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Special Issue "Hybrid Compounds, Multitarget Ligands, and Conjugate Derivatives as New Targeted Anticancer Agents"

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

Deadline for manuscript submissions: 31 December 2021.

Special Issue Editors

Prof. Dr. Loredana Salerno
E-Mail Website
Guest Editor
Department of Drug Sciences, University of Catania, V.le A. Doria 6, 95125 Catania, Italy
Interests: medicinal chemistry; drug design; enzyme inhibitors; heme oxygenase-1 inhibitors; nitric oxide inhibitors; heme oxygenase-1 inducers; antitumor drugs; imidazole; receptor ligands; hybrid compounds
Special Issues, Collections and Topics in MDPI journals
Dr. Sebastiano Intagliata
E-Mail Website
Guest Editor
Department of Drug Sciences, University of Catania, V.le A. Doria 6, 95125 Catania, Italy
Interests: medicinal chemistry; dual ligands, anticancer agents, sigma receptor ligands, HO-1 inhibitors, 5-HT7 receptor ligands

Special Issue Information

Dear Colleagues,

Cancer is a multigenic disease characterized by dysregulated signaling pathways, molecular alterations, and cells' abnormal functions, cellular modifications that make cancer a highly complex medical condition to treat. Moreover, the clinical efficacy of certain anticancer mono-therapies can be mitigated by the development of drug resistance during the treatment. For these reasons, frequently, the combination of drug therapies is needed to obtain additive or synergistic effects as well as to overcome drug resistance. To this extend, the simultaneous modulation of multiple targets by using one molecule acting as a multitarget ligand or hybrid compound may represent a valuable option to avoid general issues associated with the co-administration of two or more agents.

This Special Issue aims to collect original research papers, short communications, and review articles on last advances in the development of hybrid compounds, multitarget ligands, and conjugate derivatives as new targeted anticancer agents. Contributions may cover multidisciplinary aspects of the design, synthesis, and pharmacological evaluation of novel polypharmacological agents with potential therapeutic innovation.

Prof. Dr. Loredana Salerno
Dr. Sebastiano Intagliata
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 papers will be 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. 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 2000 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

  • Hybrid compounds
  • Multitarget Ligands
  • Conjugate derivatives
  • Polypharmacology
  • Anticancer agents
  • Anticancer therapy
  • Cancer
  • Drug development
  • Chemical synthesis
  • Pharmacological evaluation
  • Biological activity
  • Drug resistance

Published Papers (7 papers)

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Research

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Article
Tributyltin(IV) Butyrate: A Novel Epigenetic Modifier with ER Stress- and Apoptosis-Inducing Properties in Colon Cancer Cells
Molecules 2021, 26(16), 5010; https://doi.org/10.3390/molecules26165010 - 19 Aug 2021
Viewed by 564
Abstract
Organotin(IV) compounds are a class of non-platinum metallo-conjugates exhibiting antitumor activity. The effects of different organotin types has been related to several mechanisms, including their ability to modify acetylation protein status and to promote apoptosis. Here, we focus on triorganotin(IV) complexes of butyric [...] Read more.
Organotin(IV) compounds are a class of non-platinum metallo-conjugates exhibiting antitumor activity. The effects of different organotin types has been related to several mechanisms, including their ability to modify acetylation protein status and to promote apoptosis. Here, we focus on triorganotin(IV) complexes of butyric acid, a well-known HDAC inhibitor with antitumor properties. The conjugated compounds were synthesized and characterised by FTIR spectroscopy, multi-nuclear (1H, 13C and 119Sn) NMR, and mass spectrometry (ESI-MS). In the triorganotin(IV) complexes, an anionic monodentate butyrate ligand was observed, which coordinated the tin atom on a tetra-coordinated, monomeric environment similar to ester. FTIR and NMR findings confirm this structure both in solid state and solution. The antitumor efficacy of the triorganotin(IV) butyrates was tested in colon cancer cells and, among them, tributyltin(IV) butyrate (BT2) was selected as the most efficacious. BT2 induced G2/M cell cycle arrest, ER stress, and apoptotic cell death. These effects were obtained using low concentrations of BT2 up to 1 μM, whereas butyric acid alone was completely inefficacious, and the parent compound TBT was poorly effective at the same treatment conditions. To assess whether butyrate in the coordinated form maintains its epigenetic effects, histone acetylation was evaluated and a dramatic decrease in acetyl-H3 and -H4 histones was found. In contrast, butyrate alone stimulated histone acetylation at a higher concentration (5 mM). BT2 was also capable of preventing histone acetylation induced by SAHA, another potent HDAC inhibitor, thus suggesting that it may activate HDACs. These results support a potential use of BT2, a novel epigenetic modulator, in colon cancer treatment. Full article
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Communication
Combination of Heme Oxygenase-1 Inhibition and Sigma Receptor Modulation for Anticancer Activity
Molecules 2021, 26(13), 3860; https://doi.org/10.3390/molecules26133860 - 24 Jun 2021
Viewed by 521
Abstract
Cancer is a multifactorial disease that may be tackled by targeting different signaling pathways. Heme oxygenase-1 (HO-1) and sigma receptors (σRs) are both overexpressed in different human cancers, including prostate and brain, contributing to the cancer spreading. In the present study, we investigated [...] Read more.
Cancer is a multifactorial disease that may be tackled by targeting different signaling pathways. Heme oxygenase-1 (HO-1) and sigma receptors (σRs) are both overexpressed in different human cancers, including prostate and brain, contributing to the cancer spreading. In the present study, we investigated whether HO-1 inhibitors and σR ligands, as well a combination of the two, may influence DU145 human prostate and U87MG human glioblastoma cancer cells proliferation. In addition, we synthesized, characterized, and tested a small series of novel hybrid compounds (HO-1/σRs) 14 containing the chemical features needed for HO-1 inhibition and σR modulation. Herein, we report for the first time that targeting simultaneously HO-1 and σR proteins may be a good strategy to achieve increased antiproliferative activity against DU145 and U87MG cells, with respect to the mono administration of the parent compounds. The obtained outcomes provide an initial proof of concept useful to further optimize the structure of HO-1/σRs hybrids to develop novel potential anticancer agents. Full article
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Article
Selective Targeting of Breast Cancer by Tafuramycin A Using SMA-Nanoassemblies
Molecules 2021, 26(12), 3532; https://doi.org/10.3390/molecules26123532 - 09 Jun 2021
Viewed by 654
Abstract
Triple-negative breast cancer (TNBC) is a heterogeneous subtype of tumors that tests negative for estrogen receptors, progesterone receptors, and excess HER2 protein. The mainstay of treatment remains chemotherapy, but the therapeutic outcome remains inadequate. This paper investigates the potential of a duocarmycin derivative, [...] Read more.
Triple-negative breast cancer (TNBC) is a heterogeneous subtype of tumors that tests negative for estrogen receptors, progesterone receptors, and excess HER2 protein. The mainstay of treatment remains chemotherapy, but the therapeutic outcome remains inadequate. This paper investigates the potential of a duocarmycin derivative, tafuramycin A (TFA), as a new and more effective chemotherapy agent in TNBC treatment. To this extent, we optimized the chemical synthesis of TFA, and we encapsulated TFA in a micellar system to reduce side effects and increase tumor accumulation. In vitro and in vivo studies suggest that both TFA and SMA–TFA possess high anticancer effects in TNBC models. Finally, the encapsulation of TFA offered a preferential avenue to tumor accumulation by increasing its concentration at the tumor tissues by around four times in comparison with the free drug. Overall, the results provide a new potential strategy useful for TNBC treatment. Full article
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Article
Design, Synthesis, and Antitumor Activity of Olmutinib Derivatives Containing Acrylamide Moiety
Molecules 2021, 26(10), 3041; https://doi.org/10.3390/molecules26103041 - 20 May 2021
Cited by 2 | Viewed by 707
Abstract
Two series of olmutinib derivatives containing an acrylamide moiety were designed and synthesized, and their IC50 values against cancer cell lines (A549, H1975, NCI-H460, LO2, and MCF-7) were evaluated. Most of the compounds exhibited moderate cytotoxic activity against the five cancer cell [...] Read more.
Two series of olmutinib derivatives containing an acrylamide moiety were designed and synthesized, and their IC50 values against cancer cell lines (A549, H1975, NCI-H460, LO2, and MCF-7) were evaluated. Most of the compounds exhibited moderate cytotoxic activity against the five cancer cell lines. The most promising compound, H10, showed not only excellent activity against EGFR kinase but also positive biological activity against PI3K kinase. The structure–activity relationship (SAR) suggested that the introduction of dimethylamine scaffolds with smaller spatial structures was more favorable for antitumor activity. Additionally, the substitution of different acrylamide side chains had different effects on the activity of compounds. Generally, compounds H7 and H10 were confirmed as promising antitumor agents. Full article
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Article
Photocytotoxic Activity of Ruthenium(II) Complexes with Phenanthroline-Hydrazone Ligands
Molecules 2021, 26(7), 2084; https://doi.org/10.3390/molecules26072084 - 06 Apr 2021
Cited by 1 | Viewed by 758
Abstract
This paper reports on the synthesis and characterization of two new polypyridyl-hydrazone Schiff bases, (E)-N′-(6-oxo-1,10-phenanthrolin-5(6H)-ylidene)thiophene-2-carbohydrazide (L1) and (E)-N′-(6-oxo-1,10-phenanthrolin-5(6H)-ylidene)furan-2-carbohydrazide (L2), and their two Ru(II) complexes of [...] Read more.
This paper reports on the synthesis and characterization of two new polypyridyl-hydrazone Schiff bases, (E)-N′-(6-oxo-1,10-phenanthrolin-5(6H)-ylidene)thiophene-2-carbohydrazide (L1) and (E)-N′-(6-oxo-1,10-phenanthrolin-5(6H)-ylidene)furan-2-carbohydrazide (L2), and their two Ru(II) complexes of the general formula [RuCl(DMSO)(phen)(Ln)](PF6). Considering that hydrazides are a structural part of severa l drugs and metal complexes containing phenanthroline derivatives are known to interact with DNA and to exhibit antitumor activity, more potent anticancer agents can be obtained by covalently linking the thiophene acid hydrazide or the furoic acid hydrazide to a 1,10-phenanthroline moiety. These ligands and the Ru(II) complexes were characterized by elemental analyses, electronic, vibrational, 1H NMR, and ESI-MS spectroscopies. Ru is bound to two different N-heterocyclic ligands. One chloride and one S-bonded DMSO in cis-configuration to each other complete the octahedral coordination sphere around the metal ion. The ligands are very effective in inhibiting cellular growth in a chronic myelogenous leukemia cell line, K562. Both complexes are able to interact with DNA and present moderate cytotoxic activity, but 5 min of UV-light exposure increases cytotoxicity by three times. Full article
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Review

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Review
σ2 Receptor and Its Role in Cancer with Focus on a MultiTarget Directed Ligand (MTDL) Approach
Molecules 2021, 26(12), 3743; https://doi.org/10.3390/molecules26123743 - 19 Jun 2021
Viewed by 571
Abstract
Sigma-2 (σ2) is an endoplasmic receptor identified as the Endoplasmic Reticulum (ER) transmembrane protein TMEM97. Despite its controversial identity, which was only recently solved, this protein has gained scientific interest because of its role in the proliferative status of cells; many [...] Read more.
Sigma-2 (σ2) is an endoplasmic receptor identified as the Endoplasmic Reticulum (ER) transmembrane protein TMEM97. Despite its controversial identity, which was only recently solved, this protein has gained scientific interest because of its role in the proliferative status of cells; many tumor cells from different organs overexpress the σ2 receptor, and many σ2 ligands display cytotoxic actions in (resistant) cancer cells. These properties have shed light on the σ2 receptor as a potential druggable target to be bound/activated for the diagnosis or therapy of tumors. Additionally, diverse groups have shown how the σ2 receptor can be exploited for the targeted delivery of the anticancer drugs to tumors. As the cancer disease is a multifactorial pathology with multiple cell populations, a polypharmacological approach is very often needed. Instead of the simultaneous administration of different classes of drugs, the use of one molecule that interacts with diverse pharmacological targets, namely MultiTarget Directed Ligand (MTDL), is a promising and currently pursued strategy, that may overcome the pharmacokinetic problems associated with the administration of multiple molecules. This review aims to point out the progress regarding the σ2 ligands in the oncology field, with a focus on MTDLs directed towards σ2 receptors as promising weapons against (resistant) cancer diseases. Full article
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Review
Hybrid Drugs—A Strategy for Overcoming Anticancer Drug Resistance?
Molecules 2021, 26(9), 2601; https://doi.org/10.3390/molecules26092601 - 29 Apr 2021
Cited by 5 | Viewed by 806
Abstract
Despite enormous progress in the treatment of many malignancies, the development of cancer resistance is still an important reason for cancer chemotherapy failure. Increasing knowledge of cancers’ molecular complexity and mechanisms of their resistance to anticancer drugs, as well as extensive clinical experience, [...] Read more.
Despite enormous progress in the treatment of many malignancies, the development of cancer resistance is still an important reason for cancer chemotherapy failure. Increasing knowledge of cancers’ molecular complexity and mechanisms of their resistance to anticancer drugs, as well as extensive clinical experience, indicate that an effective fight against cancer requires a multidimensional approach. Multi-target chemotherapy may be achieved using drugs combination, co-delivery of medicines, or designing hybrid drugs. Hybrid drugs simultaneously targeting many points of signaling networks and various structures within a cancer cell have been extensively explored in recent years. The single hybrid agent can modulate multiple targets involved in cancer cell proliferation, possesses a simpler pharmacokinetic profile to reduce the possibility of drug interactions occurrence, and facilitates the process of drug development. Moreover, a single medication is expected to enhance patient compliance due to a less complicated treatment regimen, as well as a diminished number of adverse reactions and toxicity in comparison to a combination of drugs. As a consequence, many efforts have been made to design hybrid molecules of different chemical structures and functions as a means to circumvent drug resistance. The enormous number of studies in this field encouraged us to review the available literature and present selected research results highlighting the possible role of hybrid drugs in overcoming cancer drug resistance. Full article
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