acid writhing test (ED₅₀ (and 95% C.I.) = 14.7 (10.6–20) mg/kg, i.p.) and the formalin assay (ED₅₀ (and 95% C.I.) = 0.86 (0.44–1.81) mg/kg, i.p.) but was without effect in the 55 °C warm-water tail-withdrawal assay. A high dose of CM-398 (45 mg/kg, i.p.) exhibited modest locomotor impairment in a rotarod assay and conditioned place aversion, potentially complicating the interpretation of nociceptive testing. However, in an operant pain model resistant to these confounds, mice experiencing CCI and treated with CM-398 demonstrated robust conditioned place preference. Overall, these results demonstrate the S2R selective antagonist CM-398 produces antinociception and anti-allodynia with fewer liabilities than established therapeutics, adding to emerging data suggesting possible mediation of nociception by S2R, and the development of S2R ligands as potential treatments for chronic pain. Full article

(This article belongs to the Special Issue Featured Papers in Medicinal Chemistry)

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13 pages, 3336 KiB

Open AccessFeature PaperArticle

Antiviral Activity of a Cyclic Pro-Pro-β³-HoPhe-Phe Tetrapeptide against HSV-1 and HAdV-5

by Ewa Zaczyńska, Krzysztof Kaczmarek, Janusz Zabrocki, Jolanta Artym and Michał Zimecki

Molecules 2022, 27(11), 3552; https://doi.org/10.3390/molecules27113552 - 31 May 2022

Cited by 1 | Viewed by 1556

Abstract

The core of Cyclolinopeptide A (CLA, cyclo(LIILVPPFF)), responsible for its high immunosuppressive activity, contains a Pro-Pro-Phe-Phe sequence. A newly synthesized cyclic tetrapeptide, cyclo(Pro-Pro-β³-HoPhe-Phe) (denoted as 4B8M) bearing the active sequence of CLA, was recently shown to exhibit a wide array [...] Read more.

The core of Cyclolinopeptide A (CLA, cyclo(LIILVPPFF)), responsible for its high immunosuppressive activity, contains a Pro-Pro-Phe-Phe sequence. A newly synthesized cyclic tetrapeptide, cyclo(Pro-Pro-β³-HoPhe-Phe) (denoted as 4B8M) bearing the active sequence of CLA, was recently shown to exhibit a wide array of anti-inflammatory properties in mouse models. In this investigation, we demonstrate that the peptide significantly inhibits the replication of human adenovirus C serotype 5 (HAdV-5) and Herpes simplex virus type-1 (HSV-1) in epithelial lung cell line A-549, applying Cidofovir and Acyclovir as reference drugs. Based on a previously established mechanism of its action, we propose that the peptide may inhibit virus replication by the induction of PGE2 acting via EP2/EP4 receptors in epithelial cells. In summary, we reveal a new, antiviral property of this anti-inflammatory peptide. Full article

(This article belongs to the Special Issue Featured Papers in Medicinal Chemistry)

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13 pages, 2950 KiB

Open AccessArticle

Targeted Drug Delivery Biopolymers Effectively Inhibit Breast Tumor Growth and Prevent Doxorubicin-Induced Cardiotoxicity

by Sonja Dragojevic, Jung Su Ryu, Michael E. Hall and Drazen Raucher

Molecules 2022, 27(11), 3371; https://doi.org/10.3390/molecules27113371 - 24 May 2022

Cited by 5 | Viewed by 2088

Abstract

The anticancer agent doxorubicin(dox) has been widely used in the treatment of a variety of hematological malignancies and solid tumors. Despite doxorubicin’s efficiency in killing tumor cells, severe damage to healthy tissues, along with cardiotoxicity, limits its clinical use. To overcome these adverse [...] Read more.

The anticancer agent doxorubicin(dox) has been widely used in the treatment of a variety of hematological malignancies and solid tumors. Despite doxorubicin’s efficiency in killing tumor cells, severe damage to healthy tissues, along with cardiotoxicity, limits its clinical use. To overcome these adverse side effects, improve patient safety, and enhance therapeutic efficacy, we have designed a thermally responsive biopolymer doxorubicin carrier that can be specifically targeted to tumor tissue by locally applying mild hyperthermia (41 °C). The developed drug vehicle is composed of the following: a cell penetrating peptide (SynB1) to promote tumor and cellular uptake; thermally responsive Elastin-like polypeptide (ELP); and the (6-maleimidocaproyl) hydrazone derivative of doxorubicin (DOXO-EMCH) containing a pH-sensitive hydrazone linker that releases doxorubicin in the acidic tumor environment. We used the in vivo imaging system, IVIS, to determine biodistribution of doxorubicin-delivered ELP in MDA-MB-231 xenografts in nude mice. Tumor bearing mice were treated with a single IV injection of 10 mg/kg doxorubicin equivalent dose with free doxorubicin, thermally responsive SynB1 ELP 1-DOXO, and a thermally nonresponsive control biopolymer, SynB1 ELP 2-DOXO. Following a 2 h treatment with hyperthermia, tumors showed a 2-fold higher uptake when treated with SynB1 ELP 1-DOXO compared to free doxorubicin. Accumulation of the thermally non-responsive control SynB1 ELP2 –DOXO was comparable to free doxorubicin, indicating that an increase in dox accumulation with ELP is due to aggregation in response to thermal targeting. Higher levels of SynB1 ELP1–DOXO and SynB1 ELP2 –DOXO with respect to free doxorubicin were observed in kidneys. Fluorescence intensity from hearts of animals treated with SynB1 ELP1–DOXO show a 5-fold decrease in accumulation of doxorubicin than the same dose of free doxorubicin. SynB1-ELP1-DOXO biopolymers demonstrated a 6-fold increase in tumor/heart ratio in comparison to free doxorubicin, indicating preferential accumulation of the drug in tumors. These results demonstrate that thermally targeted polymers are a promising therapy to enhance tumor targeting and uptake of anticancer drugs and to minimize free drug toxicity in healthy tissues, representing a great potential for clinical application. Full article

(This article belongs to the Special Issue Featured Papers in Medicinal Chemistry)

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16 pages, 2687 KiB

Open AccessArticle

A Calixarene Assembly Strategy of Combined Anti-Neuroinflammation and Drug Delivery Functions for Traumatic Brain Injury Therapy

by Chunxiao Wang, Yu-Xuan Chang, Xi Chen, Lihuan Bai, Heping Wang, Yu-Chen Pan, Chunqiu Zhang, Dong-Sheng Guo and Xue Xue

Molecules 2022, 27(9), 2967; https://doi.org/10.3390/molecules27092967 - 06 May 2022

Cited by 4 | Viewed by 2237

Abstract

Excessive inflammatory reaction aggravates brain injury and hinders the recovery of neural function in nervous system diseases. Microglia, as the major players of neuroinflammation, control the progress of the disease. There is an urgent need for effective non-invasive therapy to treat neuroinflammation mediated [...] Read more.

Excessive inflammatory reaction aggravates brain injury and hinders the recovery of neural function in nervous system diseases. Microglia, as the major players of neuroinflammation, control the progress of the disease. There is an urgent need for effective non-invasive therapy to treat neuroinflammation mediated by microglia. However, the lack of specificity of anti-inflammatory agents and insufficient drug dose penetrating into the brain lesion area are the main problems. Here, we evaluated a series of calixarenes and found that among them the self-assembling architecture of amphiphilic sulfonatocalix[8]arene (SC8A12C) had the most potent ability to suppress neuroinflammation in vitro and in vivo. Moreover, SC8A12C assemblies were internalized into microglia through macropinocytosis. In addition, after applying the SC8A12C assemblies to the exposed brain tissue, we observed that SC8A12C assemblies penetrated into the brain parenchyma and eliminated the inflammatory factor storm, thereby restoring neurobiological functions in a mouse model of traumatic brain injury. Full article

(This article belongs to the Special Issue Featured Papers in Medicinal Chemistry)

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14 pages, 2003 KiB

Open AccessArticle

Combined Treatment with PI3K Inhibitors BYL-719 and CAL-101 Is a Promising Antiproliferative Strategy in Human Rhabdomyosarcoma Cells

by Manuela Piazzi, Alberto Bavelloni, Vittoria Cenni, Sara Salucci, Anna Bartoletti Stella, Enrica Tomassini, Katia Scotlandi, William L. Blalock and Irene Faenza

Molecules 2022, 27(9), 2742; https://doi.org/10.3390/molecules27092742 - 24 Apr 2022

Cited by 3 | Viewed by 2141

Abstract

Rhabdomyosarcoma (RMS) is a highly malignant and metastatic pediatric cancer arising from skeletal muscle myogenic progenitors. Recent studies have shown an important role for AKT signaling in RMS progression. Aberrant activation of the PI3K/AKT axis is one of the most frequent events occurring [...] Read more.

Rhabdomyosarcoma (RMS) is a highly malignant and metastatic pediatric cancer arising from skeletal muscle myogenic progenitors. Recent studies have shown an important role for AKT signaling in RMS progression. Aberrant activation of the PI3K/AKT axis is one of the most frequent events occurring in human cancers and serves to disconnect the control of cell growth, survival, and metabolism from exogenous growth stimuli. In the study reported here, a panel of five compounds targeting the catalytic subunits of the four class I PI3K isoforms (p110α, BYL-719 inhibitor; p110β, TGX-221 inhibitor; p110γ, CZC24832; p110δ, CAL-101 inhibitor) and the dual p110α/p110δ, AZD8835 inhibitor, were tested on the RMS cell lines RD, A204, and SJCRH30. Cytotoxicity, cell cycle, apoptosis, and the activation of downstream targets were analyzed. Of the individual inhibitors, BYL-719 demonstrated the most anti-tumorgenic properties. BYL-719 treatment resulted in G1/G0 phase cell cycle arrest and apoptosis. When combined with CAL-101, BYL-719 decreased cell viability and induced apoptosis in a synergistic manner, equaling or surpassing results achieved with AZD8835. In conclusion, our findings indicate that BYL-719, either alone or in combination with the p110δ inhibitor, CAL-101, could represent an efficient treatment for human rhabdomyosarcoma presenting with aberrant upregulation of the PI3K signaling pathway. Full article

(This article belongs to the Special Issue Featured Papers in Medicinal Chemistry)

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12 pages, 4883 KiB

Open AccessArticle

Apis mellifera syriaca Venom: Evaluation of Its Anticoagulant Effect, Proteolytic Activity, and Cytotoxicity along with Its Two Main Compounds—MEL and PLA2—On HeLa Cancer Cells

by Carole Yaacoub, Rim Wehbe, Yahya Salma, Dany El-Obeid, Romeo El Bersaoui, Bruno Coutard and Ziad Fajloun

Molecules 2022, 27(5), 1653; https://doi.org/10.3390/molecules27051653 - 02 Mar 2022

Cited by 5 | Viewed by 2164

Abstract

Bee venom (BV) is one of the most remarkable natural products that has been a subject of studies since ancient times. Recent studies have shown that Apis mellifera syriaca venom possesses antibacterial as well as cytotoxic effects on cancer cell lines. The venom [...] Read more.

Bee venom (BV) is one of the most remarkable natural products that has been a subject of studies since ancient times. Recent studies have shown that Apis mellifera syriaca venom possesses antibacterial as well as cytotoxic effects on cancer cell lines. The venom contains a variety of bioactive molecules—mainly melittin (MEL) and phospholipase A2 (PLA2), as well as other compounds that are not well characterized. In this work, we continue the biological characterization of A. mellifera syriaca venom by testing its anticoagulant effect on human plasma using the prothrombin time (PT) test, as well as assessing its proteolytic activity. In addition, the cytotoxicity of the crude venom—and of its two main components, MEL and PLA2—was tested on HeLa cancer cell lines for the first time. The results obtained showed the capacity of A. mellifera syriaca venom to increase clotting time, thereby proving its anticoagulant effect. Moreover, the venom did not demonstrate a significant proteolytic activity unless administrated at concentrations ≥ 5 mg/mL. Finally, we showed that crude A. mellifera syriaca venom, along with MEL, exhibit a strong in vitro cytotoxic effect on HeLa cancer cell lines, even at low concentrations. In summary, our findings could serve as a basis for the development of new natural-based drug candidates in the therapeutic field. Full article

(This article belongs to the Special Issue Featured Papers in Medicinal Chemistry)

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27 pages, 3218 KiB

Open AccessArticle

Design, Synthesis, and In Vivo Evaluation of C1-Linked 4,5-Epoxymorphinan Haptens for Heroin Vaccines

by Agnieszka Sulima, Fuying Li, Jeffrey Brian Morgan, Phong Truong, Joshua F. G. Antoline, Therese Oertel, Rodell C. Barrientos, Oscar B. Torres, Zoltan Beck, Gregory H. Imler, Jeffrey R. Deschamps, Gary R. Matyas, Arthur E. Jacobson and Kenner C. Rice

Molecules 2022, 27(5), 1553; https://doi.org/10.3390/molecules27051553 - 25 Feb 2022

Cited by 3 | Viewed by 2578

Abstract

In our continuing effort to develop effective anti-heroin vaccines as potential medications for the treatment of opioid use disorder, herein we present the design and synthesis of the haptens: 1-AmidoMorHap (1), 1-AmidoMorHap epimer (2), 1 Amido-DihydroMorHap (3), [...] Read more.

In our continuing effort to develop effective anti-heroin vaccines as potential medications for the treatment of opioid use disorder, herein we present the design and synthesis of the haptens: 1-AmidoMorHap (1), 1-AmidoMorHap epimer (2), 1 Amido-DihydroMorHap (3), and 1 Amido-DihydroMorHap epimer (4). This is the first report of hydrolytically stable haptenic surrogates of heroin with the attachment site at the C1 position in the 4,5-epoxymorophinan nucleus. We prepared respective tetanus toxoid (TT)–hapten conjugates as heroin vaccine immunogens and evaluated their efficacy in vivo. We showed that all TT–hapten conjugates induced high antibody endpoint titers against the targets but only haptens 2 and 3 can induce protective effects against heroin in vivo. The epimeric analogues of these haptens, 1 and 4, failed to protect mice from the effects of heroin. We also showed that the in vivo efficacy is consistent with the results of the in vitro drug sequestration assay. Attachment of the linker at the C1 position induced antibodies with weak binding to the target drugs. Only TT-2 and TT-3 yielded antibodies that bound heroin and 6-acetyl morphine. None of the TT–hapten conjugates induced antibodies that cross-reacted with morphine, methadone, naloxone, or naltrexone, and only TT-3 interacted weakly with buprenorphine, and that subtle structural difference, especially at the C6 position, can vastly alter the specificity of the induced antibodies. This study is an important contribution in the field of vaccine development against small-molecule targets, providing proof that the chirality at C6 in these epoxymorphinans is a vital key to their effectiveness. Full article

(This article belongs to the Special Issue Featured Papers in Medicinal Chemistry)

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19 pages, 8596 KiB

Open AccessEditor’s ChoiceArticle

Identification of a Common Pharmacophore for Binding to MMP2 and RGD Integrin: Towards a Multitarget Approach to Inhibit Cancer Angiogenesis and Metastasis

by Lorenzo Baldini, Elena Lenci, Francesca Bianchini and Andrea Trabocchi

Molecules 2022, 27(4), 1249; https://doi.org/10.3390/molecules27041249 - 12 Feb 2022

Cited by 3 | Viewed by 2741

Abstract

During tumor angiogenesis different growth factors, cytokines and other molecules interact closely with each other to facilitate tumor cell invasion and metastatic diffusion. The most intensively studied as molecular targets in anti-angiogenic therapies are vascular endothelial growth factor (VEGF) and related receptors, integrin [...] Read more.

During tumor angiogenesis different growth factors, cytokines and other molecules interact closely with each other to facilitate tumor cell invasion and metastatic diffusion. The most intensively studied as molecular targets in anti-angiogenic therapies are vascular endothelial growth factor (VEGF) and related receptors, integrin receptors and matrix metalloproteinases (MMPs). Considering the poor efficacy of cancer angiogenesis monotherapies, we reasoned combining the inhibition of α_vβ₃ and MMP2 as a multitarget approach to deliver a synergistic blockade of tumor cell migration, invasion and metastasis. Accordingly, we identified a common pharmacophore in the binding cavity of MMP2 and α_vβ₃, demonstrating such approach with the design, synthesis and bioassays of tyrosine-derived peptidomimetics carrying the necessary functional groups to bind to key pharmacophoric elements of MMP2 and α_vβ₃ RGD integrin. Full article

(This article belongs to the Special Issue Featured Papers in Medicinal Chemistry)

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23 pages, 2510 KiB

Open AccessArticle

Facial Synthesis and Bioevaluation of Well-Defined OEGylated Betulinic Acid-Cyclodextrin Conjugates for Inhibition of Influenza Infection

by Yingying Chen, Xinchen Wang, Xinyuan Ma, Shuobin Liang, Qianqian Gao, Elena V. Tretyakova, Yongmin Zhang, Demin Zhou and Sulong Xiao

Molecules 2022, 27(4), 1163; https://doi.org/10.3390/molecules27041163 - 09 Feb 2022

Cited by 4 | Viewed by 2013

Abstract

Betulinic acid (BA) and its derivatives exhibit a variety of biological activities, especially their anti-HIV-1 activity, but generally have only modest inhibitory potency against influenza virus. The entry of influenza virus into host cells can be competitively inhibited by multivalent derivatives targeting hemagglutinin. [...] Read more.

Betulinic acid (BA) and its derivatives exhibit a variety of biological activities, especially their anti-HIV-1 activity, but generally have only modest inhibitory potency against influenza virus. The entry of influenza virus into host cells can be competitively inhibited by multivalent derivatives targeting hemagglutinin. In this study, a series of hexa-, hepta- and octavalent BA derivatives based on α-, β- and γ-cyclodextrin scaffolds, respectively, with varying lengths of flexible oligo(ethylene glycol) linkers was designed and synthesized using a microwave-assisted copper-catalyzed 1,3-dipolar cycloaddition reaction. The generated BA-cyclodextrin conjugates were tested for their in vitro activity against influenza A/WSN/33 (H1N1) virus and cytotoxicity. Among the tested compounds, 58, 80 and 82 showed slight cytotoxicity to Madin-Darby canine kidney cells with viabilities ranging from 64 to 68% at a high concentration of 100 μM. Four conjugates 51 and 69–71 showed significant inhibitory effects on influenza infection with half maximal inhibitory concentration values of 5.20, 9.82, 7.48 and 7.59 μM, respectively. The structure-activity relationships of multivalent BA-cyclodextrin conjugates were discussed, highlighting that multivalent BA derivatives may be potential antiviral agents against influenza infection. Full article

(This article belongs to the Special Issue Featured Papers in Medicinal Chemistry)

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14 pages, 12591 KiB

Open AccessArticle

Structural Refinement of 2,4-Thiazolidinedione Derivatives as New Anticancer Agents Able to Modulate the BAG3 Protein

by Dafne Ruggiero, Stefania Terracciano, Gianluigi Lauro, Michela Pecoraro, Silvia Franceschelli, Giuseppe Bifulco and Ines Bruno

Molecules 2022, 27(3), 665; https://doi.org/10.3390/molecules27030665 - 20 Jan 2022

Cited by 4 | Viewed by 2074

Abstract

The multidomain BAG3 protein is a member of the BAG (Bcl-2-associated athanogene) family of co-chaperones, involved in a wide range of protein–protein interactions crucial for many key cellular pathways, including autophagy, cytoskeletal dynamics, and apoptosis. Basal expression of BAG3 is elevated in several [...] Read more.

The multidomain BAG3 protein is a member of the BAG (Bcl-2-associated athanogene) family of co-chaperones, involved in a wide range of protein–protein interactions crucial for many key cellular pathways, including autophagy, cytoskeletal dynamics, and apoptosis. Basal expression of BAG3 is elevated in several tumor cell lines, where it promotes cell survival signaling and apoptosis resistance through the interaction with many protein partners. In addition, its role as a key player of several hallmarks of cancer, such as metastasis, angiogenesis, autophagy activation, and apoptosis inhibition, has been established. Due to its involvement in malignant transformation, BAG3 has emerged as a potential and effective biological target to control multiple cancer-related signaling pathways. Recently, by using a multidisciplinary approach we reported the first synthetic BAG3 modulator interfering with its BAG domain (BD), based on a 2,4-thiazolidinedione scaffold and endowed with significant anti-proliferative activity. Here, a further in silico-driven selection of a 2,4-thiazolidinedione-based compound was performed. Thanks to a straightforward synthesis, relevant binding affinity for the BAG3BD domain, and attractive biological activities, this novel generation of compounds is of great interest for the development of further BAG3 binders, as well as for the elucidation of the biological roles of this protein in tumors. Specifically, we found compound 6 as a new BAG3 modulator with a relevant antiproliferative effect on two different cancer cell lines (IC₅₀: A375 = 19.36 μM; HeLa = 18.67 μM). Full article

(This article belongs to the Special Issue Featured Papers in Medicinal Chemistry)

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15 pages, 1399 KiB

Open AccessCommunication

trans-Dichloro(triphenylarsino)(N,N-dialkylamino)platinum(II) Complexes: In Search of New Scaffolds to Circumvent Cisplatin Resistance

by Mariafrancesca Hyeraci, Laura Agnarelli, Luca Labella, Fabio Marchetti, Maria Luisa Di Paolo, Simona Samaritani and Lisa Dalla Via

Molecules 2022, 27(3), 644; https://doi.org/10.3390/molecules27030644 - 19 Jan 2022

Cited by 5 | Viewed by 1998

Abstract

The high incidence of the resistance phenomenon represents one of the most important limitations to the clinical usefulness of cisplatin as an anticancer drug. Notwithstanding the considerable efforts to solve this problem, the circumvention of cisplatin resistance remains a challenge in the treatment [...] Read more.

The high incidence of the resistance phenomenon represents one of the most important limitations to the clinical usefulness of cisplatin as an anticancer drug. Notwithstanding the considerable efforts to solve this problem, the circumvention of cisplatin resistance remains a challenge in the treatment of cancer. In this work, the synthesis and characterization of two trans-dichloro(triphenylarsino)(N,N-dialkylamino)platinum(II) complexes (1 and 2) were described. The trypan blue exclusion assay demonstrated an interesting antiproliferative effect for complex 1 in ovarian carcinoma-resistant cells, A2780cis. Quantitative analysis performed by ICP-AES demonstrated a scarce ability to platinate DNA, and a significant intracellular accumulation. The investigation of the mechanism of action highlighted the ability of 1 to inhibit the relaxation of supercoiled plasmid DNA mediated by topoisomerase II and to stabilize the cleavable complex. Cytofluorimetric analyses indicated the activation of the apoptotic pathway and the mitochondrial membrane depolarization. Therefore, topoisomerase II and mitochondria could represent possible intracellular targets. The biological properties of 1 and 2 were compared to those of the related trans-dichloro(triphenylphosphino)(N,N-dialkylamino)platinum(II) complexes in order to draw structure–activity relationships useful to face the resistance phenotype. Full article

(This article belongs to the Special Issue Featured Papers in Medicinal Chemistry)

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20 pages, 3478 KiB

Open AccessArticle

Total Synthesis of the Natural Chalcone Lophirone E, Synthetic Studies toward Benzofuran and Indole-Based Analogues, and Investigation of Anti-Leishmanial Activity

by Luca Pozzetti, Roberta Ibba, Sara Rossi, Orazio Taglialatela-Scafati, Donatella Taramelli, Nicoletta Basilico, Sarah D’Alessandro, Silvia Parapini, Stefania Butini, Giuseppe Campiani and Sandra Gemma

Molecules 2022, 27(2), 463; https://doi.org/10.3390/molecules27020463 - 11 Jan 2022

Cited by 13 | Viewed by 2717

Abstract

The potential of natural and synthetic chalcones as therapeutic leads against different pathological conditions has been investigated for several years, and this class of compounds emerged as a privileged chemotype due to its interesting anti-inflammatory, antimicrobial, antiviral, and anticancer properties. The objective of [...] Read more.

The potential of natural and synthetic chalcones as therapeutic leads against different pathological conditions has been investigated for several years, and this class of compounds emerged as a privileged chemotype due to its interesting anti-inflammatory, antimicrobial, antiviral, and anticancer properties. The objective of our study was to contribute to the investigation of this class of natural products as anti-leishmanial agents. We aimed at investigating the structure–activity relationships of the natural chalcone lophirone E, characterized by the presence of benzofuran B-ring, and analogues on anti-leishmania activity. Here we describe an effective synthetic strategy for the preparation of the natural chalcone lophirone E and its application to the synthesis of a small set of chalcones bearing different substitution patterns at both the A and heterocyclic B rings. The resulting compounds were investigated for their activity against Leishmania infantum promastigotes disclosing derivatives 1 and 28a,b as those endowed with the most interesting activities (IC₅₀ = 15.3, 27.2, 15.9 μM, respectively). The synthetic approaches here described and the early SAR investigations highlighted the potential of this class of compounds as antiparasitic hits, making this study worthy of further investigation. Full article

(This article belongs to the Special Issue Featured Papers in Medicinal Chemistry)

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16 pages, 2579 KiB

Open AccessArticle

Anti-Inflammatory Activity of a CB2 Selective Cannabinoid Receptor Agonist: Signaling and Cytokines Release in Blood Mononuclear Cells

by Antonella Capozzi, Daniela Caissutti, Vincenzo Mattei, Francesca Gado, Stefano Martellucci, Agostina Longo, Serena Recalchi, Valeria Manganelli, Gloria Riitano, Tina Garofalo, Maurizio Sorice, Clementina Manera and Roberta Misasi

Molecules 2022, 27(1), 64; https://doi.org/10.3390/molecules27010064 - 23 Dec 2021

Cited by 10 | Viewed by 3117

Abstract

The endocannabinoid system (ECS) exerts immunosuppressive effects, which are mostly mediated by cannabinoid receptor 2 (CBR2), whose expression on leukocytes is higher than CBR1, mainly localized in the brain. Targeted CBR2 activation could limit inflammation, avoiding CBR1-related psychoactive effects. Herein, we evaluated in [...] Read more.

The endocannabinoid system (ECS) exerts immunosuppressive effects, which are mostly mediated by cannabinoid receptor 2 (CBR2), whose expression on leukocytes is higher than CBR1, mainly localized in the brain. Targeted CBR2 activation could limit inflammation, avoiding CBR1-related psychoactive effects. Herein, we evaluated in vitro the biological activity of a novel, selective and high-affinity CBR2 agonist, called JT11, studying its potential CBR2-mediated anti-inflammatory effect. Trypan Blue and MTT assays were used to test the cytotoxic and anti-proliferative effect of JT11 in Jurkat cells. Its pro-apoptotic activity was investigated analyzing both cell cycle and poly PARP cleavage. Finally, we evaluated its impact on LPS-induced ERK1/2 and NF-kB-p65 activation, TNF-α, IL-1β, IL-6 and IL-8 release in peripheral blood mononuclear cells (PBMCs) from healthy donors. Selective CB2R antagonist SR144528 and CBR2 knockdown were used to further verify the selectivity of JT11. We confirmed selective CBR2 activation by JT11. JT11 regulated cell viability and proliferation through a CBR2-dependent mechanism in Jurkat cells, exhibiting a mild pro-apoptotic activity. Finally, it reduced LPS-induced ERK1/2 and NF-kB-p65 phosphorylation and pro-inflammatory cytokines release in human PBMCs, proving to possess in vitro anti-inflammatory properties. JT11 as CBR2 ligands could enhance ECS immunoregulatory activity and our results support the view that therapeutic strategies targeting CBR2 signaling could be promising for the treatment of chronic inflammatory diseases. Full article

(This article belongs to the Special Issue Featured Papers in Medicinal Chemistry)

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18 pages, 4908 KiB

Open AccessArticle

One-Pot Synthesis of Phosphinylphosphonate Derivatives and Their Anti-Tumor Evaluations

by Jade Dussart-Gautheret, Julia Deschamp, Thibaut Legigan, Maelle Monteil, Evelyne Migianu-Griffoni and Marc Lecouvey

Molecules 2021, 26(24), 7609; https://doi.org/10.3390/molecules26247609 - 15 Dec 2021

Cited by 3 | Viewed by 2649

Abstract

This paper reports on the synthesis of new hydroxymethylene-(phosphinyl)phosphonates (HMPPs). A methodology has been developed to propose an optimized one-pot procedure without any intermediate purifications. Various aliphatic and (hetero)aromatic HMPPs were synthesized in good to excellent yields (53–98%) and the influence of electron [...] Read more.

This paper reports on the synthesis of new hydroxymethylene-(phosphinyl)phosphonates (HMPPs). A methodology has been developed to propose an optimized one-pot procedure without any intermediate purifications. Various aliphatic and (hetero)aromatic HMPPs were synthesized in good to excellent yields (53–98%) and the influence of electron withdrawing/donating group substitution on aromatic substrates was studied. In addition, the one-pot synthesis of HMPP was monitored by ³¹P NMR spectroscopy, allowing effective control of the end of the reaction and identification of all phosphorylated intermediate species, which enabled us to propose a reaction mechanism. Optimized experimental conditions were applied to the preparation of biological relevant aminoalkyl-HMPPs. A preliminary study of the complexation to hydroxyapatite (bone matrix) was carried out in order to verify its lower affinity towards bone compared to bisphosphonate molecules. Moreover, in vitro anti-tumor activity study revealed encouraging antiproliferative activities on three human cancer cell lines (breast, pancreas and lung). Full article

(This article belongs to the Special Issue Featured Papers in Medicinal Chemistry)

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45 pages, 8578 KiB

Open AccessEditor’s ChoiceArticle

Substituted Aryl Benzylamines as Potent and Selective Inhibitors of 17β-Hydroxysteroid Dehydrogenase Type 3

by Nigel Vicker, Helen V. Bailey, Joanna M. Day, Mary F. Mahon, Andrew Smith, Helena J. Tutill, Atul Purohit and Barry V. L. Potter

Molecules 2021, 26(23), 7166; https://doi.org/10.3390/molecules26237166 - 26 Nov 2021

Cited by 1 | Viewed by 3283

Abstract

17β-Hydroxysteroid dehydrogenase type 3 (17β-HSD3) is expressed at high levels in testes and seminal vesicles; it is also present in prostate tissue and involved in gonadal and non-gonadal testosterone biosynthesis. The enzyme is membrane-bound, and a crystal structure is not yet available. Selective [...] Read more.

17β-Hydroxysteroid dehydrogenase type 3 (17β-HSD3) is expressed at high levels in testes and seminal vesicles; it is also present in prostate tissue and involved in gonadal and non-gonadal testosterone biosynthesis. The enzyme is membrane-bound, and a crystal structure is not yet available. Selective aryl benzylamine-based inhibitors were designed and synthesised as potential agents for prostate cancer therapeutics through structure-based design, using a previously built homology model with docking studies. Potent, selective, low nanomolar IC₅₀ 17β-HSD3 inhibitors were discovered using N-(2-([2-(4-chlorophenoxy)phenylamino]methyl)phenyl)acetamide (1). The most potent compounds have IC₅₀ values of approximately 75 nM. Compound 29, N-[2-(1-Acetylpiperidin-4-ylamino)benzyl]-N-[2-(4-chlorophenoxy)phenyl]acetamide, has an IC₅₀ of 76 nM, while compound 30, N-(2-(1-[2-(4-chlorophenoxy)-phenylamino]ethyl)phenyl)acetamide, has an IC₅₀ of 74 nM. Racemic C-allyl derivative 26 (IC₅₀ of 520 nM) was easily formed from 1 in good yield and, to determine binding directionality, its enantiomers were separated by chiral chromatography. Absolute configuration was determined using single crystal X-ray crystallography. Only the S-(+)-enantiomer (32) was active with an IC₅₀ of 370 nM. Binding directionality was predictable through our in silico docking studies, giving confidence to our model. Importantly, all novel inhibitors are selective over the type 2 isozyme of 17β-HSD2 and show <20% inhibition when tested at 10 µM. Lead compounds from this series are worthy of further optimisation and development as inhibitors of testosterone production by 17β-HSD3 and as inhibitors of prostate cancer cell growth. Full article

(This article belongs to the Special Issue Featured Papers in Medicinal Chemistry)

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25 pages, 2329 KiB

Open AccessFeature PaperArticle

Small Molecule CD38 Inhibitors: Synthesis of 8-Amino-N1-inosine 5′-monophosphate, Analogues and Early Structure-Activity Relationship

by Joanna M. Watt, Richard Graeff and Barry V. L. Potter

Molecules 2021, 26(23), 7165; https://doi.org/10.3390/molecules26237165 - 26 Nov 2021

Viewed by 2415

Abstract

Although a monoclonal antibody targeting the multifunctional ectoenzyme CD38 is an FDA-approved drug, few small molecule inhibitors exist for this enzyme that catalyzes inter alia the formation and metabolism of the N1-ribosylated, Ca²⁺-mobilizing, second messenger cyclic adenosine 5′-diphosphoribose (cADPR). N [...] Read more.

Although a monoclonal antibody targeting the multifunctional ectoenzyme CD38 is an FDA-approved drug, few small molecule inhibitors exist for this enzyme that catalyzes inter alia the formation and metabolism of the N1-ribosylated, Ca²⁺-mobilizing, second messenger cyclic adenosine 5′-diphosphoribose (cADPR). N1-Inosine 5′-monophosphate (N1-IMP) is a fragment directly related to cADPR. 8-Substituted-N1-IMP derivatives, prepared by degradation of cyclic parent compounds, inhibit CD38-mediated cADPR hydrolysis more efficiently than related cyclic analogues, making them attractive for inhibitor development. We report a total synthesis of the N1-IMP scaffold from adenine and a small initial compound series that facilitated early delineation of structure-activity parameters, with analogues evaluated for inhibition of CD38-mediated hydrolysis of cADPR. The 5′-phosphate group proved essential for useful activity, but substitution of this group by a sulfonamide bioisostere was not fruitful. 8-NH₂-N1-IMP is the most potent inhibitor (IC₅₀ = 7.6 μM) and importantly HPLC studies showed this ligand to be cleaved at high CD38 concentrations, confirming its access to the CD38 catalytic machinery and demonstrating the potential of our fragment approach. Full article

(This article belongs to the Special Issue Featured Papers in Medicinal Chemistry)

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15 pages, 4161 KiB

Open AccessFeature PaperArticle

Response of Osteosarcoma Cell Metabolism to Platinum and Palladium Chelates as Potential New Drugs

by Ana S. Martins, Ana L. M. Batista de Carvalho, Maria P. M. Marques and Ana M. Gil

Molecules 2021, 26(16), 4805; https://doi.org/10.3390/molecules26164805 - 08 Aug 2021

Cited by 7 | Viewed by 2227

Abstract

This paper reports the first metabolomics study of the impact of new chelates Pt₂Spm and Pd₂Spm (Spm = Spermine) on human osteosarcoma cellular metabolism, compared to the conventional platinum drugs cisplatin and oxaliplatin, in order to investigate the effects [...] Read more.

This paper reports the first metabolomics study of the impact of new chelates Pt₂Spm and Pd₂Spm (Spm = Spermine) on human osteosarcoma cellular metabolism, compared to the conventional platinum drugs cisplatin and oxaliplatin, in order to investigate the effects of different metal centers and ligands. Nuclear Magnetic Resonance metabolomics was used to identify meaningful metabolite variations in polar cell extracts collected during exposure to each of the four chelates. Cisplatin and oxaliplatin induced similar metabolic fingerprints of changing metabolite levels (affecting many amino acids, organic acids, nucleotides, choline compounds and other compounds), thus suggesting similar mechanisms of action. For these platinum drugs, a consistent uptake of amino acids is noted, along with an increase in nucleotides and derivatives, namely involved in glycosylation pathways. The Spm chelates elicit a markedly distinct metabolic signature, where inverse features are observed particularly for amino acids and nucleotides. Furthermore, Pd₂Spm prompts a weaker response from osteosarcoma cells as compared to its platinum analogue, which is interesting as the palladium chelate exhibits higher cytotoxicity. Putative suggestions are discussed as to the affected cellular pathways and the origins of the distinct responses. This work demonstrates the value of untargeted metabolomics in measuring the response of cancer cells to either conventional or potential new drugs, seeking further understanding (or possible markers) of drug performance at the molecular level. Full article

(This article belongs to the Special Issue Featured Papers in Medicinal Chemistry)

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15 pages, 7960 KiB

Open AccessArticle

Comparative Study of a Series of ^99mTc(CO)₃ Mannosylated Dextran Derivatives for Sentinel Lymph Node Detection

by Afroditi Papasavva, Antonio Shegani, Christos Kiritsis, Ioanna Roupa, Myrto Ischyropoulou, Konstantina Makrypidi, Irineos Pilatis, George Loudos, Maria Pelecanou, Minas Papadopoulos and Ioannis Pirmettis

Molecules 2021, 26(16), 4797; https://doi.org/10.3390/molecules26164797 - 07 Aug 2021

Cited by 2 | Viewed by 2484

Abstract

Sentinel lymph node detection (SLND) is rapidly entering common practice in the management of patients with tumors. The introduction of mannose molecules to ^99mTc-labeled dextrans, so far, showed that the sentinel node could trap these agents due to their recognition by the [...] Read more.

Sentinel lymph node detection (SLND) is rapidly entering common practice in the management of patients with tumors. The introduction of mannose molecules to ^99mTc-labeled dextrans, so far, showed that the sentinel node could trap these agents due to their recognition by the mannose receptors of lymph node macrophages. The current study aimed to synthesize, characterize, and biologically evaluate a series of mannosylated dextran derivatives labeled with ^99mTc for potential use in SLND. The compounds were designed to have a dextran with a molecular weight of 10–500 kDa as a backbone, S-derivatized cysteines, efficient SNO chelators, and mannose moieties for binding to mannose receptors. They were successfully synthesized, thoroughly characterized using NMR techniques, and labeled with the fac-[^99mTc(CO)₃]⁺ synthon. Labeling with high yields and radiochemical purities was achieved with all derivatives. In vivo biodistribution and imaging studies demonstrated high uptake in the first lymph node and low uptakes in the following node and confirmed the ability to visualize the SLN. Among the compounds studied, ^99mTc-D75CM demonstrated the most attractive biological features, and in combination with the high radiochemical yield and stability of the compound, its further evaluation as a new radiopharmaceutical for sentinel lymph node detection was justified. Full article

(This article belongs to the Special Issue Featured Papers in Medicinal Chemistry)

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22 pages, 20953 KiB

Open AccessArticle

Synthesis and Biological Assessment of 4,1-Benzothiazepines with Neuroprotective Activity on the Ca²⁺ Overload for the Treatment of Neurodegenerative Diseases and Stroke

by Lucía Viejo, Marcos Rubio-Alarcón, Raquel L. Arribas, Manuel Moreno-Castro, Raquel Pérez-Marín, María Braun-Cornejo, Martín Estrada-Valencia and Cristóbal de los Ríos

Molecules 2021, 26(15), 4473; https://doi.org/10.3390/molecules26154473 - 24 Jul 2021

Cited by 9 | Viewed by 2736

Abstract

In excitable cells, mitochondria play a key role in the regulation of the cytosolic Ca²⁺ levels. A dysregulation of the mitochondrial Ca²⁺ buffering machinery derives in serious pathologies, where neurodegenerative diseases highlight. Since the mitochondrial Na⁺/Ca²⁺ exchanger (NCLX) [...] Read more.

In excitable cells, mitochondria play a key role in the regulation of the cytosolic Ca²⁺ levels. A dysregulation of the mitochondrial Ca²⁺ buffering machinery derives in serious pathologies, where neurodegenerative diseases highlight. Since the mitochondrial Na⁺/Ca²⁺ exchanger (NCLX) is the principal efflux pathway of Ca²⁺ to the cytosol, drugs capable of blocking NCLX have been proposed to act as neuroprotectants in neuronal damage scenarios exacerbated by Ca²⁺ overload. In our search of optimized NCLX blockers with augmented drug-likeness, we herein describe the synthesis and pharmacological characterization of new benzothiazepines analogues to the first-in-class NCLX blocker CGP37157 and its further derivative ITH12575, synthesized by our research group. As a result, we found two new compounds with an increased neuroprotective activity, neuronal Ca²⁺ regulatory activity and improved drug-likeness and pharmacokinetic properties, such as clog p or brain permeability, measured by PAMPA experiments. Full article

(This article belongs to the Special Issue Featured Papers in Medicinal Chemistry)

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18 pages, 1984 KiB

Open AccessArticle

Pyrazoles and Pyrazolines as Anti-Inflammatory Agents

by Martha Mantzanidou, Eleni Pontiki and Dimitra Hadjipavlou-Litina

Molecules 2021, 26(11), 3439; https://doi.org/10.3390/molecules26113439 - 05 Jun 2021

Cited by 60 | Viewed by 3976

Abstract

The five-membered heterocyclic group of pyrazoles/pyrazolines plays important role in drug discovery. Pyrazoles and pyrazolines present a wide range of biological activities. The synthesis of the pyrazolines and pyrazole derivatives was accomplished via the condensation of the appropriate substituted aldehydes and acetophenones, suitable [...] Read more.

The five-membered heterocyclic group of pyrazoles/pyrazolines plays important role in drug discovery. Pyrazoles and pyrazolines present a wide range of biological activities. The synthesis of the pyrazolines and pyrazole derivatives was accomplished via the condensation of the appropriate substituted aldehydes and acetophenones, suitable chalcones and hydrazine hydrate in absolute ethanol in the presence of drops of glacial acetic acid. The compounds are obtained in good yields 68–99% and their structure was confirmed using IR, ¹H-NMR, ¹³C-NMR and elemental analysis. The novel derivatives were studied in vitro for their antioxidant, anti-lipid peroxidation (AAPH) activities and inhibitory activity of lipoxygenase. Both classes strongly inhibit lipid peroxidation. Compound 2g was the most potent lipoxygenase inhibitor (IC₅₀ = 80 µM). The inhibition of the carrageenin-induced paw edema (CPE) and nociception was also determined, with compounds 2d and 2e being the most potent. Compound 2e inhibited nociception higher than 2d. Pyrazoline 2d was found to be active in a preliminary test, for the investigation of anti-adjuvant-induced disease (AID) activity. Pyrazoline derivatives were found to be more potent than pyrazoles. Docking studies of the most potent LOX inhibitor 2g highlight hydrophobic interactions with VAL126, PHE143, VAL520 and LYS526 and a halogen bond between the chlorine atom and ARG182. Full article

(This article belongs to the Special Issue Featured Papers in Medicinal Chemistry)

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15 pages, 2794 KiB

Open AccessArticle

AdipoRon, an Orally Active, Synthetic Agonist of AdipoR1 and AdipoR2 Receptors Has Gastroprotective Effect in Experimentally Induced Gastric Ulcers in Mice

by Hubert Zatorski, Maciej Salaga, Marta Zielińska, Kinga Majchrzak, Agata Binienda, Radzisław Kordek, Ewa Małecka-Panas and Jakub Fichna

Molecules 2021, 26(10), 2946; https://doi.org/10.3390/molecules26102946 - 15 May 2021

Cited by 10 | Viewed by 2503

Abstract

Introduction: Adiponectin is a hormone secreted by adipocytes, which exhibits insulin-sensitizing and anti-inflammatory properties and acts through adiponectin receptors: AdipoR1 and AdipoR2. The aim of the study was to evaluate whether activation of adiponectin receptors AdipoR1 and AdipoR2 with an orally active agonist [...] Read more.

Introduction: Adiponectin is a hormone secreted by adipocytes, which exhibits insulin-sensitizing and anti-inflammatory properties and acts through adiponectin receptors: AdipoR1 and AdipoR2. The aim of the study was to evaluate whether activation of adiponectin receptors AdipoR1 and AdipoR2 with an orally active agonist AdipoRon has gastroprotective effect and to investigate the possible underlying mechanism. Methods: We used two well-established mouse models of gastric ulcer (GU) induced by oral administration of EtOH (80% solution in water) or diclofenac (30 mg/kg, p.o.). Gastroprotective effect of AdipoRon (dose 5 and 50 mg /kg p.o) was compared to omeprazole (20 mg/kg p.o.) or 5% DMSO solution (control). Clinical parameters of gastroprotection were assessed using macroscopic (gastric lesion area) and microscopic (evaluation of the gastric mucosa damage) scoring. To establish the molecular mechanism, we measured: myeloperoxidase (MPO), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) activities; glutathione (GSH) level; and IL-1β, adenosine monophosphate-activated protein kinase (AMPK), and phosphorylated AMPK expression in gastric tissue. Results: AdipoRon produced a gastroprotective effect in both GU mouse models as evidenced by significantly lower macroscopic and microscopic damage scores. AdipoRon exhibited anti-inflammatory effect by reduction in MPO activity and IL-1β expression in the gastric tissue. Moreover, AdipoRon induced antioxidative action, as demonstrated with higher GSH levels, and increased SOD and GPX activity. Conclusions: Activation of AdipoR1 and AdipoR2 using AdipoRon reduced gastric lesions and enhanced cell response to oxidative stress. Our data suggest that AdipoR1 and AdipoR2 activation may be an attractive therapeutic strategy to inhibit development of gastric ulcers. Full article

(This article belongs to the Special Issue Featured Papers in Medicinal Chemistry)

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Review

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15 pages, 2230 KiB

Open AccessReview

Pathophysiological Role and Medicinal Chemistry of A_2A Adenosine Receptor Antagonists in Alzheimer’s Disease

by Stefania Merighi, Pier Andrea Borea, Katia Varani, Fabrizio Vincenzi, Alessia Travagli, Manuela Nigro, Silvia Pasquini, R. Rama Suresh, Sung Won Kim, Nora D. Volkow, Kenneth A. Jacobson and Stefania Gessi

Molecules 2022, 27(9), 2680; https://doi.org/10.3390/molecules27092680 - 21 Apr 2022

Cited by 14 | Viewed by 3392

Abstract

The A_2A adenosine receptor is a protein belonging to a family of four GPCR adenosine receptors. It is involved in the regulation of several pathophysiological conditions in both the central nervous system and periphery. In the brain, its localization at pre- and [...] Read more.

The A_2A adenosine receptor is a protein belonging to a family of four GPCR adenosine receptors. It is involved in the regulation of several pathophysiological conditions in both the central nervous system and periphery. In the brain, its localization at pre- and postsynaptic level in striatum, cortex, hippocampus and its effects on glutamate release, microglia and astrocyte activation account for a crucial role in neurodegenerative diseases, including Alzheimer’s disease (AD). This ailment is considered the main form of dementia and is expected to exponentially increase in coming years. The pathological tracts of AD include amyloid peptide-β extracellular accumulation and tau hyperphosphorylation, causing neuronal cell death, cognitive deficit, and memory loss. Interestingly, in vitro and in vivo studies have demonstrated that A_2A adenosine receptor antagonists may counteract each of these clinical signs, representing an important new strategy to fight a disease for which unfortunately only symptomatic drugs are available. This review offers a brief overview of the biological effects mediated by A_2A adenosine receptors in AD animal and human studies and reports the state of the art of A_2A adenosine receptor antagonists currently in clinical trials. As an original approach, it focuses on the crucial role of pharmacokinetics and ability to pass the blood–brain barrier in the discovery of new agents for treating CNS disorders. Considering that A_2A receptor antagonist istradefylline is already commercially available for Parkinson’s disease treatment, if the proof of concept of these ligands in AD is confirmed and reinforced, it will be easier to offer a new hope for AD patients. Full article

(This article belongs to the Special Issue Featured Papers in Medicinal Chemistry)

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15 pages, 5681 KiB

Open AccessReview

Advances in the Development of SARS-CoV-2 Mpro Inhibitors

by Laura Agost-Beltrán, Sergio de la Hoz-Rodríguez, Lledó Bou-Iserte, Santiago Rodríguez, Adrián Fernández-de-la-Pradilla and Florenci V. González

Molecules 2022, 27(8), 2523; https://doi.org/10.3390/molecules27082523 - 14 Apr 2022

Cited by 28 | Viewed by 4185

Abstract

Since the outbreak of COVID-19, one of the strategies used to search for new drugs has been to find inhibitors of the main protease (Mpro) of the virus SARS-CoV-2. Initially, previously reported inhibitors of related proteases such as the main proteases of SARS-CoV [...] Read more.

Since the outbreak of COVID-19, one of the strategies used to search for new drugs has been to find inhibitors of the main protease (Mpro) of the virus SARS-CoV-2. Initially, previously reported inhibitors of related proteases such as the main proteases of SARS-CoV and MERS-CoV were tested. A huge effort was then carried out by the scientific community to design, synthesize and test new small molecules acting as inactivators of SARS-CoV-2 Mpro. From the chemical structure view, these compounds can be classified into two main groups: one corresponds to modified peptides displaying an adequate sequence for high affinity and a reactive warhead; and the second is a diverse group including chemical compounds that do not have a peptide framework. Although a drug including a SARS-CoV-2 main protease inhibitor has already been commercialized, denoting the importance of this field, more compounds have been demonstrated to be promising potent inhibitors as potential antiviral drugs. Full article

(This article belongs to the Special Issue Featured Papers in Medicinal Chemistry)

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31 pages, 8755 KiB

Open AccessReview

Recent Advances in the Chemistry and Therapeutic Evaluation of Naturally Occurring and Synthetic Withanolides

by Amandeep Singh, Asif Raza, Shantu Amin, Chendil Damodaran and Arun K. Sharma

Molecules 2022, 27(3), 886; https://doi.org/10.3390/molecules27030886 - 28 Jan 2022

Cited by 12 | Viewed by 3969

Abstract

Natural products are a major source of biologically active compounds that make promising lead molecules for developing efficacious drug-like molecules. Natural withanolides are found in many flora and fauna, including plants, algae, and corals, that traditionally have shown multiple health benefits and are [...] Read more.

Natural products are a major source of biologically active compounds that make promising lead molecules for developing efficacious drug-like molecules. Natural withanolides are found in many flora and fauna, including plants, algae, and corals, that traditionally have shown multiple health benefits and are known for their anti-cancer, anti-inflammatory, anti-bacterial, anti-leishmaniasis, and many other medicinal properties. Structures of these withanolides possess a few reactive sites that can be exploited to design and synthesize more potent and safe analogs. In this review, we discuss the literature evidence related to the medicinal implications, particularly anticancer properties of natural withanolides and their synthetic analogs, and provide perspectives on the translational potential of these promising compounds. Full article

(This article belongs to the Special Issue Featured Papers in Medicinal Chemistry)

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