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Synthesis and Evaluation of Novel Anticancer Agents

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

Deadline for manuscript submissions: closed (1 July 2023) | Viewed by 6569

Special Issue Editors


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Guest Editor
Graduate Institute of Marine Biology, National Dong Hwa University, Hualien 944, Taiwan
Interests: Structural elucidation; marine secondary metabolites; marine natural products; biological activities; cytotoxic mechanism; in vitro and in vivo assays
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

One of the most influential synthetic chemists, Nobel Laurate Prof. Robert Burns Woodward, once said “The synthesis of substances occurring in Nature, perhaps in greater measure than activities in any other area of organic  chemistry, provides a measure of the conditions and powers of science.” Since the advent of industrial and scientific revolution in the mid of nineteenth century, scientists always tried to mimic natural products and extensively researched on the most efficient methodologies for their synthesis. Many breakthroughs were reported in the synthesis of natural products since the production of the first natural compound, ammonia. To date, more than 60% of synthetic drugs are derived from natural sources and many analogs were developed based on natural scaffolds including Taxoteres, Jevtanas, Camptobells, Hycamtins, Camptosars, Velbans, Oncovins, Eldisines and Navelbines. In the current special issue, we would like to highlight the most important recent findings in the field of synthesis of anticancer agents and the evaluation of their biological activities. Contributors are encouraged to submit manuscripts and reviews covering but not limited to the following topics:

  • Synthesis of novel anticancer agents and evaluation of their biological activity.
  • Application of new technologies in the synthesis of known anticancer agents.
  • Application of green technologies for the preparation of novel and known anticancer agents.
  • Application of computational methods for the design of novel anticancer agents.
  • Synthesis of novel anticancer analogs and study their synergistic or antagonistic affects with other anticancer agents.
  • Development of new models for the evaluation of anticancer agents including 3D cell techniques and ex vivo models.
  • Development of computational methods for the biological evaluation of anticancer agents.
  • Application of biotechnological methods for the synthesis of anticancer agents.

Prof. Dr. Mei-Chin Lu
Prof. Dr. Mohamed El-Shazly
Guest Editors

Manuscript Submission Information

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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

  • Anticancer agents
  • Synthesis of natural product
  • Organic methodologies
  • computational methods
  • Design, synthesis and evaluation
  • biological activity

Published Papers (4 papers)

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Research

13 pages, 3865 KiB  
Article
Synthesis and Antineoplastic Activity of a Dimer, Spiroindolinone Pyrrolidinecarboxamide
by Jingyi Cui, Yujie Wang, Xiaoxin Li, Fei Xiao, Hongjun Ren and Meng Wu
Molecules 2023, 28(9), 3912; https://doi.org/10.3390/molecules28093912 - 05 May 2023
Viewed by 1148
Abstract
The mutation or function loss of tumour suppressor p53 plays an important role in abnormal cell proliferation and cancer generation. Murine Double Minute 2 (MDM2) is one of the key negative regulators of p53. p53 reactivation by inhibiting MDM2–p53 interaction represents a promising [...] Read more.
The mutation or function loss of tumour suppressor p53 plays an important role in abnormal cell proliferation and cancer generation. Murine Double Minute 2 (MDM2) is one of the key negative regulators of p53. p53 reactivation by inhibiting MDM2–p53 interaction represents a promising therapeutic option in cancer treatment. Here, to develop more effective MDM2 inhibitors with lower off-target toxicities, we synthesized a dimer, spiroindolinone pyrrolidinecarboxamide XR-4, with potent MDM2-p53 inhibition activity. Western blotting and qRT-PCR were performed to detect the impact of XR-4 on MDM2 and p53 protein levels and p53 downstream target gene levels in different cancers. Cancer cell proliferation inhibition and clonogenic activity were also investigated via the CCK8 assay and colony formation assay. A subcutaneous 22Rv1-derived xenografts mice model was used to investigate the in vivo anti-tumour activity of XR-4. The results reveal that XR-4 can induce wild-type p53 accumulation in cancer cells, upregulate the levels of the p53 target genes p21 and PUMA levels, and then inhibit cancer cell proliferation and induce cell apoptosis. XR-4 can also act as a homo-PROTAC that induces MDM2 protein degradation. Meanwhile, the in vivo study results show that XR-4 possesses potent antitumour efficacy and a favourable safety property. In summary, XR-4 is an interesting spiroindolinone pyrrolidinecarboxamide-derivative dimer with effective p53 activation activity and a cancer inhibition ability. Full article
(This article belongs to the Special Issue Synthesis and Evaluation of Novel Anticancer Agents)
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13 pages, 2373 KiB  
Communication
Identification of Flavone Derivative Displaying a 4′-Aminophenoxy Moiety as Potential Selective Anticancer Agent in NSCLC Tumor Cells
by Giovanna Mobbili, Brenda Romaldi, Giulia Sabbatini, Adolfo Amici, Massimo Marcaccio, Roberta Galeazzi, Emiliano Laudadio, Tatiana Armeni and Cristina Minnelli
Molecules 2023, 28(7), 3239; https://doi.org/10.3390/molecules28073239 - 05 Apr 2023
Cited by 1 | Viewed by 1601
Abstract
Five heterocyclic derivatives were synthesized by functionalization of a flavone nucleus with an aminophenoxy moiety. Their cytotoxicity was investigated in vitro in two models of human non-small cell lung cancer (NSCLC) cells (A549 and NCI-H1975) by using MTT assay and the results compared [...] Read more.
Five heterocyclic derivatives were synthesized by functionalization of a flavone nucleus with an aminophenoxy moiety. Their cytotoxicity was investigated in vitro in two models of human non-small cell lung cancer (NSCLC) cells (A549 and NCI-H1975) by using MTT assay and the results compared to those obtained in healthy fibroblasts as a non-malignant cell model. One of the aminophenoxy flavone derivatives (APF-1) was found to be effective at low micromolar concentrations in both lung cancer cell lines with a higher selective index (SI). Flow cytometric analyses showed that APF-1 induced apoptosis and cell cycle arrest in the G2/M phase through the up-regulation of p21 expression. Therefore, the aminophenoxy flavone-based compounds may be promising cancer-selective agents and could serve as a base for further research into the design of flavone-based anticancer drugs. Full article
(This article belongs to the Special Issue Synthesis and Evaluation of Novel Anticancer Agents)
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14 pages, 3525 KiB  
Article
Effect of Copper Chelators via the TGF-β Signaling Pathway on Glioblastoma Cell Invasion
by Heabin Kim, Seonmi Jo, In-Gyu Kim, Rae-Kwon Kim, Yeon-Jee Kahm, Seung-Hyun Jung and Jei Ha Lee
Molecules 2022, 27(24), 8851; https://doi.org/10.3390/molecules27248851 - 13 Dec 2022
Cited by 3 | Viewed by 1736
Abstract
Glioblastoma multiforme (GBM) is a fast-growing and aggressive type of brain cancer. Unlike normal brain cells, GBM cells exhibit epithelial–mesenchymal transition (EMT), which is a crucial biological process in embryonic development and cell metastasis, and are highly invasive. Copper reportedly plays a critical [...] Read more.
Glioblastoma multiforme (GBM) is a fast-growing and aggressive type of brain cancer. Unlike normal brain cells, GBM cells exhibit epithelial–mesenchymal transition (EMT), which is a crucial biological process in embryonic development and cell metastasis, and are highly invasive. Copper reportedly plays a critical role in the progression of a variety of cancers, including brain, breast, and lung cancers. However, excessive copper is toxic to cells. D-penicillamine (DPA) and triethylenetetramine (TETA) are well-known copper chelators and are the mainstay of treatment for copper-associated diseases. Following treatment with copper sulfate and DPA, GBM cells showed inhibition of proliferation and suppression of EMT properties, including reduced expression levels of N-cadherin, E-cadherin, and Zeb, which are cell markers associated with EMT. In contrast, treatment with copper sulfate and TETA yielded the opposite effects in GBM. Genes, including TGF-β, are associated with an increase in copper levels, implying their role in EMT. To analyze the invasion and spread of GBM, we used zebrafish embryos xenografted with the GBM cell line U87. The invasion of GBM cells into zebrafish embryos was markedly inhibited by copper treatment with DPA. Our findings suggest that treatment with copper and DPA inhibits proliferation and EMT through a mechanism involving TGF-β/Smad signaling in GBM. Therefore, DPA, but not TETA, could be used as adjuvant therapy for GBM with high copper concentrations. Full article
(This article belongs to the Special Issue Synthesis and Evaluation of Novel Anticancer Agents)
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20 pages, 7018 KiB  
Article
Synthesis, Characterization and Anticancer Efficacy Studies of Iridium (III) Polypyridyl Complexes against Colon Cancer HCT116 Cells
by Biao Xie, Yi Wang, Di Wang, Xingkui Xue and Yuqiang Nie
Molecules 2022, 27(17), 5434; https://doi.org/10.3390/molecules27175434 - 25 Aug 2022
Cited by 3 | Viewed by 1588
Abstract
In this paper, two new iridium (III) complexes, [Ir(ppy)2(ipbp)](PF6) (Ir1) (ppy = 2-phenylpyridine, ipbp = 3-(1H-imidazo[4,5-f][1,10]phenanthrolin-2yl)-4H-chromen-4-one) and [Ir(bzq)2(ipbp)](PF6) (Ir2) (bzq = benzo[h]quinolone), were synthesized and [...] Read more.
In this paper, two new iridium (III) complexes, [Ir(ppy)2(ipbp)](PF6) (Ir1) (ppy = 2-phenylpyridine, ipbp = 3-(1H-imidazo[4,5-f][1,10]phenanthrolin-2yl)-4H-chromen-4-one) and [Ir(bzq)2(ipbp)](PF6) (Ir2) (bzq = benzo[h]quinolone), were synthesized and characterized. The cytotoxicity of the complexes against human colon cancer HCT116 and normal LO2 cells was evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. The complexes Ir1 and Ir2 show high cytotoxic efficacy toward HCT116 cells with a low IC50 value of 1.75 ± 0.10 and 6.12 ± 0.2 µM. Interestingly, Ir1 only kills cancer cells, not normal LO2 cells (IC50 > 200 µM). The inhibition of cell proliferation and migration were investigated by multiple tumor spheroid (3D) and wound healing experiments. The cellular uptake was explored under a fluorescence microscope. The intracellular reactive oxygen species (ROS), change of mitochondrial membrane potential, glutathione (GSH) and adenine nucleoside triphosphate (ATP) were studied. Apoptosis and cell cycle arrest were performed by flow cytometry. The results show that the complexes induce early apoptosis and inhibit the cell proliferation at the G0/G1 phase. Additionally, the apoptotic mechanism was researched by Western blot analysis. The results obtained demonstrate that the complexes cause apoptosis in HCT116 cells through ROS-mediated mitochondrial dysfunction and the inhibition of PI3K/AKT signaling pathways. Full article
(This article belongs to the Special Issue Synthesis and Evaluation of Novel Anticancer Agents)
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