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Novel Antiproliferative Molecules: The Challenge of the Target-Oriented Development of...
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Novel Antiproliferative Molecules: The Challenge of the Target-Oriented Development of Anticancer and/or Antiprotozoal Agents

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Natural and Bio-inspired Molecules".

Deadline for manuscript submissions: closed (30 September 2022) | Viewed by 13206

Special Issue Editors

Prof. Dr. Anna Sparatore

E-Mail Website
Guest Editor
Department of Pharmaceuticals Sciences (DISFARM), University of Milan, Via L. Mangiagalli 25, 20133 Milan, Italy
Interests: medicinal chemistry; hydrogen sulfide releasing compounds; antimalarials; anti-leishmaniasis agents; anticancer compounds; drug discovery; natural compounds derivatives; alkaloids derivatives; quinolizidine derivatives; structure-activity relationship
Special Issues, Collections and Topics in MDPI journals
Dr. Ivan Bassanini

E-Mail Website
Guest Editor
Istituto di Scienze e Tecnologie Chimiche “Giulio Natta” - SCITEC, Consiglio Nazionale delle Ricerche, Via Mario Privata Bianco 9, 20131 Milan, Italy
Interests: organic synthesis; antiprotozoal compounds; antiproliferative agents; chaperone targeting in diseases treatment; biotechnological tools for diagnosis and therapy; biocatalytic strategies for synthesis and derivatization of natural compounds.

Special Issue Information

Dear Colleagues,

The intrinsic (cyto)toxicity of anticancer agents and the rise of drug-resistant protozoan strains are currently two major issues concerning small molecule-based chemotherapies. Accordingly, as reported by the WHO, the continuous use of first-line antimalarial and leishmanicidal agents, whose mechanism of action and molecular target is often known, triggers the spread of drug resistance, which could eventually have a massive impact on human health. Furthermore, most of the available anticancer therapies are affected by low selectivity towards cancer cells, leading to severe side and undesired effects in oncological patients.

In this scenario, the need for novel target-oriented strategies to approach the design and development of antiproliferative agents able to act on selected biomolecules and/or cellular pathways via well-defined mechanism(s) of action is highly highlighted. Therefore, both the identification and characterization of druggable targets that are used as a framework for the design of novel antiprotozoal and/or anticancer drugs and the target-oriented optimization of known bioactive compounds is cherished. Additionally, the development of novel bio-inspired antiproliferative molecules, as well as the identification of cytotoxic natural products endowed with a demonstrated on-target potency (e.g., alkaloids, triterpenes, polyphenols, small peptides, etc.), is still desirable.

On this basis, and as a follow-up to the Special Issue "Bio-Inspired Antiproliferative Molecules for the Treatment of Protozoan and/or Cancer Diseases" previously organized by us, we would like to invite you to submit papers to this new Special Issue that addresses all the different and multidisciplinary aspects of the research challenge of the target-oriented development of anticancer and antiprotozoal agents (mainly Plasmodium and Leishmania). Both research and review articles including novelties or updated overviews, respectively, are welcomed.

Prof. Dr. Anna Sparatore
Dr. Ivan Bassanini
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. Biomolecules is an international peer-reviewed open access monthly 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

  • Antiproliferative activity
  • Antiprotozoal compounds
  • Antiplasmodial activity
  • Antileishmaniasis activity
  • Anticancer agents
  • Natural products
  • Bio-inspired molecules
  • Target oriented chemiotherapy

Related Special Issue

Published Papers (5 papers)

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Research

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23 pages, 3026 KiB  
Article
Favorable Preclinical Pharmacological Profile of a Novel Antimalarial Pyrrolizidinylmethyl Derivative of 4-amino-7-chloroquinoline with Potent In Vitro and In Vivo Activities
by Nicoletta Basilico, Silvia Parapini, Sarah D’Alessandro, Paola Misiano, Sergio Romeo, Giulio Dondio, Vanessa Yardley, Livia Vivas, Shereen Nasser, Laurent Rénia, Bruce M. Russell, Rossarin Suwanarusk, François Nosten, Anna Sparatore and Donatella Taramelli
Biomolecules 2023, 13(5), 836; https://doi.org/10.3390/biom13050836 - 14 May 2023
Viewed by 1833
Abstract
The 4-aminoquinoline drugs, such as chloroquine (CQ), amodiaquine or piperaquine, are still commonly used for malaria treatment, either alone (CQ) or in combination with artemisinin derivatives. We previously described the excellent in vitro activity of a novel pyrrolizidinylmethyl derivative of 4-amino-7-chloroquinoline, named MG3, [...] Read more.
The 4-aminoquinoline drugs, such as chloroquine (CQ), amodiaquine or piperaquine, are still commonly used for malaria treatment, either alone (CQ) or in combination with artemisinin derivatives. We previously described the excellent in vitro activity of a novel pyrrolizidinylmethyl derivative of 4-amino-7-chloroquinoline, named MG3, against P. falciparum drug-resistant parasites. Here, we report the optimized and safer synthesis of MG3, now suitable for a scale-up, and its additional in vitro and in vivo characterization. MG3 is active against a panel of P. vivax and P. falciparum field isolates, either alone or in combination with artemisinin derivatives. In vivo MG3 is orally active in the P. berghei, P. chabaudi, and P. yoelii models of rodent malaria with efficacy comparable, or better, than that of CQ and of other quinolines under development. The in vivo and in vitro ADME-Tox studies indicate that MG3 possesses a very good pre-clinical developability profile associated with an excellent oral bioavailability, and low toxicity in non-formal preclinical studies on rats, dogs, and non-human primates (NHP). In conclusion, the pharmacological profile of MG3 is in line with those obtained with CQ or the other quinolines in use and seems to possess all the requirements for a developmental candidate. Full article
(This article belongs to the Special Issue Novel Antiproliferative Molecules: The Challenge of the Target-Oriented Development of Anticancer and/or Antiprotozoal Agents)
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26 pages, 8022 KiB  
Article
Computational Investigation of 1, 3, 4 Oxadiazole Derivatives as Lead Inhibitors of VEGFR 2 in Comparison with EGFR: Density Functional Theory, Molecular Docking and Molecular Dynamics Simulation Studies
by Muhammad Sajjad Bilal, Syeda Abida Ejaz, Seema Zargar, Naveed Akhtar, Tanveer A. Wani, Naheed Riaz, Adullahi Tunde Aborode, Farhan Siddique, Nojood Altwaijry, Hamad M. Alkahtani and Haruna Isiyaku Umar
Biomolecules 2022, 12(11), 1612; https://doi.org/10.3390/biom12111612 - 01 Nov 2022
Cited by 13 | Viewed by 2288
Abstract
Vascular endothelial growth factor (VEGF) is an angiogenic factor involved in tumor growth and metastasis. Gremlin has been proposed as a novel therapeutic pathway for the treatment of renal inflammatory diseases, acting via VEGFR 2 receptor. To date, most FDA-approved tyrosine kinase (TK) [...] Read more.
Vascular endothelial growth factor (VEGF) is an angiogenic factor involved in tumor growth and metastasis. Gremlin has been proposed as a novel therapeutic pathway for the treatment of renal inflammatory diseases, acting via VEGFR 2 receptor. To date, most FDA-approved tyrosine kinase (TK) inhibitors have been reported as dual inhibitors of EGFR and VEGFR 2. The aim of the present study was to find the potent and selective inhibitor of VEGFR 2 specifically for the treatment of renal cancer. Fourteen previously identified anti-inflammatory compounds i.e., 1, 3, 4 oxadiazoles derivatives by our own group were selected for their anti-cancer potential, targeting the tyrosine kinase (TK) domain of VEGFR2 and EGFR. A detailed virtual screening-based study was designed viz density functional theory (DFT) study to find the compounds’ stability and reactivity, molecular docking for estimating binding affinity, SeeSAR analysis and molecular dynamic simulations to confirm protein ligand complex stability and ADMET properties to find the pharmacokinetic profile of all compounds. The DFT results suggested that among all the derivatives, the 7g, 7j, and 7l were chemically reactive and stable derivatives. The optimized structures obtained from the DFTs were further selected for molecular docking, and the results suggested that 7g, 7j and 7l derivatives as the best inhibitors of VEGFR 2 with binding energy values −46.32, −48.89 and −45.01 kJ/mol. The Estimated inhibition constant (IC50) of hit compound 7j (0.009 µM) and simulation studies of its complexes confirms its high potency and best inhibitor of VEGFR2. All the derivatives were also docked with EGFR, where they showed weak binding energies and poor interactions, important compound 7g, 7j and 7i exhibited binding energy of −31.01, −33.23 and −34.19 kJ/mol respectively. Furthermore, the anticancer potential of the derivatives was confirmed by cell viability (MTT) assay using breast cancer and cervical cancer cell lines. At the end, the results of ADMET studies confirmed these derivatives as drug like candidates. Conclusively, the current study suggested substituted oxadiazoles as the potential anticancer compounds which exhibited more selectivity towards VEGFR2 in comparison to EGFR. Therefore, the identified lead molecules can be used for the synthesis of more potent derivatives of VEGFR2, along with extensive in vitro and in vivo experiments, that can be used to treat various cancers, especially renal cancers, and to prevent angiogenesis due to aberrant expression of VEGFR2. Full article
(This article belongs to the Special Issue Novel Antiproliferative Molecules: The Challenge of the Target-Oriented Development of Anticancer and/or Antiprotozoal Agents)
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17 pages, 2102 KiB  
Article
New Betulin Derivatives with Nitrogen Heterocyclic Moiety—Synthesis and Anticancer Activity In Vitro
by Ewa Bębenek, Elwira Chrobak, Zuzanna Rzepka and Dorota Wrześniok
Biomolecules 2022, 12(10), 1540; https://doi.org/10.3390/biom12101540 - 21 Oct 2022
Cited by 4 | Viewed by 1506
Abstract
As part of the search for new medicinal substances with potential application in oncology, the synthesis of new compounds combining the betulin molecule and the indole system was carried out. The structure of the ester derivatives obtained in the Steglich reaction was confirmed [...] Read more.
As part of the search for new medicinal substances with potential application in oncology, the synthesis of new compounds combining the betulin molecule and the indole system was carried out. The structure of the ester derivatives obtained in the Steglich reaction was confirmed by spectroscopic methods (1H and 13C NMR, HR-MS). The obtained new 3-indolyl betulin derivatives were evaluated for anticancer activity against several human cancer cell lines (melanomas, breast cancers, colorectal adenocarcinomas, lung cancer) as well as normal human fibroblasts. The significant reduction in MCF-7 cells viability for 28-hydroxy-(lup-20(29)-ene)-3-yl 2-(1H-indol-3-yl)acetate was observed at a concentration of 10 µg/mL (17 µM). In addition, cytometric analysis showed that this compound strongly reduces the proliferation rate of breast cancer cells. For this, the derivative showing the promising cytotoxic effect on MCF-7 breast cancer cells, the pharmacokinetic profile prediction was performed using in silico methods. Based on the results obtained in the study, it can be concluded that indole-functionalized triterpene EB367 is a promising starting point for further research in the field of breast cancer therapy or the synthesis of new derivatives. Full article
(This article belongs to the Special Issue Novel Antiproliferative Molecules: The Challenge of the Target-Oriented Development of Anticancer and/or Antiprotozoal Agents)
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20 pages, 7933 KiB  
Article
Triple Isozyme Lactic Acid Dehydrogenase Inhibition in Fully Viable MDA-MB-231 Cells Induces Cytostatic Effects That Are Not Reversed by Exogenous Lactic Acid
by Elizabeth Mazzio, Nzinga Mack, Ramesh B. Badisa and Karam F. A. Soliman
Biomolecules 2021, 11(12), 1751; https://doi.org/10.3390/biom11121751 - 24 Nov 2021
Cited by 4 | Viewed by 2066
Abstract
A number of aggressive human malignant tumors are characterized by an intensified glycolytic rate, over-expression of lactic acid dehydrogenase A (LDHA), and subsequent lactate accumulation, all of which contribute toward an acidic peri-cellular immunosuppressive tumor microenvironment (TME). While recent focus has been directed [...] Read more.
A number of aggressive human malignant tumors are characterized by an intensified glycolytic rate, over-expression of lactic acid dehydrogenase A (LDHA), and subsequent lactate accumulation, all of which contribute toward an acidic peri-cellular immunosuppressive tumor microenvironment (TME). While recent focus has been directed at how to inhibit LDHA, it is now becoming clear that multiple isozymes of LDH must be simultaneously inhibited in order to fully suppress lactic acid and halt glycolysis. In this work we explore the biochemical and genomic consequences of an applied triple LDH isozyme inhibitor (A, B, and C) (GNE-140) in MDA-MB-231 triple-negative breast cancer cells (TNBC) cells. The findings confirm that GNE-140 does in fact, fully block the production of lactic acid, which also results in a block of glucose utilization and severe impedance of the glycolytic pathway. Without a fully functional glycolytic pathway, breast cancer cells continue to thrive, sustain viability, produce ample energy, and maintain mitochondrial potential (ΔΨM). The only observable negative consequence of GNE-140 in this work, was the attenuation of cell division, evident in both 2D and 3D cultures and occurring in fully viable cells. Of important note, the cytostatic effects were not reversed by the addition of exogenous (+) lactic acid. While the effects of GNE-140 on the whole transcriptome were mild (12 up-regulated differential expressed genes (DEGs); 77 down-regulated DEGs) out of the 48,226 evaluated, the down-regulated DEGS collectively centered around a loss of genes related to mitosis, cell cycle, GO/G1–G1/S transition, and DNA replication. These data were also observed with digital florescence cytometry and flow cytometry, both corroborating a G0/G1 phase blockage. In conclusion, the findings in this work suggest there is an unknown element linking LDH enzyme activity to cell cycle progression, and this factor is completely independent of lactic acid. The data also establish that complete inhibition of LDH in cancer cells is not a detriment to cell viability or basic production of energy. Full article
(This article belongs to the Special Issue Novel Antiproliferative Molecules: The Challenge of the Target-Oriented Development of Anticancer and/or Antiprotozoal Agents)
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Review

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22 pages, 2285 KiB  
Review
Amygdalin: A Review on Its Characteristics, Antioxidant Potential, Gastrointestinal Microbiota Intervention, Anticancer Therapeutic and Mechanisms, Toxicity, and Encapsulation
by Hassan Barakat, Thamer Aljutaily, Mona S. Almujaydil, Reham M. Algheshairy, Raghad M. Alhomaid, Abdulkarim S. Almutairi, Saleh I. Alshimali and Ahmed A. H. Abdellatif
Biomolecules 2022, 12(10), 1514; https://doi.org/10.3390/biom12101514 - 19 Oct 2022
Cited by 14 | Viewed by 4780
Abstract
Bioactive amygdalin, found in high concentrations in bitter almonds, has been recognized as a symbol of the cyanogenic glycoside chemical organic substance, which was initially developed as a pharmaceutical for treating cancer after being hydrolyzed to hydrogen cyanide (HCN). Regrettably, research has shown [...] Read more.
Bioactive amygdalin, found in high concentrations in bitter almonds, has been recognized as a symbol of the cyanogenic glycoside chemical organic substance, which was initially developed as a pharmaceutical for treating cancer after being hydrolyzed to hydrogen cyanide (HCN). Regrettably, research has shown that HCN can also damage normal cells, rendering it non-toxic to the human body. Extreme controversy surrounds both in vivo and in vitro studies, making its use risky. This review provides an extensive update on characteristics, antioxidant potential, gastrointestinal microbiota intervention, anticancer therapeutic, mechanisms, toxicity, and encapsulation of amygdalin. Antioxidant, anti-tumor, anti-fibrotic, antiatherosclerosis, anti-inflammatory, immunomodulatory, and analgesic characteristics, and the ability to improve digestive and reproductive systems, neurodegeneration, and cardiac hypertrophy are just some of the benefits of amygdalin. Studies verified the HCN-produced amygdalin to be harmful orally, but only at very high doses. Although intravenous treatment was less effective than the oral method, the oral route has a dose range of 0.6 to 1 g daily. Amygdalin’s toxicity depends heavily on the variety of bacteria in the digestive tract. Unfortunately, there is currently no foolproof method for determining the microbial consortium and providing a safe oral dosage for every patient. Amygdalin encapsulation in alginate-chitosan nanoparticles (ACNPs) is a relatively new area of research. Amygdalin has an enhanced cytotoxic effect on malignant cells, and ACNPs can be employed as an active drug-delivery system to release this compound in a regulated, sustained manner without causing any harm to healthy cells or tissues. In conclusion, a large area of research for a substance that might be the next step in cancer therapy is opened up due to unverified and conflicting data. Full article
(This article belongs to the Special Issue Novel Antiproliferative Molecules: The Challenge of the Target-Oriented Development of Anticancer and/or Antiprotozoal Agents)
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