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Novel Anti-proliferative Agents
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Novel Anti-proliferative Agents

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (20 May 2023) | Viewed by 47995

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editor

Prof. Dr. Valentina Onnis

E-Mail Website1 Website2
Guest Editor
Department of Life and Environmental Sciences, Unit of Pharmaceutical, Pharmacological and Nutraceutical Sciences, University of Cagliari, University Campus, I-09042 Monserrato, Italy
Interests: medicinal chemistry; nitrogen heterocycles; antiproliferative compounds; enzyme inhibitors
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cancer is one of the most widely spread and complex forms of disease, cancer cells being distinguished from healthy cells for their altered proliferation and survival. In the past three decades, only the National Cancer Institute (NCI) has screened millions of small molecules for potential anticancer activity. Despite a number of conventional cytotoxic approaches having been developed, their limited effectiveness, in accordance with the heterogeneity of cancer cells, prompts the constant search for novel natural or synthetic compounds with growth inhibition or tumor cell activity killing properties.

This Pharmaceuticals journal Special Issue invites both reviews and original articles regarding basic, preclinical and clinical studies on antiproliferative chemical entities.

I look forward to receiving your contribution.

Prof. Dr. Valentina Onnis
Guest Editor

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. Pharmaceuticals 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 2900 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

  • medicinal chemistry
  • drug discovery
  • natural compounds
  • synthetic compounds
  • organic synthesis
  • bioactivity
  • anticancer drugs
  • antiproliferative activity

Published Papers (21 papers)

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Editorial

Jump to: Research, Review

5 pages, 228 KiB  
Editorial
Special Issue “Novel Anti-Proliferative Agents”
by Valentina Onnis
Pharmaceuticals 2023, 16(10), 1437; https://0-doi-org.brum.beds.ac.uk/10.3390/ph16101437 - 10 Oct 2023
Viewed by 632
Abstract
Cancer is a disease that can affect any organ and spread to other nearby or distant organs [...] Full article
(This article belongs to the Special Issue Novel Anti-proliferative Agents)

Research

Jump to: Editorial, Review

17 pages, 2149 KiB  
Article
Synthesis and Structure Determination of Substituted Thiazole Derivatives as EGFR/BRAFV600E Dual Inhibitors Endowed with Antiproliferative Activity
by Lamya H. Al-Wahaibi, Essmat M. El-Sheref, Alaa A. Hassan, S. Bräse, M. Nieger, Bahaa G. M. Youssif, Mahmoud A. A. Ibrahim and Hendawy N. Tawfeek
Pharmaceuticals 2023, 16(7), 1014; https://0-doi-org.brum.beds.ac.uk/10.3390/ph16071014 - 17 Jul 2023
Cited by 1 | Viewed by 1354
Abstract
2,3,4-trisubstituted thiazoles 3a–i, having a methyl group in position four, were synthesized by the reaction of 1,4-disubstituted thiosemicarbazides with chloroacetone in ethyl acetate/Et3N at room temperature or in ethanol under reflux. The structures of new compounds were determined [...] Read more.
2,3,4-trisubstituted thiazoles 3a–i, having a methyl group in position four, were synthesized by the reaction of 1,4-disubstituted thiosemicarbazides with chloroacetone in ethyl acetate/Et3N at room temperature or in ethanol under reflux. The structures of new compounds were determined using NMR spectroscopy, mass spectrometry, and elemental analyses. Moreover, the structure of compound 3a was unambiguously confirmed with X-ray analysis. The cell viability assay of 3a–i at 50 µM was greater than 87%, and none of the tested substances were cytotoxic. Compounds 3a–i demonstrated good antiproliferative activity, with GI50 values ranging from 37 to 86 nM against the four tested human cancer cell lines, compared to the reference erlotinib, which had a GI50 value of 33 nM. The most potent derivatives were found to be compounds 3a, 3c, 3d, and 3f, with GI50 values ranging from 37 nM to 54 nM. The EGFR-TK and BRAFV600E inhibitory assays’ results matched the antiproliferative assay’s results, with the most potent derivatives, as antiproliferative agents, also being the most potent EGFR and BRAFV600E inhibitors. The docking computations were employed to investigate the docking modes and scores of compounds 3a, 3c, 3d, and 3f toward BRAFV600E and EGFR. Docking computations demonstrated the good affinity of compound 3f against BRAFV600E and EGFR, with values of −8.7 and −8.5 kcal/mol, respectively. Full article
(This article belongs to the Special Issue Novel Anti-proliferative Agents)
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15 pages, 2757 KiB  
Article
Design, Synthesis, and Anti-Proliferative Action of Purine/Pteridine-Based Derivatives as Dual Inhibitors of EGFR and BRAFV600E
by Samar A. El-Kalyoubi, Hesham A. M. Gomaa, Elshimaa M. N. Abdelhafez, Mohamed Ramadan, Fatimah Agili and Bahaa G. M. Youssif
Pharmaceuticals 2023, 16(5), 716; https://0-doi-org.brum.beds.ac.uk/10.3390/ph16050716 - 08 May 2023
Cited by 5 | Viewed by 1305
Abstract
The investigation of novel EGFR and BRAFV600E dual inhibitors is intended to serve as targeted cancer treatment. Two sets of purine/pteridine-based derivatives were designed and synthesized as EGFR/BRAFV600E dual inhibitors. The majority of the compounds exhibited promising antiproliferative activity on the [...] Read more.
The investigation of novel EGFR and BRAFV600E dual inhibitors is intended to serve as targeted cancer treatment. Two sets of purine/pteridine-based derivatives were designed and synthesized as EGFR/BRAFV600E dual inhibitors. The majority of the compounds exhibited promising antiproliferative activity on the cancer cell lines tested. Compounds 5a, 5e, and 7e of purine-based and pteridine-based scaffolds were identified as the most potent hits in anti-proliferative screening, with GI50 values of 38 nM, 46 nM, and 44 nM, respectively. Compounds 5a, 5e, and 7e demonstrated promising EGFR inhibitory activity, with IC50 values of 87 nM, 98 nM, and 92 nM, respectively, when compared to erlotinib’s IC50 value of 80 nM. According to the results of the BRAFV600E inhibitory assay, BRAFV600E may not be a viable target for this class of organic compounds. Finally, molecular docking studies were carried out at the EGFR and BRAFV600E active sites to suggest possible binding modes. Full article
(This article belongs to the Special Issue Novel Anti-proliferative Agents)
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18 pages, 7837 KiB  
Article
In Vitro and In Vivo Effects of Ulvan Polysaccharides from Ulva rigida
by Jorge García-Márquez, Bruna Rodrigues Moreira, Piedad Valverde-Guillén, Sofía Latorre-Redoli, Candela T. Caneda-Santiago, Gabriel Acién, Eduardo Martínez-Manzanares, Manuel Marí-Beffa and Roberto T. Abdala-Díaz
Pharmaceuticals 2023, 16(5), 660; https://0-doi-org.brum.beds.ac.uk/10.3390/ph16050660 - 28 Apr 2023
Cited by 3 | Viewed by 1811
Abstract
One of the main bioactive compounds of interest from the Ulva species is the sulfated polysaccharide ulvan, which has recently attracted attention for its anticancer properties. This study investigated the cytotoxic activity of ulvan polysaccharides obtained from Ulva rigida in the following scenarios: [...] Read more.
One of the main bioactive compounds of interest from the Ulva species is the sulfated polysaccharide ulvan, which has recently attracted attention for its anticancer properties. This study investigated the cytotoxic activity of ulvan polysaccharides obtained from Ulva rigida in the following scenarios: (i) in vitro against healthy and carcinogenic cell lines (1064sk (human fibroblasts), HACAT (immortalized human keratinocytes), U-937 (a human leukemia cell line), G-361 (a human malignant melanoma), and HCT-116 (a colon cancer cell line)) and (ii) in vivo against zebrafish embryos. Ulvan exhibited cytotoxic effects on the three human cancer cell lines tested. However, only HCT-116 demonstrated sufficient sensitivity to this ulvan to make it relevant as a potential anticancer treatment, presenting an LC50 of 0.1 mg mL−1. The in vivo assay on the zebrafish embryos showed a linear relationship between the polysaccharide concentration and growth retardation at 7.8 hpf mL mg−1, with an LC50 of about 5.2 mg mL−1 at 48 hpf. At concentrations near the LC50, toxic effects, such as pericardial edema or chorion lysis, could be found in the experimental larvae. Our in vitro study supports the potential use of polysaccharides extracted from U. rigida as candidates for treating human colon cancer. However, the in vivo assay on zebrafish indicated that the potential use of ulvan as a promising, safe compound should be limited to specific concentrations below 0.001 mg mL−1 since it revealed side effects on the embryonic growth rate and osmolar balance. Full article
(This article belongs to the Special Issue Novel Anti-proliferative Agents)
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17 pages, 3435 KiB  
Article
One-Pot Synthesis of 1-Thia-4-azaspiro[4.4/5]alkan-3-ones via Schiff Base: Design, Synthesis, and Apoptotic Antiproliferative Properties of Dual EGFR/BRAFV600E Inhibitors
by Lamya H. Al-Wahaibi, Essmat M. El-Sheref, Mohamed M. Hammouda and Bahaa G. M. Youssif
Pharmaceuticals 2023, 16(3), 467; https://0-doi-org.brum.beds.ac.uk/10.3390/ph16030467 - 22 Mar 2023
Cited by 3 | Viewed by 1592
Abstract
In this investigation, novel 4-((quinolin-4-yl)amino)-thia-azaspiro[4.4/5]alkan-3-ones were synthesized via interactions between 4-(2-cyclodenehydrazinyl)quinolin-2(1H)-one and thioglycolic acid catalyzed by thioglycolic acid. We prepared a new family of spiro-thiazolidinone derivatives in a one-step reaction with excellent yields (67–79%). The various NMR, mass spectra, and elemental [...] Read more.
In this investigation, novel 4-((quinolin-4-yl)amino)-thia-azaspiro[4.4/5]alkan-3-ones were synthesized via interactions between 4-(2-cyclodenehydrazinyl)quinolin-2(1H)-one and thioglycolic acid catalyzed by thioglycolic acid. We prepared a new family of spiro-thiazolidinone derivatives in a one-step reaction with excellent yields (67–79%). The various NMR, mass spectra, and elemental analyses verified the structures of all the newly obtained compounds. The antiproliferative effects of 6a–e, 7a, and 7b against four cancer cells were investigated. The most effective antiproliferative compounds were 6b, 6e, and 7b. Compounds 6b and 7b inhibited EGFR with IC50 values of 84 and 78 nM, respectively. Additionally, 6b and 7b were the most effective inhibitors of BRAFV600E (IC50 = 108 and 96 nM, respectively) and cancer cell proliferation (GI50 = 35 and 32 nM against four cancer cell lines, respectively). Finally, the apoptosis assay results revealed that compounds 6b and 7b had dual EGFR/BRAFV600E inhibitory properties and showed promising antiproliferative and apoptotic activity. Full article
(This article belongs to the Special Issue Novel Anti-proliferative Agents)
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20 pages, 2164 KiB  
Article
Indoline-5-Sulfonamides: A Role of the Core in Inhibition of Cancer-Related Carbonic Anhydrases, Antiproliferative Activity and Circumventing of Multidrug Resistance
by Stepan K. Krymov, Alexander M. Scherbakov, Lyubov G. Dezhenkova, Diana I. Salnikova, Svetlana E. Solov’eva, Danila V. Sorokin, Daniela Vullo, Viviana De Luca, Clemente Capasso, Claudiu T. Supuran and Andrey E. Shchekotikhin
Pharmaceuticals 2022, 15(12), 1453; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15121453 - 23 Nov 2022
Cited by 4 | Viewed by 1541
Abstract
The overexpression and activity of carbonic anhydrase (CA, EC 4.2.1.1) isoforms CA IX and CA XII promote the accumulation of exceeding protons and acidosis in the extracellular tumor environment. Sulfonamides are effective inhibitors of most families of CAs. In this study, using scaffold-hopping, [...] Read more.
The overexpression and activity of carbonic anhydrase (CA, EC 4.2.1.1) isoforms CA IX and CA XII promote the accumulation of exceeding protons and acidosis in the extracellular tumor environment. Sulfonamides are effective inhibitors of most families of CAs. In this study, using scaffold-hopping, indoline-5-sulfonamide analogs 4a–u of the CA IX-selective inhibitor 3 were designed and synthesized to evaluate their biological properties. 1-Acylated indoline-5-sulfonamides demonstrated inhibitory activity against tumor-associated CA IX and XII with KI values up to 132.8 nM and 41.3 nM. Compound 4f, as one of the most potent inhibitors of CA IX and XII, exhibits hypoxic selectivity, suppressing the growth of MCF7 cells at 12.9 µM, and causes partial inhibition of hypoxia-induced CA IX expression in A431 skin cancer cells. 4e and 4f reverse chemoresistance to doxorubicin of K562/4 with overexpression of P-gp. Full article
(This article belongs to the Special Issue Novel Anti-proliferative Agents)
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19 pages, 3781 KiB  
Article
In Vitro Cytotoxicity Evaluation of Plastoquinone Analogues against Colorectal and Breast Cancers along with In Silico Insights
by Halilibrahim Ciftci, Belgin Sever, Nilüfer Bayrak, Mahmut Yıldız, Hatice Yıldırım, Hiroshi Tateishi, Masami Otsuka, Mikako Fujita and Amaç Fatih TuYuN
Pharmaceuticals 2022, 15(10), 1266; https://doi.org/10.3390/ph15101266 - 14 Oct 2022
Cited by 7 | Viewed by 1699
Abstract
Colorectal cancer (CRC) and breast cancer are leading causes of death globally, due to significant challenges in detection and management. The late-stage diagnosis and treatment failures require the discovery of potential anticancer agents to achieve a satisfactory therapeutic effect. We have previously reported [...] Read more.
Colorectal cancer (CRC) and breast cancer are leading causes of death globally, due to significant challenges in detection and management. The late-stage diagnosis and treatment failures require the discovery of potential anticancer agents to achieve a satisfactory therapeutic effect. We have previously reported a series of plastoquinone analogues to understand their cytotoxic profile. Among these derivatives, three of them (AQ-11, AQ-12, and AQ-15) were selected by the National Cancer Institute (NCI) to evaluate their in vitro antiproliferative activity against a panel of 60 human tumor cell lines. AQ-12 exhibited significant antiproliferative activity against HCT-116 CRC and MCF-7 breast cancer cells at a single dose and further five doses. MTT assay was also performed for AQ-12 at different concentrations against these two cells, implying that AQ-12 exerted notable cytotoxicity toward HCT-116 (IC50 = 5.11 ± 2.14 μM) and MCF-7 (IC50 = 6.06 ± 3.09 μM) cells in comparison with cisplatin (IC50 = 23.68 ± 6.81 μM and 19.67 ± 5.94 μM, respectively). This compound also augmented apoptosis in HCT-116 (62.30%) and MCF-7 (64.60%) cells comparable to cisplatin (67.30% and 78.80%, respectively). Molecular docking studies showed that AQ-12 bound to DNA, forming hydrogen bonding through the quinone scaffold. In silico pharmacokinetic determinants indicated that AQ-12 demonstrated drug-likeness with a remarkable pharmacokinetic profile for future mechanistic anti-CRC and anti-breast cancer activity studies. Full article
(This article belongs to the Special Issue Novel Anti-proliferative Agents)
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23 pages, 5826 KiB  
Article
Identification of Novel Aryl Carboxamide Derivatives as Death-Associated Protein Kinase 1 (DAPK1) Inhibitors with Anti-Proliferative Activities: Design, Synthesis, In Vitro, and In Silico Biological Studies
by Ahmed Elkamhawy, Sora Paik, Eslam M. H. Ali, Ahmed H. E. Hassan, So Jin Kang, Kyeong Lee and Eun Joo Roh
Pharmaceuticals 2022, 15(9), 1050; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15091050 - 25 Aug 2022
Cited by 7 | Viewed by 1819
Abstract
Death-associated protein kinase 1 (DAPK1) is a serine/threonine protein kinase involved in diverse fundamental cellular processes such as apoptosis and autophagy. DAPK1 isoform plays an essential role as a tumor suppressor and inhibitor of metastasis. Consequently, DAPK1 became a promising target protein for [...] Read more.
Death-associated protein kinase 1 (DAPK1) is a serine/threonine protein kinase involved in diverse fundamental cellular processes such as apoptosis and autophagy. DAPK1 isoform plays an essential role as a tumor suppressor and inhibitor of metastasis. Consequently, DAPK1 became a promising target protein for developing new anti-cancer agents. In this work, we present the rational design and complete synthetic routes of a novel series of eighteen aryl carboxamide derivatives as potential DAPK1 inhibitors. Using a custom panel of forty-five kinases, a single dose of 10 µM of the picolinamide derivative 4a was able to selectively inhibit DAPK1 kinase by 44.19%. Further investigations revealed the isonicotinamide derivative 4q as a promising DAPK1 inhibitory lead compound with an IC50 value of 1.09 µM. In an in vitro anticancer activity assay using a library of 60 cancer cell lines including blood, lung, colon, CNS, skin, ovary, renal, prostate, and breast cancers, four compounds (4d, 4e, 4o, and 4p) demonstrated high anti-proliferative activity with mean % GI ~70%. Furthermore, the most potent DAPK1 inhibitor (4q) exhibited remarkable activity against leukemia (K-562) and breast cancer (MDA-MB-468) with % GI of 72% and 75%, respectively. Full article
(This article belongs to the Special Issue Novel Anti-proliferative Agents)
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27 pages, 4102 KiB  
Article
Design, Synthesis and Biological Investigation of 2-Anilino Triazolopyrimidines as Tubulin Polymerization Inhibitors with Anticancer Activities
by Romeo Romagnoli, Paola Oliva, Filippo Prencipe, Stefano Manfredini, Federica Budassi, Andrea Brancale, Salvatore Ferla, Ernest Hamel, Diana Corallo, Sanja Aveic, Lorenzo Manfreda, Elena Mariotto, Roberta Bortolozzi and Giampietro Viola
Pharmaceuticals 2022, 15(8), 1031; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15081031 - 21 Aug 2022
Cited by 5 | Viewed by 2802
Abstract
A further investigation aiming to generate new potential antitumor agents led us to synthesize a new series of twenty-two compounds characterized by the presence of the 7-(3′,4′,5′-trimethoxyphenyl)-[1,2,4]triazolo[1,5-a]pyrimidine pharmacophore modified at its 2-position. Among the synthesized compounds, three were significantly more active [...] Read more.
A further investigation aiming to generate new potential antitumor agents led us to synthesize a new series of twenty-two compounds characterized by the presence of the 7-(3′,4′,5′-trimethoxyphenyl)-[1,2,4]triazolo[1,5-a]pyrimidine pharmacophore modified at its 2-position. Among the synthesized compounds, three were significantly more active than the others. These bore the substituents p-toluidino (3d), p-ethylanilino (3h) and 3′,4′-dimethylanilino (3f), and these compounds had IC50 values of 30–43, 160–240 and 67–160 nM, respectively, on HeLa, A549 and HT-29 cancer cells. The p-toluidino derivative 3d was the most potent inhibitor of tubulin polymerization (IC50: 0.45 µM) and strongly inhibited the binding of colchicine to tubulin (72% inhibition), with antiproliferative activity superior to CA-4 against A549 and HeLa cancer cell lines. In vitro investigation showed that compound 3d was able to block treated cells in the G2/M phase of the cell cycle and to induce apoptosis following the intrinsic pathway, further confirmed by mitochondrial depolarization and caspase-9 activation. In vivo experiments conducted on the zebrafish model showed good activity of 3d in reducing the mass of a HeLa cell xenograft. These effects occurred at nontoxic concentrations to the animal, indicating that 3d merits further developmental studies. Full article
(This article belongs to the Special Issue Novel Anti-proliferative Agents)
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17 pages, 3943 KiB  
Article
Synthesis and Biological Evaluation of Indole-2-Carboxamides with Potent Apoptotic Antiproliferative Activity as EGFR/CDK2 Dual Inhibitors
by Lamya H. Al-Wahaibi, Yaser A. Mostafa, Mostafa H. Abdelrahman, Ali H. El-Bahrawy, Laurent Trembleau and Bahaa G. M. Youssif
Pharmaceuticals 2022, 15(8), 1006; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15081006 - 16 Aug 2022
Cited by 13 | Viewed by 1939
Abstract
The apoptotic antiproliferative actions of our previously reported CB1 allosteric modulators 5-chlorobenzofuran-2-carboxamide derivatives VIIa–j prompted us to develop and synthesise a novel series of indole-2-carboxamide derivatives 5a–k, 6a–c, and 7. Different spectroscopic methods of [...] Read more.
The apoptotic antiproliferative actions of our previously reported CB1 allosteric modulators 5-chlorobenzofuran-2-carboxamide derivatives VIIa–j prompted us to develop and synthesise a novel series of indole-2-carboxamide derivatives 5a–k, 6a–c, and 7. Different spectroscopic methods of analysis were used to validate the novel compounds. Using the MTT assay method, the novel compounds were examined for antiproliferative activity against four distinct cancer cell lines. Compounds 5a–k, 6a–c, and 7 demonstrated greater antiproliferative activity against the breast cancer cell line (MCF-7) than other tested cancer cell lines, and 5a–k (which contain the phenethyl moiety in their backbone structure) demonstrated greater potency than 6a–c and 7, indicating the importance of the phenethyl moiety for antiproliferative action. Compared to reference doxorubicin (GI50 = 1.10 µM), compounds 5d, 5e, 5h, 5i, 5j, and 5k were the most effective of the synthesised derivatives, with GI50 ranging from 0.95 µM to 1.50 µM. Compounds 5d, 5e, 5h, 5i, 5j, and 5k were tested for their inhibitory impact on EGFR and CDK2, and the results indicated that the compounds tested had strong antiproliferative activity and are effective at suppressing both CDK2 and EGFR. Moreover, the studied compounds induced apoptosis with high potency, as evidenced by their effects on apoptotic markers such as Caspases 3, 8, 9, Cytochrome C, Bax, Bcl2, and p53. Full article
(This article belongs to the Special Issue Novel Anti-proliferative Agents)
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19 pages, 2031 KiB  
Article
Benzothiazole Derivatives Endowed with Antiproliferative Activity in Paraganglioma and Pancreatic Cancer Cells: Structure–Activity Relationship Studies and Target Prediction Analysis
by Rosa Amoroso, Laura De Lellis, Rosalba Florio, Nazaret Moreno, Mariangela Agamennone, Barbara De Filippis, Letizia Giampietro, Cristina Maccallini, Inmaculada Fernández, Rocío Recio, Alessandro Cama, Marialuigia Fantacuzzi and Alessandra Ammazzalorso
Pharmaceuticals 2022, 15(8), 937; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15080937 - 28 Jul 2022
Cited by 3 | Viewed by 1621
Abstract
The antiproliferative effects played by benzothiazoles in different cancers have aroused the interest for these molecules as promising antitumor agents. In this work, a library of phenylacetamide derivatives containing the benzothiazole nucleus was synthesized and compounds were tested for their antiproliferative activity in [...] Read more.
The antiproliferative effects played by benzothiazoles in different cancers have aroused the interest for these molecules as promising antitumor agents. In this work, a library of phenylacetamide derivatives containing the benzothiazole nucleus was synthesized and compounds were tested for their antiproliferative activity in paraganglioma and pancreatic cancer cell lines. The novel synthesized compounds induced a marked viability reduction at low micromolar concentrations both in paraganglioma and pancreatic cancer cells. Derivative 4l showed a greater antiproliferative effect and higher selectivity index against cancer cells, as compared to other compounds. Notably, combinations of derivative 4l with gemcitabine at low concentrations induced enhanced and synergistic effects on pancreatic cancer cell viability, thus supporting the relevance of compound 4l in the perspective of clinical translation. A target prediction analysis was also carried out on 4l by using multiple computational tools, identifying cannabinoid receptors and sentrin-specific proteases as putative targets contributing to the observed antiproliferative activity. Full article
(This article belongs to the Special Issue Novel Anti-proliferative Agents)
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14 pages, 3648 KiB  
Article
C-Myc Expression in Oral Squamous Cell Carcinoma: Molecular Mechanisms in Cell Survival and Cancer Progression
by Guya Diletta Marconi, Ylenia Della Rocca, Luigia Fonticoli, Francesco Melfi, Thangavelu Soundara Rajan, Simone Carradori, Jacopo Pizzicannella, Oriana Trubiani and Francesca Diomede
Pharmaceuticals 2022, 15(7), 890; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15070890 - 19 Jul 2022
Cited by 7 | Viewed by 1895
Abstract
Oral squamous cell carcinoma (OSCC) represents 90% of malignant epithelial cancer that occurs in the oral cavity. The c-Myc factor is expressed in multiple types of cancer, comprising head and neck squamous cell carcinoma (HNSCC), where it plays a fundamental role in tumor [...] Read more.
Oral squamous cell carcinoma (OSCC) represents 90% of malignant epithelial cancer that occurs in the oral cavity. The c-Myc factor is expressed in multiple types of cancer, comprising head and neck squamous cell carcinoma (HNSCC), where it plays a fundamental role in tumor prognosis and in the self-renewal of tumor stem cells. However, the role of c-Myc in controlling OSCC cells is not well-known. The aim of the present study is the evaluation of the biological roles and regulatory mechanism of c-Myc in the pathogenesis of OSCC. Results indicated that c-Myc, c-Jun, Bcl-2, hypoxia inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), matrix metalloproteinase-9 (MMP-9), ERK 1/2 and pERK1/2 were overexpressed in a cellular model of squamous cell carcinoma, Cal-27. Doxorubicin (Doxo), a common chemotherapeutic agent, inhibited cell invasion, hypoxia, angiogenesis and inflammation in a cellular model of Cal-27 cells as indicated by downregulation of MMP-9, VEGF, ERK 1/2 and pERK 1/2 as well as promoted apoptosis as evidenced by the downregulation of Bcl-2 protein. This work aimed at underlying the functional relevance of c-Myc in OSCC and the HIF-Myc collaboration by integrating the knowledge on this molecular link in an OSCC tumor microenvironment. The results obtained showed for the first time the vital role of c-Myc in Cal-27 in cell survival/proliferation and tumor growth as well as the negative regulatory effect of Doxo against c-Myc signaling pathway. Full article
(This article belongs to the Special Issue Novel Anti-proliferative Agents)
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17 pages, 4031 KiB  
Article
Design and Synthesis of New Hydantoin Acetanilide Derivatives as Anti-NSCLC Targeting EGFRL858R/T790M Mutations
by Moamen A. Hassanin, Muhamad Mustafa, Mohammed A. S. Abourehab, Heba A. Hassan, Omar M. Aly and Eman A. M. Beshr
Pharmaceuticals 2022, 15(7), 857; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15070857 - 12 Jul 2022
Cited by 3 | Viewed by 2099
Abstract
Epidermal Growth Factor Receptor (EGFR), its wild type and mutations L858R/T790M, is overexpressed in non-small cell lung cancer (NSCLC) patients and is considered an inevitable oncology target. However, while the potential EGFR inhibitors have been represented in the literature, their cellular activity failed [...] Read more.
Epidermal Growth Factor Receptor (EGFR), its wild type and mutations L858R/T790M, is overexpressed in non-small cell lung cancer (NSCLC) patients and is considered an inevitable oncology target. However, while the potential EGFR inhibitors have been represented in the literature, their cellular activity failed to establish broad potency against EGFR and its mutations. This study identifies a new series of EGFRL858R/T790M inhibitors bearing hydantoin acetanilides. Most compounds revealed strong antiproliferative activity in a range of NSCL cancer models (A549, H1975, and PC9), in which 5a and 5f were the most potent. Compounds 5a and 5f possessed potent anticancer activity on H1975 cells with IC50 values of 1.94 and 1.38 µM, respectively, compared to 9.70 µM for erlotinib. Favorably, 5a and 5f showed low activity on WI-38 normal cells. Western blotting and an EGFR kinase assay test proved the significant EGFR inhibitory activity of 5a. Besides, active hydantoin derivative 5a strongly arrested the cell cycle at the sub G1 and S phases and triggered apoptosis in A549 cells. These results imply that 5a could be considered a promising lead compound for additional development as a potential active agent for anticancer therapy. Full article
(This article belongs to the Special Issue Novel Anti-proliferative Agents)
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18 pages, 3717 KiB  
Article
Hybridization Approach to Identify Salicylanilides as Inhibitors of Tubulin Polymerization and Signal Transducers and Activators of Transcription 3 (STAT3)
by Marta Gargantilla, Leentje Persoons, Tereza Kauerová, Natalia del Río, Dirk Daelemans, Eva-María Priego, Peter Kollar and María-Jesús Pérez-Pérez
Pharmaceuticals 2022, 15(7), 835; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15070835 - 06 Jul 2022
Cited by 9 | Viewed by 1879
Abstract
The superimposition of the X-ray complexes of cyclohexanediones (i.e., TUB015), described by our research group, and nocodazole, within the colchicine binding site of tubulin provided an almost perfect overlap of both ligands. This structural information led us to propose hybrids of TUB015 and [...] Read more.
The superimposition of the X-ray complexes of cyclohexanediones (i.e., TUB015), described by our research group, and nocodazole, within the colchicine binding site of tubulin provided an almost perfect overlap of both ligands. This structural information led us to propose hybrids of TUB015 and nocodazole using a salicylanilide core structure. Interestingly, salicylanilides, such as niclosamide, are well-established signal transducers and activators of transcription (STAT3) inhibitors with anticancer properties. Thus, different compounds with this new scaffold have been synthesized with the aim to identify compounds inhibiting tubulin polymerization and/or STAT3 signaling. As a result, we have identified new salicylanilides (6 and 16) that showed significant antiproliferative activity against a panel of cancer cells. Both compounds were able to reduce the levels of p-STAT3Tyr705 without affecting the total expression of STAT3. While compound 6 inhibited tubulin polymerization and arrested the cell cycle of DU145 cells at G2/M, similar to TUB015, compound 16 showed a more potent effect on inhibiting STAT3 phosphorylation and arrested the cell cycle at G1/G0, similar to niclosamide. In both cases, no toxicity towards PBMC cells was detected. Thus, the salicylanilides described here represent a new class of antiproliferative agents affecting tubulin polymerization and/or STAT3 phosphorylation. Full article
(This article belongs to the Special Issue Novel Anti-proliferative Agents)
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28 pages, 5893 KiB  
Article
New Genetic Bomb Trigger: Design, Synthesis, Molecular Dynamics Simulation, and Biological Evaluation of Novel BIBR1532-Related Analogs Targeting Telomerase against Non-Small Cell Lung Cancer
by Haytham O. Tawfik, Anwar A. El-Hamaky, Eman A. El-Bastawissy, Kirill A. Shcherbakov, Alexander V. Veselovsky, Yulia A. Gladilina, Dmitry D. Zhdanov and Mervat H. El-Hamamsy
Pharmaceuticals 2022, 15(4), 481; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15040481 - 14 Apr 2022
Cited by 10 | Viewed by 3057
Abstract
Telomeres serve a critical function in cell replication and proliferation at every stage of the cell cycle. Telomerase is a ribonucleoprotein, responsible for maintaining the telomere length and chromosomal integrity of frequently dividing cells. Although it is silenced in most human somatic cells, [...] Read more.
Telomeres serve a critical function in cell replication and proliferation at every stage of the cell cycle. Telomerase is a ribonucleoprotein, responsible for maintaining the telomere length and chromosomal integrity of frequently dividing cells. Although it is silenced in most human somatic cells, telomere restoration occurs in cancer cells because of telomerase activation or alternative telomere lengthening. The telomerase enzyme is a universal anticancer target that is expressed in 85–95% of cancers. BIBR1532 is a selective non-nucleoside potent telomerase inhibitor that acts by direct noncompetitive inhibition. Relying on its structural features, three different series were designed, and 30 novel compounds were synthesized and biologically evaluated as telomerase inhibitors using a telomeric repeat amplification protocol (TRAP) assay. Target compounds 29a, 36b, and 39b reported the greatest inhibitory effect on telomerase enzyme with IC50 values of 1.7, 0.3, and 2.0 μM, respectively, while BIBR1532 displayed IC50 = 0.2 μM. Compounds 29a, 36b, and 39b were subsequently tested using a living-cell TRAP assay and were able to penetrate the cell membrane and inhibit telomerase inside living cancer cells. Compound 36b was tested for cytotoxicity against 60 cancer cell lines using the NCI (USA) procedure, and the % growth was minimally impacted, indicating telomerase enzyme selectivity. To investigate the interaction of compound 36b with the telomerase allosteric binding site, molecular docking and molecular dynamics simulations were used. Full article
(This article belongs to the Special Issue Novel Anti-proliferative Agents)
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17 pages, 17119 KiB  
Article
Design, Synthesis, and Molecular Docking Studies of Curcumin Hybrid Conjugates as Potential Therapeutics for Breast Cancer
by Siva S. Panda, Queen L. Tran, Pragya Rajpurohit, Girinath G. Pillai, Sean J. Thomas, Allison E. Bridges, Jason E. Capito, Muthusamy Thangaraju and Bal L. Lokeshwar
Pharmaceuticals 2022, 15(4), 451; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15040451 - 06 Apr 2022
Cited by 11 | Viewed by 2851
Abstract
Curcumin (CUR) has received great attention over the past two decades due to its anticancer, anti-inflammatory, and antioxidant properties. Similarly, Dichloroacetate (DCA), an pyruvate dehydrogenase kinase 1 (PKD1) inhibitor, has gained huge attention as a potential anticancer drug. However, the clinical utility of [...] Read more.
Curcumin (CUR) has received great attention over the past two decades due to its anticancer, anti-inflammatory, and antioxidant properties. Similarly, Dichloroacetate (DCA), an pyruvate dehydrogenase kinase 1 (PKD1) inhibitor, has gained huge attention as a potential anticancer drug. However, the clinical utility of these two agents is very limited because of the poor bioavailability and unsolicited side effects, respectively. We have synthesized fusion conjugates of CUR and DCA with an amino acids linker to overcome these limitations by utilizing the molecular hybridization approach. The molecular docking studies showed the potential targets of Curcumin-Modified Conjugates (CMCs) in breast cancer cells. We synthesized six hybrid conjugates named CMC1-6. These six CMC conjugates do not show any significant toxicity in a human normal immortalized mammary epithelial cell line (MCF10A) in vitro and C57BL/6 mice in vivo. However, treatment with CMC1 and CMC2 significantly reduced the growth and clonogenic survival by colony-formation assays in several human breast cancer cells (BC). Treatment by oral gavage of a transgenic mouse BC and metastatic BC tumor-bearing mice with CMC2 significantly reduced tumor growth and metastasis. Overall, our study provides strong evidence that CUR and DCA conjugates have a significant anticancer properties at a sub-micromolar concentration and overcome the clinical limitation of using CUR and DCA as potential anticancer drugs. Full article
(This article belongs to the Special Issue Novel Anti-proliferative Agents)
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18 pages, 3383 KiB  
Article
Eltrombopag as an Allosteric Inhibitor of the METTL3-14 Complex Affecting the m6A Methylation of RNA in Acute Myeloid Leukemia Cells
by Je-Heon Lee, Namjeong Choi, Subin Kim, Mi Sun Jin, Haihong Shen and Yong-Chul Kim
Pharmaceuticals 2022, 15(4), 440; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15040440 - 01 Apr 2022
Cited by 24 | Viewed by 3588
Abstract
N6A-methyladenosine (m6A) post-transcriptional modification, the most abundant internal RNA modification, is catalyzed by the METTL3-14 methyltransferase complex. Recently, attention has been drawn to the METTL3-14 complex regarding its significant roles in the pathogenesis of acute myeloid leukemia (AML), attracting [...] Read more.
N6A-methyladenosine (m6A) post-transcriptional modification, the most abundant internal RNA modification, is catalyzed by the METTL3-14 methyltransferase complex. Recently, attention has been drawn to the METTL3-14 complex regarding its significant roles in the pathogenesis of acute myeloid leukemia (AML), attracting the potential of novel therapeutic targets for the disease. Herein, we report the identification and characterization of eltrombopag as a selective allosteric inhibitor of the METTL3-14 complex. Eltrombopag exhibited selective inhibitory activity in the most active catalytic form of the METTL3-14 complex by direct binding, and the mechanism of inhibition was confirmed as a noncompetitive inhibition by interacting at a putative allosteric binding site in METTL3, which was predicted by cavity search and molecular docking studies. At a cellular level, eltrombopag displayed anti-proliferative effects in the relevant AML cell line, MOLM-13, in correlation with a reduction in m6A levels. Molecular mechanism studies of eltrombopag using m6A-seq analysis provided further evidence of its cellular function by determining the hypomethylation of leukemogenic genes in eltrombopag-treated MOLM-13 cells and the overlapping of the pattern with those of METTL3-knockdown MOLM-13 cells. In conclusion, eltrombopag was first disclosed as a functional METTL3-14 allosteric inhibitor in AML cells, which could be utilized for the further development of novel anti-AML therapy. Full article
(This article belongs to the Special Issue Novel Anti-proliferative Agents)
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17 pages, 3922 KiB  
Article
Targeting Wnt/Beta-Catenin Signaling in HPV-Positive Head and Neck Squamous Cell Carcinoma
by Faris F. Brkic, Stefan Stoiber, Tobias Maier, Elisabeth Gurnhofer, Lukas Kenner, Gregor Heiduschka and Lorenz Kadletz-Wanke
Pharmaceuticals 2022, 15(3), 378; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15030378 - 20 Mar 2022
Cited by 8 | Viewed by 3457
Abstract
Wnt/Beta-Catenin signaling is involved in the carcinogenesis of different solid malignant tumors. The interaction of Creb-binding protein (CBP) with Beta-Catenin is a pivotal component of the Wnt/Beta-Catenin signaling pathway. The first aim of this study was to evaluate the association of CBP expression [...] Read more.
Wnt/Beta-Catenin signaling is involved in the carcinogenesis of different solid malignant tumors. The interaction of Creb-binding protein (CBP) with Beta-Catenin is a pivotal component of the Wnt/Beta-Catenin signaling pathway. The first aim of this study was to evaluate the association of CBP expression with survival in patients with human papillomavirus (HPV)-positive head and neck squamous cell carcinoma (HNSCC). Second, the in vitro effects of the inhibition of CBP/Beta-Catenin interaction were analyzed. In particular, the effects of ICG-001, an inhibitor of CBP/Beta-Catenin interaction, on proliferation, cell death, modulation of Wnt/Beta-Catenin target expression, and cell migration were examined in vitro. High CBP expression is significantly associated with better survival on mRNA and protein levels. Furthermore, we observed cytotoxic as well as anti-migratory effects of ICG-001. These effects were particularly more potent in the HPV-positive than in the -negative cell line. Mechanistically, ICG-001 treatment induced apoptosis and led to a downregulation of CBP, c-MYC, and Cyclin D1 in HPV-positive cells, indicating inhibition of Wnt/Beta-Catenin signaling. In conclusion, high CBP expression is observed in HPV-positive HNSCC patients with a good prognosis, and ICG-001 showed a promising antineoplastic potential, particularly in HPV-positive HNSCC cells. Therefore, ICG-001 may potentially become an essential component of treatment de-escalation regimens for HPV-positive HNSCC. Further studies are warranted for additional assessment of the mechanistic background of our in vitro findings. Full article
(This article belongs to the Special Issue Novel Anti-proliferative Agents)
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22 pages, 5749 KiB  
Article
Design, Synthesis, Molecular Docking, and Biological Evaluation of Pyrazole Hybrid Chalcone Conjugates as Potential Anticancer Agents and Tubulin Polymerization Inhibitors
by Md. Jahangir Alam, Ozair Alam, Ahmad Perwez, Moshahid Alam Rizvi, Mohd Javed Naim, Vegi G. M. Naidu, Mohd Imran, Mohammed M. Ghoneim, Sultan Alshehri and Faiyaz Shakeel
Pharmaceuticals 2022, 15(3), 280; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15030280 - 24 Feb 2022
Cited by 12 | Viewed by 2619
Abstract
Some (E)-3-(3-(4-(benzyloxy)phenyl)-1-phenyl-1H-pyrazol-4-yl)-1-phenylprop-2-en-1-one conjugates 5a–r were designed; synthesized; characterized by 1H, 13C NMR, and ESI-MS; and evaluated for tubulin polymerization inhibitory activity and in vitro cytotoxicity against breast (MCF-7), cervical (SiHa), and prostate (PC-3) cancer cell [...] Read more.
Some (E)-3-(3-(4-(benzyloxy)phenyl)-1-phenyl-1H-pyrazol-4-yl)-1-phenylprop-2-en-1-one conjugates 5a–r were designed; synthesized; characterized by 1H, 13C NMR, and ESI-MS; and evaluated for tubulin polymerization inhibitory activity and in vitro cytotoxicity against breast (MCF-7), cervical (SiHa), and prostate (PC-3) cancer cell lines, as well as a normal cell line (HEK-293T). The compounds were also tested to determine their binding modes at the colchicine-binding site of tubulin protein (PDB ID-3E22), for in silico ADME prediction, for bioactivity study, and for PASS prediction studies. Among all the synthesized conjugates, compound 5o exhibited excellent cytotoxicity with an IC50 value of 2.13 ± 0.80 µM (MCF-7), 4.34 ± 0.98 µM (SiHa), and 4.46 ± 0.53 µM (PC-3) against cancer cell lines. The compound did not exhibit significant toxicity to the HEK cells. Results of the in silico prediction revealed that the majority of the conjugates possessed drug-like properties. Full article
(This article belongs to the Special Issue Novel Anti-proliferative Agents)
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10 pages, 5484 KiB  
Communication
Synthesis of Novel (S)-3-(1-Aminoethyl)-8-pyrimidinyl-2-phenylisoquinolin-1(2H)-ones by Suzuki–Miyaura Coupling and Their Cell Toxicity Activities
by Ok Kyoung Choi, Yong Ho Sun, Hyemi Lee, Joon Kwang Lee, Tae Hoon Lee and Hakwon Kim
Pharmaceuticals 2022, 15(1), 64; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15010064 - 04 Jan 2022
Cited by 1 | Viewed by 1488
Abstract
A series of (S)-3-(1-aminoethyl)-8-pyrimidinyl-2-phenylisoquinoline-1(2H)-ones 3a–3k was synthesized in 40–98% yield through Suzuki–Miyaura coupling using Pd(PPh3)2Cl2, Sphos, and K2CO3 in THF/H2O mixed solvent. All newly synthesized compounds [...] Read more.
A series of (S)-3-(1-aminoethyl)-8-pyrimidinyl-2-phenylisoquinoline-1(2H)-ones 3a–3k was synthesized in 40–98% yield through Suzuki–Miyaura coupling using Pd(PPh3)2Cl2, Sphos, and K2CO3 in THF/H2O mixed solvent. All newly synthesized compounds were evaluated for cell viability (IC50) against MDA-MB-231, HeLa, and HepG2 cells. The antitumor activities of 3a–3k were improved when various pyrimidine motifs were introduced at position C-8 of the isoquinolinone ring. Full article
(This article belongs to the Special Issue Novel Anti-proliferative Agents)
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Review

Jump to: Editorial, Research

56 pages, 1330 KiB  
Review
How Should the Worldwide Knowledge of Traditional Cancer Healing Be Integrated with Herbs and Mushrooms into Modern Molecular Pharmacology?
by Yulia Kirdeeva, Olga Fedorova, Alexandra Daks, Nikolai Barlev and Oleg Shuvalov
Pharmaceuticals 2022, 15(7), 868; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15070868 - 14 Jul 2022
Cited by 7 | Viewed by 4710
Abstract
Traditional herbal medicine (THM) is a “core” from which modern medicine has evolved over time. Besides this, one third of people worldwide have no access to modern medicine and rely only on traditional medicine. To date, drugs of plant origin, or their derivates [...] Read more.
Traditional herbal medicine (THM) is a “core” from which modern medicine has evolved over time. Besides this, one third of people worldwide have no access to modern medicine and rely only on traditional medicine. To date, drugs of plant origin, or their derivates (paclitaxel, vinblastine, vincristine, vinorelbine, etoposide, camptothecin, topotecan, irinotecan, and omacetaxine), are very important in the therapy of malignancies and they are included in most chemotherapeutic regimes. To date, 391,000 plant and 14,000 mushroom species exist. Their medical and biochemical capabilities have not been studied in detail. In this review, we systematized the information about plants and mushrooms, as well as their active compounds with antitumor properties. Plants and mushrooms are divided based on the regions where they are used in ethnomedicine to treat malignancies. The majority of their active compounds with antineoplastic properties and mechanisms of action are described. Furthermore, on the basis of the available information, we divided them into two priority groups for research and for their potential of use in antitumor therapy. As there are many prerequisites and some examples how THM helps and strengthens modern medicine, finally, we discuss the positive points of THM and the management required to transform and integrate THM into the modern medicine practice. Full article
(This article belongs to the Special Issue Novel Anti-proliferative Agents)
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