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New Therapeutic Tools against MDR Tumors: Discovery, Synthesis and Evaluation of Bioactive Compounds

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: 31 July 2024 | Viewed by 9586

Special Issue Editors


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Guest Editor
Department of Chemistry, University of Milan, I-20122 Milan, Italy
Interests: anticancer and anti-neurodegenerative agents; self-assembled nanoparticles; liposomal nanovectors; imaging-friendly liposomes

Special Issue Information

Dear Colleagues,

Multidrug resistance (MDR) is one of the major obstacles to clinical treatment, resulting from different defensive mechanisms in cancer. To circumvent MDR many reversal agents have been developed, from a broad collaboration between synthetic/ medicinal chemists and biologists. At present, a plethora of synthetic strategies helps researchers in building molecular libraries, often having templates directly inspired by nature. As a consequence, the development of new methods that can be applied in preparing new and powerful bioactive compounds is a fundamental need for the treatment of MDR tumors.

In this Special Issue, we wish to focus on the most recent research efforts, toward the discovery of lead compounds and the development of drug candidates for successful therapies against MDR tumors. Special attention will be given to interdisciplinary studies on novel therapeutic agents targeting specific receptors, enzymes, or cellular pathways related to MDR.

Original research articles, reviews, and focus papers will be welcome, with the aim of collecting the most recent insights and results on new and straightforward synthetic approaches to bioactive organic compounds, the preparation of molecular templates for combinatorial chemistry, as well as the application of computational methods for the rational design and synthesis of novel lead drug candidates, focusing on fighting MDR tumors.

Prof. Dr. Constantinos Athanassopoulos
Dr. Antonia Antoniou
Guest Editors

Manuscript Submission Information

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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. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). 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

  • cancer chemotherapy
  • multi-drug resistance (MDR)
  • design and synthesis of MDR reversing agents
  • structure-activity relationship studies
  • MDR active targeting
  • hybrids and conjugates
  • drug repurposing
  • modulators/ inhibitors of MDR transporters

Published Papers (5 papers)

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Research

20 pages, 5343 KiB  
Article
Novel Pyrimidine Derivatives as Antioxidant and Anticancer Agents: Design, Synthesis and Molecular Modeling Studies
by Malama Myriagkou, Evangelia Papakonstantinou, Georgia-Eirini Deligiannidou, Alexandros Patsilinakos, Christos Kontogiorgis and Eleni Pontiki
Molecules 2023, 28(9), 3913; https://doi.org/10.3390/molecules28093913 - 5 May 2023
Cited by 8 | Viewed by 2141
Abstract
The heterocyclic ring system of pyrido [2,3-d]pyrimidines is a privileged scaffold in medicinal chemistry, possessing several biological activities. The synthesis of the pyrimidine derivatives was performed via the condensation of a suitable α,β-unsaturated ketone with 4-amino-6-hydroxy-2-mercaptopyrimidine monohydrate in glacial acetic [...] Read more.
The heterocyclic ring system of pyrido [2,3-d]pyrimidines is a privileged scaffold in medicinal chemistry, possessing several biological activities. The synthesis of the pyrimidine derivatives was performed via the condensation of a suitable α,β-unsaturated ketone with 4-amino-6-hydroxy-2-mercaptopyrimidine monohydrate in glacial acetic acid. Chalcones were synthesized, as starting materials, via the Claisen–Schmidt condensation of an appropriately substituted ketone and an appropriately substituted aldehyde in the presence of aqueous KOH 40% w/v in ethanol. All the synthesized compounds were characterized using IR, 1H-NMR, 13C-NMR, LC-MS and elemental analysis. The synthesized compounds were evaluated for their antioxidant (DPPH assay), anti-lipid peroxidation (AAPH), anti-LOX activities and ability to interact with glutathione. The compounds do not interact significantly with DPPH but strongly inhibit lipid peroxidation. Pyrimidine derivatives 2a (IC50 = 42 μΜ), 2f (IC50 = 47.5 μΜ) and chalcone 1g (IC50 = 17 μM) were the most potent lipoxygenase inhibitors. All the tested compounds were found to interact with glutathione, apart from 1h. Cell viability and cytotoxicity assays were performed with the HaCaT and A549 cell lines, respectively. In the MTT assay towards the HaCaT cell line, none of the compounds presented viability at 100 μM. On the contrary, in the MTT assay towards the A549 cell line, the tested compounds showed strong cytotoxicity at 100 μM, with derivative 2d presenting the strongest cytotoxic effects at the concentration of 50 μΜ. Full article
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14 pages, 2633 KiB  
Article
Alvespimycin Inhibits Heat Shock Protein 90 and Overcomes Imatinib Resistance in Chronic Myeloid Leukemia Cell Lines
by Raquel Alves, Diogo Santos, Joana Jorge, Ana Cristina Gonçalves, Steve Catarino, Henrique Girão, Joana Barbosa Melo and Ana Bela Sarmento-Ribeiro
Molecules 2023, 28(3), 1210; https://doi.org/10.3390/molecules28031210 - 26 Jan 2023
Cited by 2 | Viewed by 2118
Abstract
Heat shock protein 90 (HSP90) facilitates folding and stability and prevents the degradation of multiple client proteins. One of these HSP90 clients is BCR-ABL, the oncoprotein characteristic of chronic myeloid leukemia (CML) and the target of tyrosine kinase inhibitors, such as imatinib. Alvespimycin [...] Read more.
Heat shock protein 90 (HSP90) facilitates folding and stability and prevents the degradation of multiple client proteins. One of these HSP90 clients is BCR-ABL, the oncoprotein characteristic of chronic myeloid leukemia (CML) and the target of tyrosine kinase inhibitors, such as imatinib. Alvespimycin is an HSP90 inhibitor with better pharmacokinetic properties and fewer side effects than other similar drugs, but its role in overcoming imatinib resistance is not yet clarified. This work studied the therapeutic potential of alvespimycin in imatinib-sensitive (K562) and imatinib-resistant (K562-RC and K562-RD) CML cell lines. Metabolic activity was determined by the resazurin assay. Cell death, caspase activity, mitochondrial membrane potential, and cell cycle were evaluated by means of flow cytometry. Cell death was also analyzed by optical microscopy. HSPs expression levels were assessed by western blotting. Alvespimycin reduced metabolic activity in a time-, dose-, and cell line-dependent manner. Resistant cells were more sensitive to alvespimycin with an IC50 of 31 nM for K562-RC and 44 nM for K562-RD, compared to 50 nM for K562. This drug induced apoptosis via the mitochondrial pathway. In K562 cells, alvespimycin induced cell cycle arrest in G0/G1. As a marker of HSP90 inhibition, a significant increase in HSP70 expression was observed. Our results suggest that alvespimycin might be a new therapeutic approach to CML treatment, even in cases of resistance to imatinib. Full article
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14 pages, 2404 KiB  
Article
Development of Polymersomes Co-Delivering Doxorubicin and Melittin to Overcome Multidrug Resistance
by Eunkyung Han, Doyeon Kim, Youngheun Cho, Seonock Lee, Jungho Kim and Hyuncheol Kim
Molecules 2023, 28(3), 1087; https://doi.org/10.3390/molecules28031087 - 21 Jan 2023
Cited by 8 | Viewed by 1713
Abstract
Multidrug resistance (MDR) is one of the major barriers in chemotherapy. It is often related to the overexpression of efflux receptors such as P-glycoprotein (P-gp). Overexpressed efflux receptors inhibit chemotherapeutic efficacy by pumping out intracellularly delivered anticancer drugs. In P-gp-mediated MDR-related pathways, PI3K/Akt [...] Read more.
Multidrug resistance (MDR) is one of the major barriers in chemotherapy. It is often related to the overexpression of efflux receptors such as P-glycoprotein (P-gp). Overexpressed efflux receptors inhibit chemotherapeutic efficacy by pumping out intracellularly delivered anticancer drugs. In P-gp-mediated MDR-related pathways, PI3K/Akt and NF-kB pathways are commonly activated signaling pathways, but these pathways are downregulated by melittin, a main component of bee venom. In this study, a polymersome based on a poly (lactic acid) (PLA)-hyaluronic acid (HA) (20k-10k) di-block copolymer and encapsulating melittin and doxorubicin was developed to overcome anticancer resistance and enhance chemotherapeutic efficacy. Through the simultaneous delivery of doxorubicin and melittin, PI3K/Akt and NF-κB pathways could be effectively inhibited, thereby downregulating P-gp and successfully enhancing chemotherapeutic efficacy. In conclusion, a polymersome carrying an anticancer drug and melittin could overcome MDR by regulating P-gp overexpression pathways. Full article
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13 pages, 2647 KiB  
Article
Highly Efficient and Mild Gold (I) Catalyzed Synthesis of 3,8-Diarylidene-2,7-dioxaspiro[4.4]nonane-1,6-diones
by Antonia Iazzetti, Dario Allevi, Andrea Calcaterra, Giancarlo Fabrizi, Antonella Goggiamani, Giulia Mazzoccanti, Alessio Sferrazza, Rosanna Verdiglione and Valeria Vergine
Molecules 2023, 28(1), 300; https://doi.org/10.3390/molecules28010300 - 30 Dec 2022
Cited by 1 | Viewed by 1278
Abstract
The gold-catalyzed cyclization of 2,2-bis(3-arylprop-2-yn1-yl)malonic acid has been proposed as an efficient approach to substituted 3,8-dibenzyl-2,7-dioxaspiro[4.4]nonane-1,6-diones. The reaction proceeds smoothly in mild reaction conditions to give the desired products in quantitative yields in the presence of variously substituted starting materials. In addition, the [...] Read more.
The gold-catalyzed cyclization of 2,2-bis(3-arylprop-2-yn1-yl)malonic acid has been proposed as an efficient approach to substituted 3,8-dibenzyl-2,7-dioxaspiro[4.4]nonane-1,6-diones. The reaction proceeds smoothly in mild reaction conditions to give the desired products in quantitative yields in the presence of variously substituted starting materials. In addition, the synthesis of γ-arylidene spirobislactone bearing different substituents on the two aromatic rings has been achieved. This kind of compound could be of great interest in pharmaceutical science given the widespread presence of this scaffold in bioactive natural and synthetic products. Full article
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12 pages, 3145 KiB  
Article
Carnosine Potentiates Doxorubicin-Induced Cytotoxicity in Resistant NCI/ADR-RES Cells by Inhibiting P-Glycoprotein—In Silico and In Vitro Evidence
by Mohamed A. Morsy, Mahmoud Kandeel, Ahmed R. N. Ibrahim, Seham A. Abdel-Gaber, Shery Jacob, Katharigatta N. Venugopala, Pottathil Shinu and Mahmoud El-Daly
Molecules 2022, 27(21), 7383; https://doi.org/10.3390/molecules27217383 - 30 Oct 2022
Viewed by 1403
Abstract
The activity of the P-glycoprotein (P-gp) transporter encoded by the ABCB1 gene confers resistance to anticancer drugs and contributes to cancer-related mortality and morbidity. Recent studies revealed the cytotoxic effects of the endogenous dipeptide carnosine. The current study aimed to investigate the role [...] Read more.
The activity of the P-glycoprotein (P-gp) transporter encoded by the ABCB1 gene confers resistance to anticancer drugs and contributes to cancer-related mortality and morbidity. Recent studies revealed the cytotoxic effects of the endogenous dipeptide carnosine. The current study aimed to investigate the role of carnosine as a potential inhibitor of P-gp activity. We used molecular docking and molecular dynamic simulations to study the possible binding and stability of carnosine-P-gp interactions compared with verapamil. In vitro assays using doxorubicin-resistant NCI/ADR-RES cells were established to test the effects of carnosine (10–300 µM) on P-gp activity by the rhodamine-123 efflux assay and its effect on cell viability and doxorubicin-induced cytotoxicity. Verapamil (10 µM) was used as a positive control. The results showed that carnosine binding depends mainly on hydrogen bonding with GLU875, GLN946, and ALA871, with a higher average Hbond than verapamil. Carnosine showed significant but weaker than verapamil-induced rhodamine-123 accumulation. Carnosine and verapamil similarly inhibited cell viability. However, verapamil showed a more significant potentiating effect on doxorubicin-induced cytotoxicity than a weaker effect of carnosine at 300 µM. These results suggest that carnosine inhibits P-gp activity and potentiates doxorubicin-induced cytotoxicity at higher concentrations. Carnosine might be a helpful lead compound in the fight against multidrug-resistant cancers. Full article
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