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Novel Anti-cancer Lead Compounds
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Novel Anti-cancer Lead Compounds

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

Deadline for manuscript submissions: closed (31 March 2023) | Viewed by 39774

Special Issue Editors

Dr. Fernando de Carvalho da Silva

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Guest Editor
Departamento de Química Orgânica, Instituto de Química, Universidade Federal Fluminense, Niterói 24020-141, RJ, Brazil
Interests: organic synthesis; medicinal chemistry; naphthoquinones; triazoles
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Vitor Francisco Ferreira

E-Mail Website
Guest Editor
Pharmacy School, Universidade Federal Fluminense, Rio de Janeiro, Brazil
Interests: organic chemistry; heterocycles; organic synthesis; medicinal chemistry
Special Issues, Collections and Topics in MDPI journals
Dr. Luana Da Silva Magalhães Forezi

E-Mail Website
Guest Editor
Adjunct Professor, Applied Organic Synthesis Laboratory, Department of Organic Chemistry, Chemistry Institute, Fluminense Federal University, Niteroi 24020-141, RJ, Brazil
Interests: organic synthesis; photocatalysis; heterogeneous catalysis; solar cell
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cancer is a disease characterized by the uncontrolled and aggressive growth of cells, and by the ability to spread to other parts of the body, which typically cripples the surrounding tissues. Cancer cells are the result of multiple genetic and epigenetic alterations, which considerably increase the complexity of the disease and, therefore, its treatment. Thus, researchers are engaged in a constant search for novel drugs with anticancer properties to increase the treatment options for this disease.

Currently, hundreds of different anticancer drugs are available on the market or are under development worldwide. However, there remains a need to screen for novel drugs utilizing innovative and combined mechanisms. This need is not merely a matter of overcoming drug resistance but also a means of fighting cancer through diverse approaches. Drugs designed for other purposes can demonstrate activity against cancer cells. Because cancer cells exhibit highly active metabolism, several pathways are active at the same time and must function in an integrated manner to guarantee cells’ ability to survive and proliferate at extremely high rates.

In this context, it is a great pleasure to invite you to contribute to this thematic Special Issue of Molecules on Novel Anti-Cancer Lead Compounds that will cover the latest research trends and applications in the field. Submissions of reviews and original research papers are highly welcome.

Dr. Fernando de Carvalho da Silva
Prof. Dr. Vitor Francisco Ferreira
Dr. Luana Da Silva Magalhães Forezi
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • antitumor
  • drug resistance
  • cytotoxicity
  • organic synthesis
  • small molecules
  • natural products
  • p53 protein

Published Papers (21 papers)

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14 pages, 3275 KiB  
Article
Inhibition of Mitochondrial Antioxidant Defense and CDK4/6 in Mesothelioma
by Marian Kratzke, George Scaria, Stephen Porter, Betsy Kren and Mark A. Klein
Molecules 2023, 28(11), 4380; https://doi.org/10.3390/molecules28114380 - 27 May 2023
Cited by 1 | Viewed by 1400
Abstract
Advanced mesothelioma is considered an incurable disease and new treatment strategies are needed. Previous studies have demonstrated that mitochondrial antioxidant defense proteins and the cell cycle may contribute to mesothelioma growth, and that the inhibition of these pathways may be effective against this [...] Read more.
Advanced mesothelioma is considered an incurable disease and new treatment strategies are needed. Previous studies have demonstrated that mitochondrial antioxidant defense proteins and the cell cycle may contribute to mesothelioma growth, and that the inhibition of these pathways may be effective against this cancer. We demonstrated that the antioxidant defense inhibitor auranofin and the cyclin-dependent kinase 4/6 inhibitor palbociclib could decrease mesothelioma cell proliferation alone or in combination. In addition, we determined the effects of these compounds on colony growth, cell cycle progression, and the expression of key antioxidant defense and cell cycle proteins. Auranofin and palbociclib were effective in decreasing cell growth and inhibiting the above-described activity across all assays. Further study of this drug combination will elucidate the contribution of these pathways to mesothelioma activity and may reveal a new treatment strategy. Full article
(This article belongs to the Special Issue Novel Anti-cancer Lead Compounds)
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17 pages, 1952 KiB  
Article
Design of the New Closo-Dodecarborate-Containing Gemcitabine Analogue for the Albumin-Based Theranostics Composition
by Valeria I. Raskolupova, Meiling Wang, Maya A. Dymova, Gleb O. Petrov, Ivan M. Shchudlo, Sergey Yu. Taskaev, Tatyana V. Abramova, Tatyana S. Godovikova, Vladimir N. Silnikov and Tatyana V. Popova
Molecules 2023, 28(6), 2672; https://doi.org/10.3390/molecules28062672 - 15 Mar 2023
Cited by 2 | Viewed by 1571
Abstract
Combination therapy is becoming an increasingly important treatment strategy because multi-drugs can maximize therapeutic effect and overcome potential mechanisms of drug resistance. A new albumin-based theranostic containing gemcitabine closo-dodecaborate analogue has been developed for combining boron neutron capture therapy (BNCT) and chemotheraphy. [...] Read more.
Combination therapy is becoming an increasingly important treatment strategy because multi-drugs can maximize therapeutic effect and overcome potential mechanisms of drug resistance. A new albumin-based theranostic containing gemcitabine closo-dodecaborate analogue has been developed for combining boron neutron capture therapy (BNCT) and chemotheraphy. An exo-heterocyclic amino group of gemcitabine was used to introduce closo-dodecaborate, and a 5′-hydroxy group was used to tether maleimide moiety through an acid-labile phosphamide linker. The N-trifluoroacylated homocysteine thiolactone was used to attach the gemcitabine analogue to human serum albumin (HSA) bearing Cy5 or Cy7 fluorescent dyes. The half-maximal inhibitory concentration (IC50) of the designed theranostic relative to T98G cells was 0.47 mM with the correlation coefficient R = 0.82. BNCT experiments resulted in a decrease in the viability of T98G cells, and the survival fraction was ≈ 0.4. Full article
(This article belongs to the Special Issue Novel Anti-cancer Lead Compounds)
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20 pages, 16604 KiB  
Article
In Silico Exploration of Microtubule Agent Griseofulvin and Its Derivatives Interactions with Different Human β-Tubulin Isotypes
by Parisa Aris, Masoud Mohamadzadeh, Alibek Kruglikov, Mahbubeh Askari Rad and Xuhua Xia
Molecules 2023, 28(5), 2384; https://doi.org/10.3390/molecules28052384 - 05 Mar 2023
Cited by 1 | Viewed by 1657
Abstract
Tubulin isotypes are known to regulate microtubule stability and dynamics, as well as to play a role in the development of resistance to microtubule-targeted cancer drugs. Griseofulvin is known to disrupt cell microtubule dynamics and cause cell death in cancer cells through binding [...] Read more.
Tubulin isotypes are known to regulate microtubule stability and dynamics, as well as to play a role in the development of resistance to microtubule-targeted cancer drugs. Griseofulvin is known to disrupt cell microtubule dynamics and cause cell death in cancer cells through binding to tubulin protein at the taxol site. However, the detailed binding mode involved molecular interactions, and binding affinities with different human β-tubulin isotypes are not well understood. Here, the binding affinities of human β-tubulin isotypes with griseofulvin and its derivatives were investigated using molecular docking, molecular dynamics simulation, and binding energy calculations. Multiple sequence analysis shows that the amino acid sequences are different in the griseofulvin binding pocket of βI isotypes. However, no differences were observed at the griseofulvin binding pocket of other β-tubulin isotypes. Our molecular docking results show the favorable interaction and significant affinity of griseofulvin and its derivatives toward human β-tubulin isotypes. Further, molecular dynamics simulation results show the structural stability of most β-tubulin isotypes upon binding to the G1 derivative. Taxol is an effective drug in breast cancer, but resistance to it is known. Modern anticancer treatments use a combination of multiple drugs to alleviate the problem of cancer cells resistance to chemotherapy. Our study provides a significant understanding of the involved molecular interactions of griseofulvin and its derivatives with β-tubulin isotypes, which may help to design potent griseofulvin analogues for specific tubulin isotypes in multidrug-resistance cancer cells in future. Full article
(This article belongs to the Special Issue Novel Anti-cancer Lead Compounds)
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19 pages, 4130 KiB  
Article
3-Heptylidene-4,6-Dimethoxy-3H-Isobenzofuran-1-One Is Genotoxic, Increases the Frequency of Cell Death, and Potentiates the Effects of Cyclophosphamide and Cisplatin
by Silvia Cordeiro das Neves, Flavio Henrique de Araújo, Willian Ayala Correa, Allana Cristina Faustino Martins, Henrique Rodrigues Scherer Coelho, Marcelo Luiz Brandão Vilela, Valter Aragão do Nascimento, Candida Aparecida Leite Kassuya, Dênis Pires de Lima, Adilson Beatriz, Rodrigo Juliano Oliveira and Roberto da Silva Gomes
Molecules 2023, 28(3), 1044; https://doi.org/10.3390/molecules28031044 - 20 Jan 2023
Viewed by 1299
Abstract
3-heptylidene-4,6-dimethoxy-3H-isobenzofuran-1-one (Phthalide 1) is the precursor of three resorcinol lipids that have been described as potential chemotherapeutic agents and capable of potentiating the effects of cyclophosphamide. In this study, we evaluated the genotoxic potential, cell-killing potential, and interactions with cyclophosphamide [...] Read more.
3-heptylidene-4,6-dimethoxy-3H-isobenzofuran-1-one (Phthalide 1) is the precursor of three resorcinol lipids that have been described as potential chemotherapeutic agents and capable of potentiating the effects of cyclophosphamide. In this study, we evaluated the genotoxic potential, cell-killing potential, and interactions with cyclophosphamide and cisplatin of phthalide 1. Twelve groups were created from 120 mice: Negative Control, cyclophosphamide (100 mg/kg), cisplatin (6 mg/kg), Phthalide 1 (5, 10 and 20 mg/kg), and associations of 1 with cyclophosphamide and 1 with cisplatin. The results demonstrate that 1 increases (p < 0.05) the frequency of chromosomal damage, liver and kidney cell death, and splenic phagocytosis. The association of 1 with cyclophosphamide and cisplatin demonstrated a chemopreventive effect and, therefore, a reduction (p < 0.05) in the frequency of chromosomal damage. However, cell death and splenic phagocytosis did not suffer significant variations. As a result of the above, 1 has potential chemotherapeutic application and may be a candidate for developing a new generation of chemotherapeutics. In addition, it has characteristics to be used as a chemotherapy adjuvant in association with cyclophosphamide and cisplatin since it increases the frequency of cell death induced by chemotherapy. We also reported that the chemopreventive effect of 1, in association with cyclophosphamide and cisplatin, can prevent adverse effects (induction of DNA damage in non-tumor cells) without interfering with the mode of action of chemotherapy drugs and, therefore, without reducing the induction of cell death. Full article
(This article belongs to the Special Issue Novel Anti-cancer Lead Compounds)
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22 pages, 2081 KiB  
Article
Identification of Therapeutic Targets for Medulloblastoma by Tissue-Specific Genome-Scale Metabolic Model
by Ilkay Irem Ozbek and Kutlu O. Ulgen
Molecules 2023, 28(2), 779; https://doi.org/10.3390/molecules28020779 - 12 Jan 2023
Cited by 1 | Viewed by 1921
Abstract
Medulloblastoma (MB), occurring in the cerebellum, is the most common childhood brain tumor. Because conventional methods decline life quality and endanger children with detrimental side effects, computer models are needed to imitate the characteristics of cancer cells and uncover effective therapeutic targets with [...] Read more.
Medulloblastoma (MB), occurring in the cerebellum, is the most common childhood brain tumor. Because conventional methods decline life quality and endanger children with detrimental side effects, computer models are needed to imitate the characteristics of cancer cells and uncover effective therapeutic targets with minimum toxic effects on healthy cells. In this study, metabolic changes specific to MB were captured by the genome-scale metabolic brain model integrated with transcriptome data. To determine the roles of sphingolipid metabolism in proliferation and metastasis in the cancer cell, 79 reactions were incorporated into the MB model. The pathways employed by MB without a carbon source and the link between metastasis and the Warburg effect were examined in detail. To reveal therapeutic targets for MB, biomass-coupled reactions, the essential genes/gene products, and the antimetabolites, which might deplete the use of metabolites in cells by triggering competitive inhibition, were determined. As a result, interfering with the enzymes associated with fatty acid synthesis (FAs) and the mevalonate pathway in cholesterol synthesis, suppressing cardiolipin production, and tumor-supporting sphingolipid metabolites might be effective therapeutic approaches for MB. Moreover, decreasing the activity of succinate synthesis and GABA-catalyzing enzymes concurrently might be a promising strategy for metastatic MB. Full article
(This article belongs to the Special Issue Novel Anti-cancer Lead Compounds)
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32 pages, 14215 KiB  
Communication
Carbohydrate-Small Molecule Hybrids as Lead Compounds Targeting IL-6 Signaling
by Daniel C. Schultz, Li Pan, Tiffany Wang, Conner Booker, Iram Hyder, Laura Hanold, Garret Rubin, Yousong Ding, Jiayuh Lin and Chenglong Li
Molecules 2023, 28(2), 677; https://doi.org/10.3390/molecules28020677 - 09 Jan 2023
Cited by 1 | Viewed by 1845
Abstract
In the past 25 years, a number of efforts have been made toward the development of small molecule interleukin-6 (IL-6) signaling inhibitors, but none have been approved to date. Monosaccharides are a diverse class of bioactive compounds, but thus far have been unexplored [...] Read more.
In the past 25 years, a number of efforts have been made toward the development of small molecule interleukin-6 (IL-6) signaling inhibitors, but none have been approved to date. Monosaccharides are a diverse class of bioactive compounds, but thus far have been unexplored as a scaffold for small molecule IL-6-signaling inhibitor design. Therefore, in this present communication, we combined a structure-based drug design approach with carbohydrate building blocks to design and synthesize novel IL-6-signaling inhibitors targeting glycoprotein 130 (gp130). Of this series of compounds, LS-TG-2P and LS-TF-3P were the top lead compounds, displaying IC50 values of 6.9 and 16 µM against SUM159 cell lines, respectively, while still retaining preferential activity against the IL-6-signaling pathway. The carbohydrate moiety was found to improve activity, as N-unsubstituted triazole analogues of these compounds were found to be less active in vitro compared to the leads themselves. Thus, LS-TG-2P and LS-TF-3P are promising scaffolds for further development and study as IL-6-signaling inhibitors. Full article
(This article belongs to the Special Issue Novel Anti-cancer Lead Compounds)
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26 pages, 3420 KiB  
Article
Chemoselective Synthesis of Mannich Adducts from 1,4-Naphthoquinones and Profile as Autophagic Inducers in Oral Squamous Cell Carcinoma
by Amanda A. Borges, Michele P. de Souza, Anna Carolina C. da Fonseca, Guilherme F. Wermelinger, Ruan C. B. Ribeiro, Adriane A. P. Amaral, Cláudio José C. de Carvalho, Lucas S. Abreu, Lucas Nicolau de Queiroz, Elan C. P. de Almeida, Vitor W. Rabelo, Paula A. Abreu, Bruno Pontes, Vitor F. Ferreira, Fernando de C. da Silva, Luana da S. M. Forezi and Bruno K. Robbs
Molecules 2023, 28(1), 309; https://doi.org/10.3390/molecules28010309 - 30 Dec 2022
Cited by 6 | Viewed by 2340
Abstract
Oral squamous cell carcinoma (OSCC) is a worldwide public health problem, accounting for approximately 90% of all oral cancers, and is the eighth most common cancer in men. Cisplatin and carboplatin are the main chemotherapy drugs used in the clinic. However, in addition [...] Read more.
Oral squamous cell carcinoma (OSCC) is a worldwide public health problem, accounting for approximately 90% of all oral cancers, and is the eighth most common cancer in men. Cisplatin and carboplatin are the main chemotherapy drugs used in the clinic. However, in addition to their serious side effects, such as damage to the nervous system and kidneys, there is also drug resistance. Thus, the development of new drugs becomes of great importance. Naphthoquinones have been described with antitumor activity. Some of them are found in nature, but semi synthesis has been used as strategy to find new chemical entities for the treatment of cancer. In the present study, we promote a multiple component reaction (MCR) among lawsone, arylaldehydes, and benzylamine to produce sixteen chemoselectively derivated Mannich adducts of 1,4-naphthoquinones in good yield (up to 97%). The antitumor activities and molecular mechanisms of action of these compounds were investigated in OSCC models and the compound 6a induced cytotoxicity in three different tumor cell lines (OSCC4, OSCC9, and OSCC25) and was more selective (IS > 2) for tumor cells than the chemotropic drug carboplatin and the controls lapachol and shikonin, which are chemically similar compounds with cytotoxic effects. The 6a selectively and significantly reduced the amount of cell colony growth, was not hemolytic, and tolerable in mice with no serious side effects at a concentration of 100 mg/kg with a LD50 of 150 mg/kg. The new compound is biologically stable with a profile similar to carboplatin. Morphologically, 6a does not induce cell retraction or membrane blebs, but it does induce intense vesicle formation and late emergence of membrane bubbles. Exploring the mechanism of cell death induction, compound 6a does not induce ROS formation, and cell viability was not affected by inhibitors of apoptosis (ZVAD) and necroptosis (necrostatin 1). Autophagy followed by a late apoptosis process appears to be the death-inducing pathway of 6a, as observed by increased viability by the autophagy inhibitor (3-MA) and by the appearance of autophagosomes, later triggering a process of late apoptosis with the presence of caspase 3/7 and DNA fragmentation. Molecular modeling suggests the ability of the compound to bind to topoisomerase I and II and with greater affinity to hPKM2 enzyme than controls, which could explain the mechanism of cell death by autophagy. Finally, the in-silico prediction of drug-relevant properties showed that compound 6a has a good pharmacokinetic profile when compared to carboplatin and doxorubicin. Among the sixteen naphthoquinones tested, compound 6a was the most effective and is highly selective and well tolerated in animals. The induction of cell death in OSCC through autophagy followed by late apoptosis possibly via inhibition of the PKM2 enzyme points to a promising potential of 6a as a new preclinical anticancer candidate. Full article
(This article belongs to the Special Issue Novel Anti-cancer Lead Compounds)
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18 pages, 4243 KiB  
Article
Synthesis, Biological Evaluation, DNA Binding, and Molecular Docking of Hybrid 4,6-Dihydrazone Pyrimidine Derivatives as Antitumor Agents
by Hairong Lan, Junying Song, Juan Yuan, Aiping Xing, Dai Zeng, Yating Hao, Zhenqiang Zhang and Shuying Feng
Molecules 2023, 28(1), 187; https://doi.org/10.3390/molecules28010187 - 26 Dec 2022
Cited by 1 | Viewed by 1482
Abstract
In the present paper, on the basis of molecular hybridization, a series of 4,6-dihydrazone pyrimidine derivatives containing the pyridine moiety were synthesized, structurally characterized, and evaluated in vitro for their antitumor activity. According to the results, all the tested compounds demonstrated broad-spectrum antitumor [...] Read more.
In the present paper, on the basis of molecular hybridization, a series of 4,6-dihydrazone pyrimidine derivatives containing the pyridine moiety were synthesized, structurally characterized, and evaluated in vitro for their antitumor activity. According to the results, all the tested compounds demonstrated broad-spectrum antitumor activity against selected tumor cell lines (MCF-7, BGC-823, A549, and BEL-7402) and no obvious toxicity toward normal cells HL-7702. In particular, compounds 10a and 10f were found to be the most promising antitumor agents among the tested compounds against BGC-823 cells (IC50 = 9.00 μM and 7.89 μM) and BEL-7402 cells (IC50 = 6.70 μM and 7.66 μM), respectively. Compounds 10a and 10f exhibited higher potency against BGC-823 and BEL-7402 than the positive control 5-FU (IC50 = 15.18 μM and 15.81 μM). Further mechanism investigations demonstrated that compounds 10a and 10f could significantly increase the level of cellular ROS and induce early apoptosis of BGC-823 cells in a dose-dependent manner. Moreover, the DNA binding results from UV/Vis, CD spectroscopy, and molecular docking studies indicated that 10a and 10f bind with DNA via groove binding and partial intercalation. These results demonstrated that 10a and 10f may serve as novel lead compounds for the discovery of more dihydrazone pyrimidine derivatives with improved antitumor potency and selectivity. Full article
(This article belongs to the Special Issue Novel Anti-cancer Lead Compounds)
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15 pages, 2103 KiB  
Article
N1-Benzyl Tryptamine Pan-SHIP1/2 Inhibitors: Synthesis and Preliminary Biological Evaluation as Anti-Tumor Agents
by Sandra Fernandes, Shea T. Meyer, Jigisha P. Shah, Arijit A. Adhikari, William G. Kerr and John D. Chisholm
Molecules 2022, 27(23), 8451; https://doi.org/10.3390/molecules27238451 - 02 Dec 2022
Cited by 2 | Viewed by 1241
Abstract
Inhibition of phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase (SHIP) with small molecule inhibitors leads to apoptosis in tumor cells. Inhibitors that target both SHIP1 and SHIP2 (pan-SHIP1/2 inhibitors) may have benefits in these areas since paralog compensation is not possible when both SHIP paralogs are being [...] Read more.
Inhibition of phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase (SHIP) with small molecule inhibitors leads to apoptosis in tumor cells. Inhibitors that target both SHIP1 and SHIP2 (pan-SHIP1/2 inhibitors) may have benefits in these areas since paralog compensation is not possible when both SHIP paralogs are being inhibited. A series of tryptamine-based pan-SHIP1/2 inhibitors have been synthesized and evaluated for their ability to inhibit the SHIP paralogs. The most active compounds were also evaluated for their effects on cancer cell lines. Full article
(This article belongs to the Special Issue Novel Anti-cancer Lead Compounds)
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17 pages, 5688 KiB  
Article
Dihydrotanshinone I Inhibits the Proliferation and Growth of Oxaliplatin-Resistant Human HCT116 Colorectal Cancer Cells
by Mengge Wang, Yusen Xiang, Ruyu Wang, Lijun Zhang, Hong Zhang, Hongzhuan Chen, Xin Luan and Lili Chen
Molecules 2022, 27(22), 7774; https://doi.org/10.3390/molecules27227774 - 11 Nov 2022
Cited by 6 | Viewed by 1691
Abstract
Oxaliplatin (OXA) is a first-line chemotherapeutic drug for the treatment of colorectal cancer (CRC), but acquired drug resistance becomes the main cause of treatment failure. Increasing evidence has shown that some natural components may serve as chemoresistant sensitizers. In this study, we discovered [...] Read more.
Oxaliplatin (OXA) is a first-line chemotherapeutic drug for the treatment of colorectal cancer (CRC), but acquired drug resistance becomes the main cause of treatment failure. Increasing evidence has shown that some natural components may serve as chemoresistant sensitizers. In this study, we discovered Dihydrotanshinone I (DHTS) through virtual screening using a ligand-based method, and explored its inhibitory effects and the mechanism on OXA-resistant CRC in vitro and in vivo. The results showed that DHTS could effectively inhibit the proliferation of HCT116 and HCT116/OXA resistant cells. DHTS-induced cell apoptosis blocked cell cycle in S and G2/M phases, and enhanced DNA damage of HCT116/OXA cells in a concentration-dependent manner. DHTS also exhibited the obvious inhibition of tumor growth in the HCT116/OXA xenograft model. Mechanistically, DHTS could downregulate the expression of Src homology 2 structural domain protein tyrosine phosphatase (SHP2) and Wnt/β-catenin, as well as conventional drug resistance and apoptosis-related proteins such as multidrug resistance associated proteins (MRP1), P-glycoprotein (P-gp), Bcl-2, and Bcl-xL. Thus, DHTS markedly induces cell apoptosis and inhibits tumor growth in OXA-resistant HCT116 CRC mice models, which can be used as a novel lead compound against OXA-resistant CRC. Full article
(This article belongs to the Special Issue Novel Anti-cancer Lead Compounds)
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21 pages, 8436 KiB  
Article
Enhanced Cytotoxic Effects of Arenite in Combination with Active Bufadienolide Compounds against Human Glioblastoma Cell Line U-87
by Bo Yuan, Jingmei Li, Shin-Ich Miyashita, Hidetomo Kikuchi, Meiyan Xuan, Hirokazu Matsuzaki, Naohiro Iwata, Shinya Kamiuchi, Katsuyoshi Sunaga, Takeshi Sakamoto, Yasuhide Hibino and Mari Okazaki
Molecules 2022, 27(19), 6577; https://doi.org/10.3390/molecules27196577 - 04 Oct 2022
Cited by 2 | Viewed by 1385
Abstract
The cytotoxicity of a trivalent arsenic derivative (arsenite, AsIII) combined with arenobufagin or gamabufotalin was evaluated in human U-87 glioblastoma cells. Synergistic cytotoxicity with upregulated intracellular arsenic levels was observed, when treated with AsIII combined with arenobufagin instead of gamabufotalin. [...] Read more.
The cytotoxicity of a trivalent arsenic derivative (arsenite, AsIII) combined with arenobufagin or gamabufotalin was evaluated in human U-87 glioblastoma cells. Synergistic cytotoxicity with upregulated intracellular arsenic levels was observed, when treated with AsIII combined with arenobufagin instead of gamabufotalin. Apoptosis and the activation of caspase-9/-8/-3 were induced by AsIII and further strengthened by arenobufagin. The magnitude of increase in the activities of caspase-9/-3 was much greater than that of caspase-8, suggesting that the intrinsic pathway played a much more important role in the apoptosis. An increase in the number of necrotic cells, enhanced LDH leakage, and intensified G2/M phase arrest were observed. A remarkable increase in the expression level of γH2AX, a DNA damage marker, was induced by AsIII+arenobufagin. Concomitantly, the activation of autophagy was observed, suggesting that autophagic cell death associated with DNA damage was partially attributed to the cytotoxicity of AsIII+arenobufagin. Suppression of Notch signaling was confirmed in the combined regimen-treated cells, suggesting that inactivation of Jagged1/Notch signaling would probably contribute to the synergistic cytotoxic effect of AsIII+arenobufagin. Given that both AsIII and arenobufagin are capable of penetrating into the blood–brain barrier, our findings may provide fundamental insight into the clinical application of the combined regimen for glioblastoma. Full article
(This article belongs to the Special Issue Novel Anti-cancer Lead Compounds)
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10 pages, 2356 KiB  
Article
Chrysomycin A Inhibits the Proliferation, Migration and Invasion of U251 and U87-MG Glioblastoma Cells to Exert Its Anti-Cancer Effects
by Dong-Ni Liu, Man Liu, Shan-Shan Zhang, Yu-Fu Shang, Fu-Hang Song, Hua-Wei Zhang, Guan-Hua Du and Yue-Hua Wang
Molecules 2022, 27(19), 6148; https://doi.org/10.3390/molecules27196148 - 20 Sep 2022
Cited by 7 | Viewed by 1650
Abstract
Chrysomycin A (Chr-A), an antibiotic from Streptomyces, is reported to have anti-tumor and anti-tuberculous activities, but its anti-glioblastoma activity and possible mechanism are not clear. Therefore, the current study was to investigate the mechanism of Chr-A against glioblastoma using U251 and U87-MG human [...] Read more.
Chrysomycin A (Chr-A), an antibiotic from Streptomyces, is reported to have anti-tumor and anti-tuberculous activities, but its anti-glioblastoma activity and possible mechanism are not clear. Therefore, the current study was to investigate the mechanism of Chr-A against glioblastoma using U251 and U87-MG human cells. CCK8 assays, EdU-DNA synthesis assays and LDH assays were carried out to detect cell viability, proliferation and cytotoxicity of U251 and U87-MG cells, respectively. Transwell assays were performed to detect the invasion and migration abilities of glioblastoma cells. Western blot was used to validate the potential proteins. Chr-A treatment significantly inhibited the growth of glioblastoma cells and weakened the ability of cell migration and invasion by down regulating the expression of slug, MMP2 and MMP9. Furthermore, Chr-A also down regulated Akt, p-Akt, GSK-3β, p-GSK-3β and their downstream proteins, such as β-catenin and c-Myc in human glioblastoma cells. In conclusion, Chr-A may inhibit the proliferation, migration and invasion of glioblastoma cells through the Akt/GSK-3β/β-catenin signaling pathway. Full article
(This article belongs to the Special Issue Novel Anti-cancer Lead Compounds)
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24 pages, 4157 KiB  
Article
Pro-Apoptotic Antitumoral Effect of Novel Acridine-Core Naphthoquinone Compounds against Oral Squamous Cell Carcinoma
by Bruna Costa Zorzanelli, Gabriel Ouverney, Fernanda P. Pauli, Anna Carolina Carvalho da Fonseca, Elan Cardozo Paes de Almeida, Danielle Gonçalves de Carvalho, Patricia Abrão Possik, Vitor Won-Held Rabelo, Paula Alvarez Abreu, Bruno Pontes, Vitor Francisco Ferreira, Luana da Silva Magalhães Forezi, Fernando de Carvalho da Silva and Bruno Kaufmann Robbs
Molecules 2022, 27(16), 5148; https://doi.org/10.3390/molecules27165148 - 12 Aug 2022
Cited by 8 | Viewed by 1862
Abstract
Oral squamous cell carcinoma (OSCC) is a global public health problem with high incidence and mortality. The chemotherapeutic agents used in the clinic, alone or in combination, usually lead to important side effects. Thus, the discovery and development of new antineoplastic drugs are [...] Read more.
Oral squamous cell carcinoma (OSCC) is a global public health problem with high incidence and mortality. The chemotherapeutic agents used in the clinic, alone or in combination, usually lead to important side effects. Thus, the discovery and development of new antineoplastic drugs are essential to improve disease prognosis and reduce toxicity. In the present study, acridine-core naphthoquinone compounds were synthesized and evaluated for their antitumor activity in OSCC cells. The mechanism of action, pharmacokinetics, and toxicity parameters of the most promising compound was further analyzed using in silico, in vitro, and in vivo methods. Among the derivatives, compound 4e was highly cytotoxic (29.99 µM) and selective (SI 2.9) at levels comparable and generally superior to chemotherapeutic controls. Besides, compound 4e proved to be non-hemolytic, stable, and well tolerated in animals at all doses tested. Mechanistically, compound 4e promoted cell death by apoptosis in the OSCC cell, and molecular docking studies suggested this compound possibly targets enzymes important for tumor progression, such as RSK2, PKM2, and topoisomerase IIα. Importantly, compound 4e presented a pharmacological profile within desirable parameters for drug development, showing promise for future preclinical trials. Full article
(This article belongs to the Special Issue Novel Anti-cancer Lead Compounds)
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14 pages, 3013 KiB  
Article
Tyrosol Derivatives, Bearing 3,5-Disubstituted Isoxazole and 1,4-Disubstituted Triazole, as Potential Antileukemia Agents by Promoting Apoptosis
by Zaineb Abdelkafi-Koubaa, Imen Aissa, Hichem Ben Jannet, Najet Srairi-Abid, Naziha Marrakchi and Samia Menif
Molecules 2022, 27(16), 5086; https://doi.org/10.3390/molecules27165086 - 10 Aug 2022
Cited by 1 | Viewed by 1306
Abstract
In the present study, we assess tyrosol derivatives bearing 3,5-disubstituted isoxazoles and 1,4-disubstituted triazoles for their ability to inhibit the proliferation of K562 cells derived from leukemia as well as primary chronic myeloid leukemia (CML) cells obtained from the peripheral blood of 15 [...] Read more.
In the present study, we assess tyrosol derivatives bearing 3,5-disubstituted isoxazoles and 1,4-disubstituted triazoles for their ability to inhibit the proliferation of K562 cells derived from leukemia as well as primary chronic myeloid leukemia (CML) cells obtained from the peripheral blood of 15 CML patients including 10 patients with untreated chronic phase and 5 patients with resistance against imatinib or multiple TKI. Our results showed that most derivatives displayed significant anti-proliferative activity against K562 cells in a dose-dependent manner. Among them, compounds 3d and 4a exhibited greater potent anticancer activity with respective IC50 values of 16 and 18 µg/mL (45 µM and 61 µM). Interestingly, compound 3d inhibited CML cell proliferation not only in newly diagnosed but also in imatinib-resistant patients. We demonstrated that the anti-proliferative effect of this compound is mediated by a pro-apoptotic activity by promoting oxidative stress and modulating the activity of the Akt, p38 MAPK and Erk 1/2 pathways. In conclusion, our data highlight the potential of this class of derivative as a novel promising therapeutic agent for CML therapy. Full article
(This article belongs to the Special Issue Novel Anti-cancer Lead Compounds)
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15 pages, 5431 KiB  
Article
Discovery of Novel Quinazoline Derivatives as Potent Antitumor Agents
by Zhenxi Niu, Shuli Ma, Lei Zhang, Qibing Liu and Shengnan Zhang
Molecules 2022, 27(12), 3906; https://doi.org/10.3390/molecules27123906 - 17 Jun 2022
Cited by 6 | Viewed by 1801
Abstract
In this work, we designed and synthesized a novel series of quinazoline derivatives 6–19 and then evaluated their broad-spectrum antitumor activity against MGC-803, MCF-7, PC-9, A549, and H1975, respectively. Most of them demonstrated low micromolar cytotoxicity towards five tested cell lines. [...] Read more.
In this work, we designed and synthesized a novel series of quinazoline derivatives 6–19 and then evaluated their broad-spectrum antitumor activity against MGC-803, MCF-7, PC-9, A549, and H1975, respectively. Most of them demonstrated low micromolar cytotoxicity towards five tested cell lines. In particular, compound 18 exhibited nanomolar level inhibitory activity against MGC-803 cells with an IC50 value of 0.85 μM, indicating approximately a 32-fold selectivity against GES-1 (IC50 = 26.75 μM). Further preclinical evaluation showed that compound 18 remarkably inhibited the migration of MGC-803 cells, induced cell cycle arrest at G2/M, and induced MGC-803 apoptosis, resulting in decreasing the expression of both Bcl-2 and Mcl-1, and up-regulating the expression of both Bax and cleaved PARP. No death or obvious pathological damage was observed in mice by acute toxicity assay. The in vivo antitumor evaluation suggested that compound 18 significantly decreased the average tumor volume and tumor weight without any effect on body weight, which is better than 5-Fu. Therefore, compound 18 can be used as a lead compound for the further development of antitumor drugs in the future. Full article
(This article belongs to the Special Issue Novel Anti-cancer Lead Compounds)
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10 pages, 1601 KiB  
Communication
Application of Pharmacokinetic Prediction Platforms in the Design of Optimized Anti-Cancer Drugs
by Tyler C. Beck, Kendra Springs, Jordan E. Morningstar, Catherine Mills, Andrew Stoddard, Lilong Guo, Kelsey Moore, Cortney Gensemer, Rachel Biggs, Taylor Petrucci, Jennie Kwon, Kristina Stayer, Natalie Koren, Jaclyn Dunne, Diana Fulmer, Ayesha Vohra, Le Mai, Sarah Dooley, Julianna Weninger, Yuri Peterson, Patrick Woster, Thomas A. Dix and Russell A. Norrisadd Show full author list remove Hide full author list
Molecules 2022, 27(12), 3678; https://doi.org/10.3390/molecules27123678 - 08 Jun 2022
Cited by 2 | Viewed by 2007
Abstract
Cancer is the second most common cause of death in the United States, accounting for 602,350 deaths in 2020. Cancer-related death rates have declined by 27% over the past two decades, partially due to the identification of novel anti-cancer drugs. Despite improvements in [...] Read more.
Cancer is the second most common cause of death in the United States, accounting for 602,350 deaths in 2020. Cancer-related death rates have declined by 27% over the past two decades, partially due to the identification of novel anti-cancer drugs. Despite improvements in cancer treatment, newly approved oncology drugs are associated with increased toxicity risk. These toxicities may be mitigated by pharmacokinetic optimization and reductions in off-target interactions. As such, there is a need for early-stage implementation of pharmacokinetic (PK) prediction tools. Several PK prediction platforms exist, including pkCSM, SuperCypsPred, Pred-hERG, Similarity Ensemble Approach (SEA), and SwissADME. These tools can be used in screening hits, allowing for the selection of compounds were reduced toxicity and/or risk of attrition. In this short commentary, we used PK prediction tools in the optimization of mitogen activated extracellular signal-related kinase kinase 1 (MEK1) inhibitors. In doing so, we identified MEK1 inhibitors with retained activity and optimized predictive PK properties, devoid of hERG inhibition. These data support the use of publicly available PK prediction platforms in early-stage drug discovery to design safer drugs. Full article
(This article belongs to the Special Issue Novel Anti-cancer Lead Compounds)
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19 pages, 3425 KiB  
Article
Targeting Mechanisms of the DNA Damage Response (DDR) and DNA Repair by Natural Compounds to Improve cAT-Triggered Tumor Cell Death
by Jana Aengenvoort, Marlena Sekeres, Peter Proksch and Gerhard Fritz
Molecules 2022, 27(11), 3567; https://doi.org/10.3390/molecules27113567 - 01 Jun 2022
Cited by 5 | Viewed by 2220
Abstract
Recently, we identified secalonic acid F (SA), 5-epi-nakijiquinone Q (NQ) and 5-epi-ilimaquinone (IQ) as natural compounds (NC) affecting mechanisms of the DNA damage response (DDR). Here, we further characterized their effects on DDR, DNA repair and cytotoxicity if used in mono- and co-treatment [...] Read more.
Recently, we identified secalonic acid F (SA), 5-epi-nakijiquinone Q (NQ) and 5-epi-ilimaquinone (IQ) as natural compounds (NC) affecting mechanisms of the DNA damage response (DDR). Here, we further characterized their effects on DDR, DNA repair and cytotoxicity if used in mono- and co-treatment with conventional anticancer therapeutics (cAT) (cisplatin (Cis), doxorubicin (Doxo)) in vitro. All three NC influence the phosphorylation level of selected DDR-related factors (i.e., pCHK1, pKAP1, pP53, pRPA32) in mono- and/or co-treatment. Both SA and NQ attenuate the Cis- and Doxo-induced G2/M-phase arrest and effectively stimulate caspase-mediated apoptosis. Notably, SA impacts DNA repair as reflected by enhanced steady-state levels of Cis-(1,2-GpG)-DNA adducts and Doxo-induced DNA double-strand breaks (DSB). Moreover, SA decreased the mRNA and protein expression of the homologous recombination (HR)-related DSB repair factors RAD51 and BRCA1. Both SA and NQ promote Cis- and Doxo-induced cytotoxicity in an additive to synergistic manner (CI ≤ 1.0). Summarizing, we conclude that SA promotes cAT-driven caspase-dependent cell death by interfering with DSB repair and DDR-related checkpoint control mechanisms. Hence, SA is considered as the most promising lead compound to evaluate its therapeutic window in forthcoming pre-clinical in vivo studies. Full article
(This article belongs to the Special Issue Novel Anti-cancer Lead Compounds)
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30 pages, 27434 KiB  
Article
Design, Synthesis and Biological Activity Testing of Library of Sphk1 Inhibitors
by Shuangshuang Geng, Haijiao Chen, Yan Li, Ying Li, Jingxiang Pang, Feipeng Zhang, Zhiqiang Qu, Mengjun Li, Na Liu, Qingqiang Yao, Yanling Mu and Bo Liu
Molecules 2022, 27(6), 2020; https://doi.org/10.3390/molecules27062020 - 21 Mar 2022
Cited by 1 | Viewed by 2040
Abstract
Our team discovered a moderate SphK1 inhibitor, SAMS10 (IC50 = 9.8 μM), which was screened by computer-assisted screening. In this study, we developed a series of novel diaryl derivatives with improved antiproliferative activities by modifying the structure of the lead compound SAMS10 [...] Read more.
Our team discovered a moderate SphK1 inhibitor, SAMS10 (IC50 = 9.8 μM), which was screened by computer-assisted screening. In this study, we developed a series of novel diaryl derivatives with improved antiproliferative activities by modifying the structure of the lead compound SAMS10. A total of 50 new compounds were synthesized. Among these compounds, the most potent compound, named CHJ04022Rb, has significant anticancer activity in melanoma A375 cell line (IC50 = 2.95 μM). Further underlying mechanism studies indicated that CHJ04022R exhibited inhibition effect against PI3K/NF-κB signaling pathways, inhibited the migration of A375 cells, promoted apoptosis and exerted antiproliferative effect by inducing G2/M phase arrest in A375 cells. Furthermore, acute toxicity experiment indicated CHJ04022R exhibited good safety in vivo. Additionally, it showed a dose-dependent inhibitory effect on the growth of xenograft tumor in nude mice. Therefore, CHJ04022R may be a potential candidate for the treatment of melanoma. Full article
(This article belongs to the Special Issue Novel Anti-cancer Lead Compounds)
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16 pages, 4071 KiB  
Article
Anti-Tumor Active Isopropylated Fused Azaisocytosine-Containing Congeners Are Safe for Developing Danio rerio as Well as Red Blood Cells and Activate Apoptotic Caspases in Human Breast Carcinoma Cells
by Małgorzata Sztanke, Jolanta Rzymowska and Krzysztof Sztanke
Molecules 2022, 27(4), 1211; https://doi.org/10.3390/molecules27041211 - 11 Feb 2022
Cited by 3 | Viewed by 1465
Abstract
New isopropylated fused azaisocytosine-containing congeners (I–VI) have previously been reported as promising anticancer drug candidates, so further research on these molecules in the preclinical development phase is fully justified and necessary. For this reason, in the present paper, we assess the [...] Read more.
New isopropylated fused azaisocytosine-containing congeners (I–VI) have previously been reported as promising anticancer drug candidates, so further research on these molecules in the preclinical development phase is fully justified and necessary. For this reason, in the present paper, we assess the toxicity/safety profiles of all the compounds using Danio rerio and red blood cell models, and examine the effect of the most selective congeners on the activation of apoptotic caspases in cancer and normal cells. In order to evaluate the effect of each molecule on the development of zebrafish embryos/larvae and to select the safest compounds for further study, various phenotypic parameters (i.e., mortality, hatchability, heart rate, heart oedema, yolk sac utilization, swim bladder development and body shape) were observed, and the half maximal lethal concentration, the maximal non-lethal concentration and no observed adverse effect concentration for each compound were established. The effect of all the isopropylated molecules was compared to that of an anticancer agent pemetrexed. The lipophilicity-dependent structure–toxicity correlations were also determined. To establish the possible interaction of the compounds with red blood cells, an ex vivo hemolysis test was performed. It was shown that almost all of the investigated isopropylated congeners have no adverse phenotypic effect on zebrafish development during five-day exposure at concentrations up to 50 μM (I–III) or up to 20 μM (IV–V), and that they are less toxic for embryos/larvae than pemetrexed, demonstrating their safety. At the same time, all the molecules did not adversely affect the red blood cells, which confirms their very good hemocompatibility. Moreover, they proved to be activators of apoptotic caspases, as they increased caspase-3, -7 and -9 levels in human breast carcinoma cells. The conducted research allows us to select—from among the anticancer active drug candidates—compounds that are safe for developing zebrafish and red blood cells, suitable for further in vivo pharmacological tests. Full article
(This article belongs to the Special Issue Novel Anti-cancer Lead Compounds)
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21 pages, 4202 KiB  
Article
Synthesis and Preliminary Evaluation of the Cytotoxicity of Potential Metabolites of Quinoline Glycoconjugates
by Monika Domińska, Gabriela Pastuch-Gawołek, Adrian Domiński, Piotr Kurcok and Karol Erfurt
Molecules 2022, 27(3), 1040; https://doi.org/10.3390/molecules27031040 - 03 Feb 2022
Cited by 4 | Viewed by 2086
Abstract
The design of prodrugs is one of the important strategies for selective anti-cancer therapies. When designing prodrugs, attention is paid to the possibility of their targeting tumor-specific markers such as proteins responsible for glucose uptake. That is why glycoconjugation of biologically active compounds [...] Read more.
The design of prodrugs is one of the important strategies for selective anti-cancer therapies. When designing prodrugs, attention is paid to the possibility of their targeting tumor-specific markers such as proteins responsible for glucose uptake. That is why glycoconjugation of biologically active compounds is a frequently used strategy. Glycoconjugates consisting of three basic building blocks: a sugar unit, a linker containing a 1,2,3-triazole ring, and an 8-hydroxyquinoline fragment was described earlier. It is not known whether their cytotoxicity is due to whole glycoconjugates action or their metabolites. To check the biological activity of products that can be released from glycoconjugates under the action of hydrolytic enzymes, the synthetically obtained potential metabolites were tested in vitro for the inhibition of proliferation of HCT-116, MCF-7, and NHDF-Neo cell lines using the MTT assay. Research shows that for the full activity of glycoconjugates, the presence of all three building blocks in the structure of a potential drug is necessary. For selected derivatives, additional tests of targeted drug delivery to tumor cells were carried out using polymer nanocarriers in which they are encapsulated. This approach significantly lowered the determined IC50 values of the tested compounds and improved their selectivity and effectiveness. Full article
(This article belongs to the Special Issue Novel Anti-cancer Lead Compounds)
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Review

Jump to: Research

29 pages, 7710 KiB  
Review
Quinazoline Based HDAC Dual Inhibitors as Potential Anti-Cancer Agents
by Jyothi Dhuguru and Ola A. Ghoneim
Molecules 2022, 27(7), 2294; https://doi.org/10.3390/molecules27072294 - 31 Mar 2022
Cited by 19 | Viewed by 3475
Abstract
Cancer is the most devastating disease and second leading cause of death around the world. Despite scientific advancements in the diagnosis and treatment of cancer which can include targeted therapy, chemotherapy, endocrine therapy, immunotherapy, radiotherapy and surgery in some cases, cancer cells appear [...] Read more.
Cancer is the most devastating disease and second leading cause of death around the world. Despite scientific advancements in the diagnosis and treatment of cancer which can include targeted therapy, chemotherapy, endocrine therapy, immunotherapy, radiotherapy and surgery in some cases, cancer cells appear to outsmart and evade almost any method of treatment by developing drug resistance. Quinazolines are the most versatile, ubiquitous and privileged nitrogen bearing heterocyclic compounds with a wide array of biological and pharmacological applications. Most of the anti-cancer agents featuring quinazoline pharmacophore have shown promising therapeutic activity. Therefore, extensive research is underway to explore the potential of these privileged scaffolds. In this context, a molecular hybridization approach to develop hybrid drugs has become a popular tool in the field of drug discovery, especially after witnessing the successful results during the past decade. Histone deacetylases (HDACs) have emerged as an important anti-cancer target in the recent years given its role in cellular growth, gene regulation, and metabolism. Dual inhibitors, especially based on HDAC in particular, have become the center stage of current cancer drug development. Given the growing significance of dual HDAC inhibitors, in this review, we intend to compile the development of quinazoline based HDAC dual inhibitors as anti-cancer agents. Full article
(This article belongs to the Special Issue Novel Anti-cancer Lead Compounds)
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