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Advances in Anticancer Drug Discovery II
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Advances in Anticancer Drug Discovery II

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

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 86769

Special Issue Editor

Dr. Jóhannes Reynisson

E-Mail Website
Guest Editor
School of Pharmacy, Keele University, Newcastle-under-Lyme ST5 5BG, UK
Interests: drug discovery; virtual screening; molecular modelling; chemical space; density functional theory
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In some developed countries, cancer is now the main cause of death. Even though great progress has been made in the treatment of cancer, and practically some cancer types are curable, there is an acute need for much-improved therapies. In particular, with aging demographics more people will develop neoplastic diseases and, eventually, cancer. A further consideration is that elderly people are less able to tolerate aggressive surgery, radiation therapy, and/or cytotoxic drugs. Therefore, oncologists are often forced to make the difficult decision not to propose any intervention and can only offer palliative care. Therefore, the need for more benign anticancer therapies is acute.

In this Special Issue, we wish to focus on the area of drug discovery, design, and development, where new biological targets are being investigated and small molecules with potency against various cancer types are being developed, which in turn will lay the foundations for novel and more benign anticancer therapies.

Dr. Jóhannes Reynisson
Guest Editor

Manuscript Submission Information

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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

  • Drug discovery
  • Drug design
  • Anti-cancer
  • Anti-neoplastic
  • Anti-tumour
  • Screening—high throughput
  • virtual and fragment-based
  • Synthesis
  • Chemical space
  • Structural activity relationship (SAR)
  • Biochemical assays
  • Biophysical assays
  • Cell-based assays
  • Druggability

Published Papers (16 papers)

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Research

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22 pages, 6261 KiB  
Article
Imidazolyl Ethanamide Pentandioic Acid (IEPA) as Potential Radical Scavenger during Tumor Therapy in Human Hematopoietic Stem Cells
by Lucas C. Pfau, Annegret Glasow, Clemens Seidel and Ina Patties
Molecules 2023, 28(5), 2008; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules28052008 - 21 Feb 2023
Viewed by 1952
Abstract
Radiochemotherapy-associated leuco- or thrombocytopenia is a common complication, e.g., in head and neck cancer (HNSCC) and glioblastoma (GBM) patients, often compromising treatments and outcomes. Currently, no sufficient prophylaxis for hematological toxicities is available. The antiviral compound imidazolyl ethanamide pentandioic acid (IEPA) has been [...] Read more.
Radiochemotherapy-associated leuco- or thrombocytopenia is a common complication, e.g., in head and neck cancer (HNSCC) and glioblastoma (GBM) patients, often compromising treatments and outcomes. Currently, no sufficient prophylaxis for hematological toxicities is available. The antiviral compound imidazolyl ethanamide pentandioic acid (IEPA) has been shown to induce maturation and differentiation of hematopoietic stem and progenitor cells (HSPCs), resulting in reduced chemotherapy-associated cytopenia. In order for it to be a potential prophylaxis for radiochemotherapy-related hematologic toxicity in cancer patients, the tumor-protective effects of IEPA should be precluded. In this study, we investigated the combinatorial effects of IEPA with radio- and/or chemotherapy in human HNSCC and GBM tumor cell lines and HSPCs. Treatment with IEPA was followed by irradiation (IR) or chemotherapy (ChT; cisplatin, CIS; lomustine, CCNU; temozolomide, TMZ). Metabolic activity, apoptosis, proliferation, reactive oxygen species (ROS) induction, long-term survival, differentiation capacity, cytokine release, and DNA double-strand breaks (DSBs) were measured. In tumor cells, IEPA dose-dependently diminished IR-induced ROS induction but did not affect the IR-induced changes in metabolic activity, proliferation, apoptosis, or cytokine release. In addition, IEPA showed no protective effect on the long-term survival of tumor cells after radio- or chemotherapy. In HSPCs, IEPA alone slightly enhanced CFU-GEMM and CFU-GM colony counts (2/2 donors). The IR- or ChT-induced decline of early progenitors could not be reversed by IEPA. Our data indicate that IEPA is a potential candidate for the prevention of hematologic toxicity in cancer treatment without affecting therapeutic benefits. Full article
(This article belongs to the Special Issue Advances in Anticancer Drug Discovery II)
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17 pages, 3180 KiB  
Article
Discovery of New Inhibitors of eEF2K from Traditional Chinese Medicine Based on In Silico Screening and In Vitro Experimental Validation
by Qinghua Fu, Xiaomei Liu, Yan Li, Peng Wang, Tian Wu, Haihan Xiao, Yameng Zhao, Qichao Liao and Ziyi Song
Molecules 2022, 27(15), 4886; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27154886 - 30 Jul 2022
Cited by 4 | Viewed by 1848
Abstract
Eukaryotic elongation factor 2 kinase (eEF2K) is a highly conserved α kinase and is increasingly considered as an attractive therapeutic target for cancer as well as other diseases. However, so far, no selective and potent inhibitors of eEF2K have been identified. In this [...] Read more.
Eukaryotic elongation factor 2 kinase (eEF2K) is a highly conserved α kinase and is increasingly considered as an attractive therapeutic target for cancer as well as other diseases. However, so far, no selective and potent inhibitors of eEF2K have been identified. In this study, pharmacophore screening, homology modeling, and molecular docking methods were adopted to screen novel inhibitor hits of eEF2K from the traditional Chinese medicine database (TCMD), and then cytotoxicity assay and western blotting were performed to verify the validity of the screen. Resultantly, after two steps of screening, a total of 1077 chemicals were obtained as inhibitor hits for eEF2K from all 23,034 compounds in TCMD. Then, to verify the validity, the top 10 purchasable chemicals were further analyzed. Afterward, Oleuropein and Rhoifolin, two reported antitumor chemicals, were found to have low cytotoxicity but potent inhibitory effects on eEF2K activity. Finally, molecular dynamics simulation, pharmacokinetic and toxicological analyses were conducted to evaluate the property and potential of Oleuropein and Rhoifolin to be drugs. Together, by integrating in silico screening and in vitro biochemical studies, Oleuropein and Rhoifolin were revealed as novel eEF2K inhibitors, which will shed new lights for eEF2K-targeting drug development and anticancer therapy. Full article
(This article belongs to the Special Issue Advances in Anticancer Drug Discovery II)
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10 pages, 1562 KiB  
Communication
Carborane-Based Analog of Rev-5901 Attenuates Growth of Colon Carcinoma In Vivo
by Svetlana Paskaš, Blagoje Murganić, Robert Kuhnert, Evamarie Hey-Hawkins, Sanja Mijatović and Danijela Maksimović-Ivanić
Molecules 2022, 27(14), 4503; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27144503 - 14 Jul 2022
Cited by 3 | Viewed by 1394
Abstract
Lipoxygenases convert polyunsaturated fatty acids into biologically active metabolites such as inflammatory mediators—prostaglandins and leukotrienes. The inhibition of lipoxygenases is increasingly employed in the treatment of cancer. We evaluated the anticancer potential of two novel 5-lipoxygenase inhibitors, named CarbZDNaph and CarbZDChin, which are [...] Read more.
Lipoxygenases convert polyunsaturated fatty acids into biologically active metabolites such as inflammatory mediators—prostaglandins and leukotrienes. The inhibition of lipoxygenases is increasingly employed in the treatment of cancer. We evaluated the anticancer potential of two novel 5-lipoxygenase inhibitors, named CarbZDNaph and CarbZDChin, which are analogues of the commercially available inhibitor Rev-5901. The in vitro segment of this study was conducted on a mouse colorectal carcinoma cell line—CT26CL25. For an in vivo model, we induced tumors in BALB/c mice by the implantation of CT26CL25 cells, and we treated the animals with potential inhibitors. A 48 h treatment resulted in diminished cell viability. Calculated IC50 values (half-maximal inhibitory concentrations) were 25 μM, 15 μM and 30 μM for CarbZDNaph, CarbZDChin and Rev-5901, respectively. The detailed analysis of mechanism revealed an induction of caspase-dependent apoptosis and autophagy. In the presence of chloroquine, an autophagy inhibitor, we observed an increased mortality of cells, implying a cytoprotective role of autophagy. Our in vivo experiment reports tumor growth attenuation in animals treated with CarbZDChin. Compounds CarbZDNaph and Rev-5901 lacked an in vivo efficacy. The results presented in this study display a strong effect of compound CarbZDChin on malignant cell growth. Having in mind the important role of inflammation in cancer development, these results have a significant impact and are worthy of further evaluation. Full article
(This article belongs to the Special Issue Advances in Anticancer Drug Discovery II)
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19 pages, 3010 KiB  
Article
Pyrazolo[4,3-e]tetrazolo[1,5-b][1,2,4]triazine Sulfonamides as Novel Potential Anticancer Agents: Cytotoxic and Genotoxic Activities In Vitro
by Karol Bukowski, Beata Marciniak, Mateusz Kciuk, Mariusz Mojzych and Renata Kontek
Molecules 2022, 27(12), 3761; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27123761 - 11 Jun 2022
Cited by 4 | Viewed by 1661
Abstract
In this paper, we present for the first time the evaluation of cytotoxicity and genotoxicity of de novo synthesized pyrazolo[4,3-e]tetrazolo[1,5-b][1,2,4]triazine sulfonamides MM129, MM130, and MM131 in human tumor cell lines: HeLa, HCT 116, PC-3, and BxPC-3. Cytotoxic [...] Read more.
In this paper, we present for the first time the evaluation of cytotoxicity and genotoxicity of de novo synthesized pyrazolo[4,3-e]tetrazolo[1,5-b][1,2,4]triazine sulfonamides MM129, MM130, and MM131 in human tumor cell lines: HeLa, HCT 116, PC-3, and BxPC-3. Cytotoxic and genotoxic properties of the tested compounds were estimated using the MTT assay, comet assay (alkaline and neutral version), and γ-H2AX immuno-staining. Examined sulfonamides exhibited strong anticancer properties towards tested cells in a very low concentration range (IC50 = 0.17–1.15 μM) after 72 h exposure time. The results of the alkaline and neutral version of the comet assay following 24 h incubation of the cells with tested compounds demonstrated the capability of heterocycles to induce significant DNA damage in exposed cells. HCT 116 cells were the most sensitive to the genotoxic activity of novel tricyclic pyrazolo[4,3-e]tetrazolo[1,5-b][1,2,4]triazine sulfonamides in the neutral version of the comet assay. Immunocytochemical detection of γ-H2AX showed an increase in DNA DSBs level in the HCT 116 cell line, after 24 h incubation with all tested compounds, confirming the results obtained in the neutral comet assay. Among all investigated compounds, MM131 showed the strongest cytotoxic and genotoxic activity toward all tested cell types. In conclusion, our results suggest that MM129, MM130, and MM131 exhibit high cytotoxic and genotoxic potential in vitro, especially towards the colorectal cancer cell line HCT 116. However, further investigations and analyses are required for their future implementation in the field of medicine. Full article
(This article belongs to the Special Issue Advances in Anticancer Drug Discovery II)
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18 pages, 7310 KiB  
Article
Adamantane-Monoterpenoid Conjugates Linked via Heterocyclic Linkers Enhance the Cytotoxic Effect of Topotecan
by Aldar A. Munkuev, Nadezhda S. Dyrkheeva, Tatyana E. Kornienko, Ekaterina S. Ilina, Dmitry I. Ivankin, Evgeniy V. Suslov, Dina V. Korchagina, Yuriy V. Gatilov, Alexandra L. Zakharenko, Anastasia A. Malakhova, Jóhannes Reynisson, Konstantin P. Volcho, Nariman F. Salakhutdinov and Olga I. Lavrik
Molecules 2022, 27(11), 3374; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27113374 - 24 May 2022
Cited by 10 | Viewed by 2766
Abstract
Inhibiting tyrosyl-DNA phosphodiesterase 1 (TDP1) is a promising strategy for increasing the effectiveness of existing antitumor therapy since it can remove the DNA lesions caused by anticancer drugs, which form covalent complexes with topoisomerase 1 (TOP1). Here, new adamantane–monoterpene conjugates with a 1,2,4-triazole [...] Read more.
Inhibiting tyrosyl-DNA phosphodiesterase 1 (TDP1) is a promising strategy for increasing the effectiveness of existing antitumor therapy since it can remove the DNA lesions caused by anticancer drugs, which form covalent complexes with topoisomerase 1 (TOP1). Here, new adamantane–monoterpene conjugates with a 1,2,4-triazole or 1,3,4-thiadiazole linker core were synthesized, where (+)-and (−)-campholenic and (+)-camphor derivatives were used as monoterpene fragments. The campholenic derivatives 14a–14b and 15a–b showed activity against TDP1 at a low micromolar range with IC50 ~5–6 μM, whereas camphor-containing compounds 16 and 17 were ineffective. Surprisingly, all the compounds synthesized demonstrated a clear synergy with topotecan, a TOP1 poison, regardless of their ability to inhibit TDP1. These findings imply that different pathways of enhancing topotecan toxicity other than the inhibition of TDP1 can be realized. Full article
(This article belongs to the Special Issue Advances in Anticancer Drug Discovery II)
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14 pages, 3050 KiB  
Article
Conjugation of Palbociclib with MHI-148 Has an Increased Cytotoxic Effect for Breast Cancer Cells and an Altered Mechanism of Action
by Peter Jaein Choi, Petr Tomek, Moana Tercel, Jóhannes Reynisson, Thomas In Hyeup Park, Elizabeth Alexandra Cooper, William Alexander Denny, Jiney Jose and Euphemia Leung
Molecules 2022, 27(3), 880; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27030880 - 27 Jan 2022
Cited by 6 | Viewed by 3365
Abstract
The CDK4/6 inhibitor palbociclib, combined with endocrine therapy, has been shown to be effective in postmenopausal women with estrogen receptor-positive, HER2-negative advanced or metastatic breast cancer. However, palbociclib is not as effective in the highly aggressive, triple-negative breast cancer that lacks sensitivity to [...] Read more.
The CDK4/6 inhibitor palbociclib, combined with endocrine therapy, has been shown to be effective in postmenopausal women with estrogen receptor-positive, HER2-negative advanced or metastatic breast cancer. However, palbociclib is not as effective in the highly aggressive, triple-negative breast cancer that lacks sensitivity to chemotherapy or endocrine therapy. We hypothesized that conjugation of the near-infrared dye MHI-148 with palbociclib can produce a potential theranostic in triple-negative, as well as estrogen receptor-positive, breast cancer cells. In our study, the conjugate was found to have enhanced activity in all mammalian cell lines tested in vitro. However, the conjugate was cytotoxic and did not induce G1 cell cycle arrest in breast cancer cells, suggesting its mechanism of action differs from the parent compound palbociclib. The study highlights the importance of investigating the mechanism of conjugates of near-infrared dyes to therapeutic compounds, as conjugation can potentially result in a change of mechanism or target, with an enhanced cytotoxic effect in this case. Full article
(This article belongs to the Special Issue Advances in Anticancer Drug Discovery II)
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22 pages, 4118 KiB  
Article
Discovery and Characterization of a Cryptic Secondary Binding Site in the Molecular Chaperone HSP70
by Suzanne O’Connor, Yann-Vaï Le Bihan, Isaac M. Westwood, Manjuan Liu, Oi Wei Mak, Gabriel Zazeri, Ana P. R. Povinelli, Alan M. Jones, Rob van Montfort, Jóhannes Reynisson and Ian Collins
Molecules 2022, 27(3), 817; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27030817 - 26 Jan 2022
Cited by 1 | Viewed by 3913
Abstract
Heat Shock Protein 70s (HSP70s) are key molecular chaperones that are overexpressed in many cancers and often associated with metastasis and poor prognosis. It has proven difficult to develop ATP-competitive, drug-like small molecule inhibitors of HSP70s due to the flexible and hydrophilic nature [...] Read more.
Heat Shock Protein 70s (HSP70s) are key molecular chaperones that are overexpressed in many cancers and often associated with metastasis and poor prognosis. It has proven difficult to develop ATP-competitive, drug-like small molecule inhibitors of HSP70s due to the flexible and hydrophilic nature of the HSP70 ATP-binding site and its high affinity for endogenous nucleotides. The aim of this study was to explore the potential for the inhibition of HSP70 through alternative binding sites using fragment-based approaches. A surface plasmon resonance (SPR) fragment screen designed to detect secondary binding sites in HSP70 led to the identification by X-ray crystallography of a cryptic binding site in the nucleotide-binding domain (NBD) of HSP70 adjacent to the ATP-binding site. Fragment binding was confirmed and characterized as ATP-competitive using SPR and ligand-observed NMR methods. Molecular dynamics simulations were applied to understand the interactions with the protein upon ligand binding, and local secondary structure changes consistent with interconversion between the observed crystal structures with and without the cryptic pocket were detected. A virtual high-throughput screen (vHTS) against the cryptic pocket was conducted, and five compounds with diverse chemical scaffolds were confirmed to bind to HSP70 with micromolar affinity by SPR. These results identified and characterized a new targetable site on HSP70. While targeting HSP70 remains challenging, the new site may provide opportunities to develop allosteric ATP-competitive inhibitors with differentiated physicochemical properties from current series. Full article
(This article belongs to the Special Issue Advances in Anticancer Drug Discovery II)
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22 pages, 5586 KiB  
Article
Evaluation of 2-Thioxoimadazolidin-4-one Derivatives as Potent Anti-Cancer Agents through Apoptosis Induction and Antioxidant Activation: In Vitro and In Vivo Approaches
by Mohamed S. Nafie, Ahmed I. Khodair, Hebat Allah Y. Hassan, Noha M. Abd El-Fadeal, Hanin A. Bogari, Sameh S. Elhady and Safwat A. Ahmed
Molecules 2022, 27(1), 83; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27010083 - 23 Dec 2021
Cited by 14 | Viewed by 2785
Abstract
Background: Hepatocellular carcinoma (HCC) is one of the most widespread malignancies and is reported as the fourth most prevalent cause of cancer deaths worldwide. Therefore, we aimed to investigate the probable mechanistic cytotoxic effect of the promising 2-thioxoimidazolidin-4-one derivative on liver cancer cells [...] Read more.
Background: Hepatocellular carcinoma (HCC) is one of the most widespread malignancies and is reported as the fourth most prevalent cause of cancer deaths worldwide. Therefore, we aimed to investigate the probable mechanistic cytotoxic effect of the promising 2-thioxoimidazolidin-4-one derivative on liver cancer cells using in vitro and in vivo approaches. The compounds were tested for the in vitro cytotoxic activity using MTT assay, and the promising compound was tested in colony forming unit assay, flow cytometric analysis, RT-PCR, Western blotting, in vivo using SEC-carcinoma and in silico to highlight the virtual mechanism of action. Both compounds 4 and 2 performed cytotoxic effects against HepG2 cells with IC50 values of 0.017 and 0.18 μM, respectively, compared to Staurosporine and 5-Fu as reference drugs with IC50 values of 5.07 and 5.18 µM, respectively. Compound 4 treatment revealed apoptosis induction by 19.35-fold (11.42% compared to 0.59% in control), arresting the cell cycle at G2/M phase. Moreover, studying gene expression that plays critical roles in cell cycle and apoptosis by RT-PCR demonstrated that compound 4 enhances the expression of the pro-apoptotic genes p53, PUMA, and Caspase 3, 8, and 9, and impedes the anti-apoptotic Bcl-2 gene in the HepG2 cells. It can also inhibit the PI3K/AKT pathway at both gene and protein levels, which was reinforced by the in silico predictions of the molecular docking simulations towards the PI3K/AKT proteins. Finally, in vivo study verified that compound 4 has a promising anti-cancer activity through activating antioxidant levels (CAT, SOD and GSH) and ameliorating hematological, biochemical, and histopathological findings. Full article
(This article belongs to the Special Issue Advances in Anticancer Drug Discovery II)
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24 pages, 21910 KiB  
Article
New Deoxycholic Acid Derived Tyrosyl-DNA Phosphodiesterase 1 Inhibitors Also Inhibit Tyrosyl-DNA Phosphodiesterase 2
by Oksana V. Salomatina, Nadezhda S. Dyrkheeva, Irina I. Popadyuk, Alexandra L. Zakharenko, Ekaterina S. Ilina, Nina I. Komarova, Jóhannes Reynisson, Nariman F. Salakhutdinov, Olga I. Lavrik and Konstantin P. Volcho
Molecules 2022, 27(1), 72; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27010072 - 23 Dec 2021
Cited by 8 | Viewed by 7620
Abstract
A series of deoxycholic acid (DCA) amides containing benzyl ether groups on the steroid core were tested against the tyrosyl-DNA phosphodiesterase 1 (TDP1) and 2 (TDP2) enzymes. In addition, 1,2,4- and 1,3,4-oxadiazole derivatives were synthesized to study the linker influence between a para [...] Read more.
A series of deoxycholic acid (DCA) amides containing benzyl ether groups on the steroid core were tested against the tyrosyl-DNA phosphodiesterase 1 (TDP1) and 2 (TDP2) enzymes. In addition, 1,2,4- and 1,3,4-oxadiazole derivatives were synthesized to study the linker influence between a para-bromophenyl moiety and the steroid scaffold. The DCA derivatives demonstrated promising inhibitory activity against TDP1 with IC50 in the submicromolar range. Furthermore, the amides and the 1,3,4-oxadiazole derivatives inhibited the TDP2 enzyme but at substantially higher concentration. Tryptamide 5 and para-bromoanilide 8 derivatives containing benzyloxy substituent at the C-3 position and non-substituted hydroxy group at C-12 on the DCA scaffold inhibited both TDP1 and TDP2 as well as enhanced the cytotoxicity of topotecan in non-toxic concentration in vitro. According to molecular modeling, ligand 5 is anchored into the catalytic pocket of TDP1 by one hydrogen bond to the backbone of Gly458 as well as by π–π stacking between the indolyl rings of the ligand and Tyr590, resulting in excellent activity. It can therefore be concluded that these derivatives contribute to the development of specific TDP1 and TDP2 inhibitors for adjuvant therapy against cancer in combination with topoisomerase poisons. Full article
(This article belongs to the Special Issue Advances in Anticancer Drug Discovery II)
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13 pages, 1894 KiB  
Article
Machine-Learning-Enabled Virtual Screening for Inhibitors of Lysine-Specific Histone Demethylase 1
by Jiajun Zhou, Shiying Wu, Boon Giin Lee, Tianwei Chen, Ziqi He, Yukun Lei, Bencan Tang and Jonathan D. Hirst
Molecules 2021, 26(24), 7492; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26247492 - 10 Dec 2021
Cited by 4 | Viewed by 3438
Abstract
A machine learning approach has been applied to virtual screening for lysine specific demethylase 1 (LSD1) inhibitors. LSD1 is an important anti-cancer target. Machine learning models to predict activity were constructed using Morgan molecular fingerprints. The dataset, consisting of 931 molecules with LSD1 [...] Read more.
A machine learning approach has been applied to virtual screening for lysine specific demethylase 1 (LSD1) inhibitors. LSD1 is an important anti-cancer target. Machine learning models to predict activity were constructed using Morgan molecular fingerprints. The dataset, consisting of 931 molecules with LSD1 inhibition activity, was obtained from the ChEMBL database. An evaluation of several candidate algorithms on the main dataset revealed that the support vector regressor gave the best model, with a coefficient of determination (R2) of 0.703. Virtual screening, using this model, identified five predicted potent inhibitors from the ZINC database comprising more than 300,000 molecules. The virtual screening recovered a known inhibitor, RN1, as well as four compounds where activity against LSD1 had not previously been suggested. Thus, we performed a machine-learning-enabled virtual screening of LSD1 inhibitors using only the structural information of the molecules. Full article
(This article belongs to the Special Issue Advances in Anticancer Drug Discovery II)
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21 pages, 2585 KiB  
Article
Design and Synthesis of (2-oxo-1,2-Dihydroquinolin-4-yl)-1,2,3-triazole Derivatives via Click Reaction: Potential Apoptotic Antiproliferative Agents
by Essmat M. El-Sheref, Mohammed A. I. Elbastawesy, Alan B. Brown, Ahmed M. Shawky, Hesham A. M. Gomaa, Stefan Bräse and Bahaa G. M. Youssif
Molecules 2021, 26(22), 6798; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26226798 - 10 Nov 2021
Cited by 8 | Viewed by 1631
Abstract
A mild and versatile method based on Cu-catalyzed [2+3] cycloaddition (Huisgen-Meldal-Sharpless reaction) was developed to tether 3,3’-((4-(prop-2-yn-1-yloxy)phenyl)methylene)bis(4-hydroxyquinolin-2(1H)-ones) with 4-azido-2-quinolones in good yields. This methodology allowed attaching three quinolone molecules via a triazole linker with the proposed mechanism. The products [...] Read more.
A mild and versatile method based on Cu-catalyzed [2+3] cycloaddition (Huisgen-Meldal-Sharpless reaction) was developed to tether 3,3’-((4-(prop-2-yn-1-yloxy)phenyl)methylene)bis(4-hydroxyquinolin-2(1H)-ones) with 4-azido-2-quinolones in good yields. This methodology allowed attaching three quinolone molecules via a triazole linker with the proposed mechanism. The products are interesting precursors for their anti-proliferative activity. Compound 8g was the most active one, achieving IC50 = 1.2 ± 0.2 µM and 1.4 ± 0.2 µM against MCF-7 and Panc-1 cell lines, respectively. Moreover, cell cycle analysis of cells MCF-7 treated with 8g showed cell cycle arrest at the G2/M phase (supported by Caspase-3,8,9, Cytochrome C, BAX, and Bcl-2 studies). Additionally, significant pro-apoptotic activity is indicated by annexin V-FITC staining. Full article
(This article belongs to the Special Issue Advances in Anticancer Drug Discovery II)
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18 pages, 5437 KiB  
Article
Autophagic Activation and Decrease of Plasma Membrane Cholesterol Contribute to Anticancer Activities in Non-Small Cell Lung Cancer
by Jui-Ling Hsu, Wohn-Jenn Leu, Nan-Shan Zhong and Jih-Hwa Guh
Molecules 2021, 26(19), 5967; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26195967 - 01 Oct 2021
Cited by 5 | Viewed by 2094
Abstract
Non-small cell lung cancer (NSCLC), an aggressive subtype of pulmonary carcinomas with high mortality, accounts for 85% of all lung cancers. Drug resistance and high recurrence rates impede the chemotherapeutic effect, making it urgent to develop new anti-NSCLC agents. Recently, we have demonstrated [...] Read more.
Non-small cell lung cancer (NSCLC), an aggressive subtype of pulmonary carcinomas with high mortality, accounts for 85% of all lung cancers. Drug resistance and high recurrence rates impede the chemotherapeutic effect, making it urgent to develop new anti-NSCLC agents. Recently, we have demonstrated that para-toluenesulfonamide is a potential anti-tumor agent in human castration-resistant prostate cancer (CRPC) through inhibition of Akt/mTOR/p70S6 kinase pathway and lipid raft disruption. In the current study, we further addressed the critical role of cholesterol-enriched membrane microdomain and autophagic activation to para-toluenesulfonamide action in killing NSCLC. Similar in CRPC, para-toluenesulfonamide inhibited the Akt/mTOR/p70S6K pathway in NSCLC cell lines NCI-H460 and A549, leading to G1 arrest of the cell cycle and apoptosis. Para-toluenesulfonamide significantly decreased the cholesterol levels of plasma membrane. External cholesterol supplement rescued para-toluenesulfonamide-mediated effects. Para-toluenesulfonamide induced a profound increase of LC3-II protein expression and a significant decrease of p62 expression. Double staining of lysosomes and cellular cholesterol showed para-toluenesulfonamide-induced lysosomal transportation of cholesterol, which was validated using flow cytometric analysis of lysosome staining. Moreover, autophagy inhibitors could blunt para-toluenesulfonamide-induced effect, indicating autophagy induction. In conclusion, the data suggest that para-toluenesulfonamide is an effective anticancer agent against NSCLC through G1 checkpoint arrest and apoptotic cell death. The disturbance of membrane cholesterol levels and autophagic activation may play a crucial role to para-toluenesulfonamide action. Full article
(This article belongs to the Special Issue Advances in Anticancer Drug Discovery II)
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14 pages, 1840 KiB  
Article
Clerodane Diterpenoids from an Edible Plant Justicia insularis: Discovery, Cytotoxicity, and Apoptosis Induction in Human Ovarian Cancer Cells
by Idowu E. Fadayomi, Okiemute R. Johnson-Ajinwo, Elisabete Pires, James McCullagh, Tim D.W. Claridge, Nicholas R. Forsyth and Wen-Wu Li
Molecules 2021, 26(19), 5933; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26195933 - 30 Sep 2021
Cited by 7 | Viewed by 2137
Abstract
Objectives: The toxicity of chemotherapeutic anticancer drugs is a serious issue in clinics. Drug discovery from edible and medicinal plants represents a promising approach towards finding safer anticancer therapeutics. Justicia insularis T. Anderson (Acanthaceae) is an edible and medicinal plant in Nigeria. This [...] Read more.
Objectives: The toxicity of chemotherapeutic anticancer drugs is a serious issue in clinics. Drug discovery from edible and medicinal plants represents a promising approach towards finding safer anticancer therapeutics. Justicia insularis T. Anderson (Acanthaceae) is an edible and medicinal plant in Nigeria. This study aims to discover cytotoxic compounds from this rarely explored J. insularis and investigate their underlying mechanism of action. Methods: The cytotoxicity of the plant extract was evaluated in human ovarian cancer cell lines and normal human ovarian surface epithelia (HOE) cells using a sulforhodamine B assay. Bioassay-guided isolation was carried out using column chromatography including HPLC, and the isolated natural products were characterized using GC-MS, LC-HRMS, and 1D/2D NMR techniques. Induction of apoptosis was evaluated using Caspase 3/7, 8, and 9, and Annexin V and PI based flow cytometry assays. SwissADME and SwissTargetPrediction web tools were used to predict the molecular properties and possible protein targets of identified active compounds. Key finding: The two cytotoxic compounds were identified as clerodane diterpenoids: 16(α/β)-hydroxy-cleroda-3,13(14)Z-dien-15,16-olide (1) and 16-oxo-cleroda-3,13(14)E-dien-15-oic acid (2) from the Acanthaceous plant for the first time. Compound 1 was a very abundant compound (0.7% per dry weight of plant material) and was shown to be more potent than compound 2 with IC50 values in the micromolar range against OVCAR-4 and OVCAR-8 cancer cells. Compounds 1 and 2 were less cytotoxic to HOE cell line. Both compounds induced apoptosis by increasing caspase 3/7 activities in a concentration dependent manner. Compound 1 further increased caspase 8 and 9 activities and apoptosis cell populations. Compounds 1 and 2 are both drug like, and compound 1 may target various proteins including a kinase. Conclusions: Clerodane diterpenoids (1 and 2) in J. insularis were identified as cytotoxic to ovarian cancer cells via the induction of apoptosis, providing an abundant and valuable source of hit compounds for the treatment of ovarian cancer. Full article
(This article belongs to the Special Issue Advances in Anticancer Drug Discovery II)
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23 pages, 6080 KiB  
Article
Novel Tdp1 Inhibitors Based on Adamantane Connected with Monoterpene Moieties via Heterocyclic Fragments
by Aldar A. Munkuev, Evgenii S. Mozhaitsev, Arina A. Chepanova, Evgeniy V. Suslov, Dina V. Korchagina, Olga D. Zakharova, Ekaterina S. Ilina, Nadezhda S. Dyrkheeva, Alexandra L. Zakharenko, Jóhannes Reynisson, Konstantin P. Volcho, Nariman F. Salakhutdinov and Olga I. Lavrik
Molecules 2021, 26(11), 3128; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26113128 - 24 May 2021
Cited by 16 | Viewed by 26526
Abstract
Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is a promising target for anticancer therapy due to its ability to counter the effects topoisomerase 1 (Top1) poison, such as topotecan, thus, decreasing their efficacy. Compounds containing adamantane and monoterpenoid residues connected via 1,2,4-triazole or 1,3,4-thiadiazole linkers were [...] Read more.
Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is a promising target for anticancer therapy due to its ability to counter the effects topoisomerase 1 (Top1) poison, such as topotecan, thus, decreasing their efficacy. Compounds containing adamantane and monoterpenoid residues connected via 1,2,4-triazole or 1,3,4-thiadiazole linkers were synthesized and tested against Tdp1. All the derivatives exhibited inhibition at low micromolar or nanomolar concentrations with the most potent inhibitors having IC50 values in the 0.35–0.57 µM range. The cytotoxicity was determined in the HeLa, HCT-116 and SW837 cancer cell lines; moderate CC50 (µM) values were seen from the mid-teens to no effect at 100 µM. Furthermore, citral derivative 20c, α-pinene-derived compounds 20f, 20g and 25c, and the citronellic acid derivative 25b were found to have a sensitizing effect in conjunction with topotecan in the HeLa cervical cancer and colon adenocarcinoma HCT-116 cell lines. The ligands are predicted to bind in the catalytic pocket of Tdp1 and have favorable physicochemical properties for further development as a potential adjunct therapy with Top1 poisons. Full article
(This article belongs to the Special Issue Advances in Anticancer Drug Discovery II)
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Graphical abstract

Review

Jump to: Research

23 pages, 5163 KiB  
Review
An Insight into FDA Approved Antibody-Drug Conjugates for Cancer Therapy
by Juliana T. W. Tong, Paul W. R. Harris, Margaret A. Brimble and Iman Kavianinia
Molecules 2021, 26(19), 5847; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26195847 - 27 Sep 2021
Cited by 152 | Viewed by 17882
Abstract
The large number of emerging antibody-drug conjugates (ADCs) for cancer therapy has resulted in a significant market ‘boom’, garnering worldwide attention. Despite ADCs presenting huge challenges to researchers, particularly regarding the identification of a suitable combination of antibody, linker, and payload, as of [...] Read more.
The large number of emerging antibody-drug conjugates (ADCs) for cancer therapy has resulted in a significant market ‘boom’, garnering worldwide attention. Despite ADCs presenting huge challenges to researchers, particularly regarding the identification of a suitable combination of antibody, linker, and payload, as of September 2021, 11 ADCs have been granted FDA approval, with eight of these approved since 2017 alone. Optimism for this therapeutic approach is clear, despite the COVID-19 pandemic, 2020 was a landmark year for deals and partnerships in the ADC arena, suggesting that there remains significant interest from Big Pharma. Herein we review the enthusiasm for ADCs by focusing on the features of those approved by the FDA, and offer some thoughts as to where the field is headed. Full article
(This article belongs to the Special Issue Advances in Anticancer Drug Discovery II)
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36 pages, 17073 KiB  
Review
Sialyltransferase Inhibitors for the Treatment of Cancer Metastasis: Current Challenges and Future Perspectives
by Ser John Lynon P. Perez, Chih-Wei Fu and Wen-Shan Li
Molecules 2021, 26(18), 5673; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26185673 - 18 Sep 2021
Cited by 10 | Viewed by 4267
Abstract
Potent, cell-permeable, and subtype-selective sialyltransferase inhibitors represent an attractive family of substances that can potentially be used for the clinical treatment of cancer metastasis. These substances operate by specifically inhibiting sialyltransferase-mediated hypersialylation of cell surface glycoproteins or glycolipids, which then blocks the sialic [...] Read more.
Potent, cell-permeable, and subtype-selective sialyltransferase inhibitors represent an attractive family of substances that can potentially be used for the clinical treatment of cancer metastasis. These substances operate by specifically inhibiting sialyltransferase-mediated hypersialylation of cell surface glycoproteins or glycolipids, which then blocks the sialic acid recognition pathway and leads to deterioration of cell motility and invasion. A vast amount of evidence for the in vitro and in vivo effects of sialyltransferase inhibition or knockdown on tumor progression and tumor cell metastasis or colonization has been accumulated over the past decades. In this regard, this review comprehensively discusses the results of studies that have led to the recent discovery and development of sialyltransferase inhibitors, their potential biomedical applications in the treatment of cancer metastasis, and their current limitations and future opportunities. Full article
(This article belongs to the Special Issue Advances in Anticancer Drug Discovery II)
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