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Small Molecule Hybrids for Anticancer and Antiviral Therapy
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Small Molecule Hybrids for Anticancer and Antiviral Therapy

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

Deadline for manuscript submissions: 30 April 2024 | Viewed by 8044

Special Issue Editors

Dr. Daniela Perrone

E-Mail Website
Guest Editor
Department of Environmental and Prevention Sciences, University of Ferrara, Via Fossato di Mortara 17, 44121 Ferrara, Italy
Interests: organic synthesis; synthetic bioactive compounds; bile acid derivatives; modified oligonucleotides
Special Issues, Collections and Topics in MDPI journals
Dr. Maria Luisa Navacchia

E-Mail Website
Guest Editor
Institute of Organic Synthesis and Photoreactivity, National Research Council, via Piero Gobetti 101, 40129 Bologna, Italy
Interests: organic synthesis; rational drug design; liquid chromatography-mass spectrometry
Special Issues, Collections and Topics in MDPI journals
Dr. Elisabetta Melloni

E-Mail Website
Guest Editor
Department of Translational Medicine and LTTA Centre, University of Ferrara, 44121 Ferrara, Italy
Interests: cell and molecular biology; anticancer and antiinflammatory effects of new compounds; flow cytometry
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cancer should not be considered a single disease, but a complex adaptive system involved with inflammation, metabolism and immunization. Conventional anticancer chemotherapies are frequently associated with significant levels of toxicity and/or multidrug resistance; additionally, many advanced and metastasized cancers remain untreatable. The development of hybrid drugs offers the chance to enhance antitumor activity not only by virtue of the synergistic effect of multiple bioactive agents but also taking advantage of the resulting high structural diversity and biodiversity. Therefore, the combination of two or more antineoplastic drugs reveals advantages over monotherapy and has been recognized as a promising therapeutic strategy. While there is considerable literature on the use of pharmacophores in combination with chemotherapeutics or phytochemicals, pharmacophore hybridization—involving the conjugation of at least one bioactive molecule through a covalent bond—is a more recent approach. This Special Issue will be focused on the design, synthesis and biological evaluation at any level of new hybrid anticancer drugs by the conjugation of natural products and/or chemically synthesized compounds, including but not limited to chemotherapeutic drugs and photosensitizers for photothermal or photodynamic therapy.

In the last two years, the outbreak of infectious diseases caused by new viruses has posed a serious threat to global public health, pushing urgently for the development of therapeutics. Molecular hybridization strategies should be also considered for the search of antiviral drugs for emerging/re-emerging infectious diseases in order to overcome drug resistance and toxicity, and to meet the challenges associated with new viruses. Therefore, this Special Issue will also consider new small-molecule hybrids for antiviral activity evaluation.

This Special Issue, “Small Molecule Hybrids for Anticancer and Antiviral Therapy”, will be of interest to researchers working on the chemistry and medicinal chemistry of small-molecule hybrids, biomaterials and drug delivery, and to chemical biologists, pharmacologists, and clinicians interested in drug discovery.

The latest advances in the development of small-molecule hybrid drugs will be accepted in the form of original research papers, short communications and review articles.

Dr. Daniela Perrone
Dr. Maria Luisa Navacchia
Dr. Elisabetta Melloni
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. 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

  • hybrid compounds
  • bioconjugation
  • anticancer agents
  • small-molecule engineered hybrids
  • antiviral activity
  • drug development
  • chemical design and synthesis
  • biological activity
  • drug resistance

Published Papers (6 papers)

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Research

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17 pages, 3112 KiB  
Article
1,2,3-Triazole Hybrids Containing Isatins and Phenolic Moieties: Regioselective Synthesis and Molecular Docking Studies
by Loredana Maiuolo, Matteo Antonio Tallarida, Angelo Meduri, Giulia Fiorani, Antonio Jiritano, Antonio De Nino, Vincenzo Algieri and Paola Costanzo
Molecules 2024, 29(7), 1556; https://doi.org/10.3390/molecules29071556 - 30 Mar 2024
Viewed by 552
Abstract
The synthesis of hybrid molecules is one of the current strategies of drug discovery for the development of new lead compounds. The 1,2,3-triazole moiety represents an important building block in Medicinal Chemistry, extensively present in recent years. In this paper, we presented the [...] Read more.
The synthesis of hybrid molecules is one of the current strategies of drug discovery for the development of new lead compounds. The 1,2,3-triazole moiety represents an important building block in Medicinal Chemistry, extensively present in recent years. In this paper, we presented the design and the synthesis of new 1,2,3-triazole hybrids, containing both an isatine and a phenolic core. Firstly, the non-commercial azide and the alkyne synthons were prepared by different isatines and phenolic acids, respectively. Then, the highly regioselective synthesis of 1,4-disubstituted triazoles was obtained in excellent yields by a click chemistry approach, catalyzed by Cu(I). Finally, a molecular docking study was performed on the hybrid library, finding four different therapeutic targets. Among them, the most promising results were obtained on 5-lipoxygenase, an enzyme involved in the inflammatory processes. Full article
(This article belongs to the Special Issue Small Molecule Hybrids for Anticancer and Antiviral Therapy)
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10 pages, 1399 KiB  
Article
Enzymatic Synthesis of New Acetoacetate–Ursodeoxycholic Acid Hybrids as Potential Therapeutic Agents and Useful Synthetic Scaffolds as Well
by Valentina Venturi, Elena Marchesi, Daniela Perrone, Valentina Costa, Martina Catani, Simona Aprile, Lindomar Alberto Lerin, Federico Zappaterra, Pier Paolo Giovannini and Lorenzo Preti
Molecules 2024, 29(6), 1305; https://doi.org/10.3390/molecules29061305 - 15 Mar 2024
Viewed by 543
Abstract
Ursodeoxycholic acid (UDCA) and acetoacetate are natural compounds present in the human intestine and blood, respectively. A number of studies highlighted that besides their well-known primary biological roles, both compounds possess the ability to influence a variety of cellular processes involved in the [...] Read more.
Ursodeoxycholic acid (UDCA) and acetoacetate are natural compounds present in the human intestine and blood, respectively. A number of studies highlighted that besides their well-known primary biological roles, both compounds possess the ability to influence a variety of cellular processes involved in the etiology of various diseases. These reasons suggested the potential of acetoacetate–UDCA hybrids as possible therapeutic agents and prompted us to develop a synthetic strategy to selectively derivatize the hydroxyl groups of the bile acid with acetoacetyl moieties. 3α-acetoacetoxy UDCA was obtained (60% isolated yield) via the regioselective transesterification of methyl acetoacetate with UDCA promoted by the Candida antarctica lipase B (CAL-B). 3α,7β-bis-acetoacetoxy UDCA was obtained instead by thermal condensation of methyl acetoacetate and UDCA (80% isolated yield). This bis-adduct was finally converted to the 7β-acetoacetoxy UDCA (82% isolated yield) via CAL-B catalyzed regioselective alcoholysis of the ester group on the 3α position. In order to demonstrate the value of the above new hybrids as UDCA-based scaffolds, 3α-acetoacetoxy UDCA was subjected to multicomponent Biginelli reaction with benzaldehyde and urea to obtain the corresponding 4-phenyl-3,4-dihydropyrimidin-2-(1H)-one derivative in 65% isolated yield. Full article
(This article belongs to the Special Issue Small Molecule Hybrids for Anticancer and Antiviral Therapy)
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17 pages, 3231 KiB  
Article
Anticancer Activity and Molecular Mechanisms of an Ursodeoxycholic Acid Methyl Ester-Dihydroartemisinin Hybrid via a Triazole Linkage in Hepatocellular Carcinoma Cells
by Ya-Fen Hsu, Fan-Lu Kung, Tzu-En Huang, Yi-Ning Deng, Jih-Hwa Guh, Paolo Marchetti, Elena Marchesi, Daniela Perrone, Maria Luisa Navacchia and Lih-Ching Hsu
Molecules 2023, 28(5), 2358; https://doi.org/10.3390/molecules28052358 - 03 Mar 2023
Cited by 3 | Viewed by 1768
Abstract
Hepatocellular carcinoma is the third most common cause of cancer-related death according to the International Agency for Research on Cancer. Dihydroartemisinin (DHA), an antimalarial drug, has been reported to exhibit anticancer activity but with a short half-life. We synthesized a series of bile [...] Read more.
Hepatocellular carcinoma is the third most common cause of cancer-related death according to the International Agency for Research on Cancer. Dihydroartemisinin (DHA), an antimalarial drug, has been reported to exhibit anticancer activity but with a short half-life. We synthesized a series of bile acid–dihydroartemisinin hybrids to improve its stability and anticancer activity and demonstrated that an ursodeoxycholic–DHA (UDC-DHA) hybrid was 10-fold more potent than DHA against HepG2 hepatocellular carcinoma cells. The objectives of this study were to evaluate the anticancer activity and investigate the molecular mechanisms of UDCMe-Z-DHA, a hybrid of ursodeoxycholic acid methyl ester and DHA via a triazole linkage. We found that UDCMe-Z-DHA was even more potent than UDC-DHA in HepG2 cells with IC50 of 1 μM. Time course experiments and stability in medium determined by cell viability assay as well as HPLC-MS/MS analysis revealed that UDCMe-Z-DHA was more stable than DHA, which in part accounted for the increased anticancer activity. Mechanistic studies revealed that UDCMe-Z-DHA caused G0/G1 arrest and induced reactive oxygen species (ROS), mitochondrial membrane potential loss and autophagy, which may in turn lead to apoptosis. Compared to DHA, UDCMe-Z-DHA displayed much lower cytotoxicity toward normal cells. Thus, UDCMe-Z-DHA may be a potential drug candidate for hepatocellular carcinoma. Full article
(This article belongs to the Special Issue Small Molecule Hybrids for Anticancer and Antiviral Therapy)
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17 pages, 2769 KiB  
Article
Small Structural Differences Govern the Carbonic Anhydrase II Inhibition Activity of Cytotoxic Triterpene Acetazolamide Conjugates
by Toni C. Denner, Niels Heise, Julian Zacharias, Oliver Kraft, Sophie Hoenke and René Csuk
Molecules 2023, 28(3), 1009; https://doi.org/10.3390/molecules28031009 - 19 Jan 2023
Cited by 5 | Viewed by 1566
Abstract
Acetylated triterpenoids betulin, oleanolic acid, ursolic acid, and glycyrrhetinic acid were converted into their succinyl-spacered acetazolamide conjugates. These conjugates were screened for their inhibitory activity onto carbonic anhydrase II and their cytotoxicity employing several human tumor cell lines and non-malignant fibroblasts. As a [...] Read more.
Acetylated triterpenoids betulin, oleanolic acid, ursolic acid, and glycyrrhetinic acid were converted into their succinyl-spacered acetazolamide conjugates. These conjugates were screened for their inhibitory activity onto carbonic anhydrase II and their cytotoxicity employing several human tumor cell lines and non-malignant fibroblasts. As a result, the best inhibitors were derived from betulin and glycyrrhetinic acid while those derived from ursolic or oleanolic acid were significantly weaker inhibitors but also of diminished cytotoxicity. A betulin-derived conjugate held a Ki = 0.129 μM and an EC50 = 8.5 μM for human A375 melanoma cells. Full article
(This article belongs to the Special Issue Small Molecule Hybrids for Anticancer and Antiviral Therapy)
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20 pages, 2701 KiB  
Article
Design, Synthesis, and Antiproliferative Activity of Novel Neocryptolepine–Rhodanine Hybrids
by Mohamed El-Bahnsawye, Mona K. Abo Hussein, Elshaymaa I. Elmongy, Hanem Mohamed Awad, Aliaa Abd El-Kader Tolan, Yasmine Shafik Moemen, Ahmed El-Shaarawy and Ibrahim El-Tantawy El-Sayed
Molecules 2022, 27(21), 7599; https://doi.org/10.3390/molecules27217599 - 05 Nov 2022
Cited by 2 | Viewed by 1924
Abstract
A series of novel neocryptolepine–rhodanine hybrids (9a,b, 11a–d, 14, and 16a,b) have been synthesized by combining neocryptolepine core 5 modified at the C-11 position with rhodanine condensed with the appropriate aryl/hetero aryl aldehydes. Based on these [...] Read more.
A series of novel neocryptolepine–rhodanine hybrids (9a,b, 11a–d, 14, and 16a,b) have been synthesized by combining neocryptolepine core 5 modified at the C-11 position with rhodanine condensed with the appropriate aryl/hetero aryl aldehydes. Based on these findings, the structures of the hybrids were confirmed by spectral analyses. By employing the MTT assay, all hybrids were tested for their in vitro antiproliferative activity against two cancer cell lines, including MDA-MB-231 (human breast) and HepG-2 (hepatocellular carcinoma). Interestingly, the IC50 values of all hybrids except 9b and 11c showed activity comparable to the standard anticancer drug, 5-fluorouracil, against HepG-2 cancer cells. Furthermore, the cytotoxicity of all the synthesized hybrids was investigated on a normal skin human cell line (BJ-1), and the results showed that these compounds had no significant cytotoxicity toward these healthy cells at the highest concentration used in this study. This study also indicated that the active hybrids exert their cytotoxic activity via the induction of apoptosis. A molecular docking study was used to shed light on the molecular mechanism of their anticancer activity. The docking results revealed that the hybrids exert their mode of action through DNA intercalation. Furthermore, in silico assessment for pharmacokinetic properties was performed on the most potent compounds, which revealed candidates with good bioavailability, high tolerability with cell membranes, and positive drug-likeness values. Full article
(This article belongs to the Special Issue Small Molecule Hybrids for Anticancer and Antiviral Therapy)
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Review

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23 pages, 10815 KiB  
Review
Suberoylanilide Hydroxamic Acid Analogs with Heteroaryl Amide Group and Different Chain Length: Synthesis and Effect on Histone Deacetylase
by Gabriele Micheletti, Carla Boga, Giacomo Drius, Silvia Bordoni and Natalia Calonghi
Molecules 2024, 29(1), 238; https://doi.org/10.3390/molecules29010238 - 01 Jan 2024
Viewed by 1002
Abstract
This review covers the last 25 years of the literature on analogs of suberoylanilide hydroxamic acid (SAHA, known also as vorinostat) acting as an HDAC inhibitor. In particular, the topic has been focused on the synthesis and biological activity of compounds where the [...] Read more.
This review covers the last 25 years of the literature on analogs of suberoylanilide hydroxamic acid (SAHA, known also as vorinostat) acting as an HDAC inhibitor. In particular, the topic has been focused on the synthesis and biological activity of compounds where the phenyl group (the surface recognition moiety, CAP) of SAHA has been replaced by an azaheterocycle through a direct bond with amide nitrogen atom, and the methylene chain in the linker region is of variable length. Most of the compounds displayed good to excellent inhibitory activity against HDACs and in many cases showed antiproliferative activity against human cancer cell lines. Full article
(This article belongs to the Special Issue Small Molecule Hybrids for Anticancer and Antiviral Therapy)
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