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22 pages, 16615 KiB

Open AccessArticle

The Mechanism of a Novel Mitochondrial-Targeted Icaritin Derivative in Regulating Apoptosis of BEL-7402 Cells Based on the SIRT3 and CypD-Mediated ROS/p38 MAPK Signaling Pathway

by Zenan Chen, Wei Li, Yan Zhao, Dingrui Liu, Jiahong Han and Enbo Cai

Molecules 2025, 30(8), 1667; https://doi.org/10.3390/molecules30081667 - 8 Apr 2025

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Abstract

Tumorigenesis and progression are closely associated with apoptosis and primarily regulated by mitochondria, which are considered major targets for cancer therapy. In this study, twelve novel icaritin (ICT) derivatives were designed and synthesized, four of which were specifically targeted to mitochondria. Biological studies [...] Read more.

Tumorigenesis and progression are closely associated with apoptosis and primarily regulated by mitochondria, which are considered major targets for cancer therapy. In this study, twelve novel icaritin (ICT) derivatives were designed and synthesized, four of which were specifically targeted to mitochondria. Biological studies demonstrated that all compounds containing triphenylphosphine (TPP⁺) exhibited a substantial increase in antitumor activity compared to ICT and control compounds while also exhibiting notable selectivity for tumor cells over normal cells. Among these derivatives, Mito-ICT-4 exhibited the strongest antiproliferative effect, with an IC₅₀ value of 0.73 ± 0.06 μM for BEL-7402 cells, which is 29 times lower than that of ICT, and an IC₅₀ value of 67.11 ± 2.09 μM for HEK293 cells, indicating approximately 33-fold selectivity for tumor cells. High-performance liquid chromatography (HPLC) analysis revealed that Mito-ICT-4 significantly accumulated in the mitochondria of BEL-7402 cells, with the level of accumulation approximately 2.5 times greater than that of ICT. Further investigations demonstrated that upon entering the mitochondria of tumor cells, Mito-ICT-4 downregulated SIRT3 protein expression, disrupted intracellular redox homeostasis, and led to a substantial increase in mitochondrial ROS levels, abnormal CypD-dependent MPTP opening, mitochondrial membrane potential depolarization, and ROS release into the cytoplasm, ultimately triggering ROS-mediated apoptosis in BEL-7402 cells. Transcriptomic analysis identified differentially expressed genes and enriched pathways, highlighting the ROS-mediated p38-MAPK signaling pathway as a key mediator of Mito-ICT-4-induced mitochondria-dependent apoptosis. The effects of Mito-ICT-4 on the expression of key genes (SIRT3, CypD, P-MKK6, P-P38, and DDIT3) were further validated by qRT-PCR and Western blot analysis, with results aligning with transcriptomic data. The novel ICT derivatives synthesized in this study, with mitochondria-targeting functionality, provide a basis for the development of targeted antitumor drugs. Full article

(This article belongs to the Special Issue Design, Synthesis and Biological Activity of Novel Antitumor Drugs)

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14 pages, 939 KiB

Open AccessArticle

Synthesis and Evaluation of the Antiproliferative Activity of the Derivatives of 3,5-Diaryl-3,4-dihydro-2H-pyrrole-2-carboxylic Acids

by Vesela Mihaylova, Ivan Iliev, Anelia Vasileva, Elizabeth Mazzio, Bereket Mochona, Nelly Mateeva and Donka Tasheva

Molecules 2025, 30(7), 1602; https://doi.org/10.3390/molecules30071602 - 3 Apr 2025

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Abstract

The metabolic cycle of L-proline plays a crucial role in cancer cell survival, proliferation, and metastasis. A key intermediate in the biosynthesis and degradation of proline is 3,4-dihydro-2H-pyrrole-2-carboxylic acid. A direct route for synthesizing substituted derivatives of this acid involves the [...] Read more.

The metabolic cycle of L-proline plays a crucial role in cancer cell survival, proliferation, and metastasis. A key intermediate in the biosynthesis and degradation of proline is 3,4-dihydro-2H-pyrrole-2-carboxylic acid. A direct route for synthesizing substituted derivatives of this acid involves the cyclization of 2-amino-5-oxonitriles. Michael additions of [(diphenylmethylene)amino]acetonitrile to enones in a basic medium—either with aqueous sodium hydroxide or under solid–liquid phase-transfer catalysis conditions using CaO as a base—enable the synthesis of substituted 2-amino-5-oxonitriles as single diastereoisomers or as diastereoisomeric mixtures. Selective removal of the diphenylmethylene-protecting group, followed by in situ cyclization in acidic conditions, yields trans- and cis-3,5-diaryl-3,4-dihydro-2H-pyrrole-2-carbonitriles. The reaction of nitriles with HCl/dioxane/methanol followed by treatment with water produces esters and amides as by-products. In vitro screening of the synthesized compounds against multiple human cancer cell lines revealed that some compounds exhibit a good or high selectivity index. In conclusion, the synthetic schemes presented offer simple and efficient routes for the preparation of the derivatives of substituted 3,4-dihydro-2H-pyrrole-2-carboxylic acids, with some compounds exhibiting promising antiproliferative activity. Full article

(This article belongs to the Special Issue Design, Synthesis and Biological Activity of Novel Antitumor Drugs)

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12 pages, 2453 KiB

Open AccessArticle

RNA-Binding Motif Protein 22 Induces Apoptosis via c-Myc Pathway in Colon Cancer Cells

by Ye-Rin Park, So-Mi Park, Nanyeong Kim, Jihoon Jung, Seokwoo Kim, Kwan-Il Kim and Hyeung-Jin Jang

Molecules 2025, 30(6), 1227; https://doi.org/10.3390/molecules30061227 - 9 Mar 2025

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Abstract

RNA-binding motif 22 (RBM22) is an RNA-binding protein involved in gene regulation, with the capacity to bind DNA and function as a transcription factor for various target genes. Recent studies demonstrated that RBM22 depletion affects cell viability and proliferation of glioblastoma and breast [...] Read more.

RNA-binding motif 22 (RBM22) is an RNA-binding protein involved in gene regulation, with the capacity to bind DNA and function as a transcription factor for various target genes. Recent studies demonstrated that RBM22 depletion affects cell viability and proliferation of glioblastoma and breast cancer cells. However, the role of RBM22 in colon cancer and the molecular mechanisms underlying its tumor-suppressive function remain largely unclear. In this study, we demonstrate that RBM22 induces apoptosis and suppresses colon cancer cell viability and proliferation by modulating c-Myc expression. Furthermore, RBM22 knockdown reduces c-Myc stability. Therefore, our findings suggest that RBM22 depletion regulates cancer cell proliferation and induces apoptosis via the c-Myc pathway. Full article

(This article belongs to the Special Issue Design, Synthesis and Biological Activity of Novel Antitumor Drugs)

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20 pages, 1416 KiB

Open AccessArticle

Effect of Drying Methods on the Phenolic Profile and Antioxidant Capacity of Pithecellobium dulce (Roxb.) Benth. Aril and Its Inhibitory Properties on Human SW480 Colon Adenocarcinoma Cells

by Ángel Félix Vargas-Madriz, Aarón Kuri-García, Ivan Luzardo-Ocampo, Roberto Augusto Ferriz-Martínez, Teresa García-Gasca, Carlos Saldaña, Haidel Vargas-Madriz, Salvador Horacio Guzmán-Maldonado and Jorge Luis Chávez-Servín

Molecules 2025, 30(2), 233; https://doi.org/10.3390/molecules30020233 - 9 Jan 2025

Cited by 1 | Viewed by 1130

Abstract

Pithecellobium dulce (P. dulce) is a Mexican plant that is consumed raw or in different preparations, and its anti-inflammatory and antioxidant properties have traditionally been useful in treating several conditions. However, the post-harvest drying process can alter the content of bioactive [...] Read more.

Pithecellobium dulce (P. dulce) is a Mexican plant that is consumed raw or in different preparations, and its anti-inflammatory and antioxidant properties have traditionally been useful in treating several conditions. However, the post-harvest drying process can alter the content of bioactive compounds in P. dulce. This study aims to evaluate the impact of different drying methods on the phenolic profile and antioxidant capacity of this plant, as well as its inhibitory effect on human SW480 colon adenocarcinoma cells. After oven drying, the samples showed a higher amount (p < 0.05) of phenolic compounds, up to 1149.45 ± 69.27 mg GAE/100 g LE, which is 80% more than the freeze-dried samples. Also, the antioxidant capacity was higher in oven-dried samples, with 44.63 ± 2.00 µmol Trolox equivalents/g LE, 108% more than the freeze-dried method. Methanolic extraction, in turn, yielded better results than aqueous and ethanolic extractions. Up to 14 polyphenolic compounds were detected in oven-dried samples. For in vitro assays in SW480 cells, the 50% v/v methanolic extract was used. From this extract, the median lethal concentration (LC₅₀) was determined to be 13.76 mg/mL, which represents the concentration necessary to inhibit the growth of half of the cancer cells of this cell line. The extract led to cell cycle arrest in the G1 phase and an increase in apoptosis-induced cell death. The P. dulce extract augmented p53 and decreased KRAS gene expressions. Results suggested pro-apoptotic mechanisms in colon cancer cells in vitro linked to P. dulce bioactive compounds, which are better preserved when oven-dried plants are subjected to methanolic extraction. Full article

(This article belongs to the Special Issue Design, Synthesis and Biological Activity of Novel Antitumor Drugs)

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15 pages, 5847 KiB

Open AccessArticle

Thiazole Functionalization of Thiosemicarbazone for Cu(II) Complexation: Moving toward Highly Efficient Anticancer Drugs with Promising Oral Bioavailability

by Song-Yu Luo, Chun-Mei Zeng, Ping Xu, Ye Ning, Meng-Lin Dong, Wen-Hua Zhang and Guangliang Yu

Molecules 2024, 29(16), 3832; https://doi.org/10.3390/molecules29163832 - 13 Aug 2024

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Abstract

In this work, we report the synthesis of a new thiosemicarbazone-based drug of N′-(di(pyridin-2-yl)methylene)-4-(thiazol-2-yl)piperazine-1-carbothiohydrazide (HL) featuring a thiazole spectator for efficient coordination with Cu(II) to give [CuCl(L)]₂ (1) and [Cu(NO₃)(L)]₂ ( [...] Read more.

In this work, we report the synthesis of a new thiosemicarbazone-based drug of N′-(di(pyridin-2-yl)methylene)-4-(thiazol-2-yl)piperazine-1-carbothiohydrazide (HL) featuring a thiazole spectator for efficient coordination with Cu(II) to give [CuCl(L)]₂ (1) and [Cu(NO₃)(L)]₂ (2). Both 1 and 2 exhibit dimeric structures ascribed to the presence of di-2-pyridylketone moieties that demonstrate dual functions of chelation and intermolecular bridging. HL, 1, and 2 are highly toxic against hepatocellular carcinoma cell lines Hep-G2, PLC/PRF/5, and HuH-7 with half maximal inhibitory concentration (IC₅₀) values as low as 3.26 nmol/mL (HL), 2.18 nmol/mL (1), and 2.54 × 10⁻⁵ nmol/mL (2) for PLC/PRF/5. While the free ligand HL may elicit its anticancer effect via the sequestration of bio-relevant metal ions (i.e., Fe³⁺ and Cu²⁺), 1 and 2 are also capable of generating cytotoxic reactive oxygen species (ROS) to inhibit cancer cell proliferation. Our preliminary pharmacokinetic studies revealed that oral administration (per os, PO) of HL has a significantly longer half-life t_1/2 of 21.61 ± 9.4 h, nearly doubled as compared with that of the intravenous (i.v.) administration of 11.88 ± 1.66 h, certifying HL as an effective chemotherapeutic drug via PO administration. Full article

(This article belongs to the Special Issue Design, Synthesis and Biological Activity of Novel Antitumor Drugs)

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17 pages, 3856 KiB

Open AccessArticle

Novel PD-L1-Targeted Phenyl-Pyrazolone Derivatives with Antioxidant Properties

by Romain Regnault, Frédérique Klupsch, Hassiba El-Bouazzati, Romain Magnez, Raphaël Le Biannic, Natascha Leleu-Chavain, Hania Ahouari, Hervé Vezin, Régis Millet, Jean-François Goossens, Xavier Thuru and Christian Bailly

Molecules 2023, 28(8), 3491; https://doi.org/10.3390/molecules28083491 - 15 Apr 2023

Cited by 4 | Viewed by 2663

Abstract

Orally-active anticancer small molecules targeting the PD-1/PD-L1 immune checkpoint are actively searched. Phenyl-pyrazolone derivatives with a high affinity for PD-L1 have been designed and characterized. In addition, the phenyl-pyrazolone unit acts as a scavenger of oxygen free radicals, providing antioxidant effects. The mechanism [...] Read more.

Orally-active anticancer small molecules targeting the PD-1/PD-L1 immune checkpoint are actively searched. Phenyl-pyrazolone derivatives with a high affinity for PD-L1 have been designed and characterized. In addition, the phenyl-pyrazolone unit acts as a scavenger of oxygen free radicals, providing antioxidant effects. The mechanism is known for the drug edaravone (1) which is also an aldehyde-reactive molecule. The present study reports the synthesis and functional characterization of new molecules (2–5) with an improved anti-PD-L1 activity. The leading fluorinated molecule 5 emerges as a potent checkpoint inhibitor, avidly binding to PD-L1, inducing its dimerization, blocking PD-1/PD-L1 signaling mediated by phosphatase SHP-2 and reactivating the proliferation of CTLL-2 cells in the presence of PD-L1. In parallel, the compound maintains a significant antioxidant activity, characterized using electron paramagnetic resonance (EPR)-based free radical scavenging assays with the probes DPPH and DMPO. The aldehyde reactivity of the molecules was investigated using 4-hydroxynonenal (4-HNE), which is a major lipid peroxidation product. The formation of drug-HNE adducts, monitored by high resolution mass spectrometry (HRMS), was clearly identified and compared for each compound. The study leads to the selection of compound 5 and the dichlorophenyl-pyrazolone unit as a scaffold for the design of small molecule PD-L1 inhibitors endowed with antioxidant properties. Full article

(This article belongs to the Special Issue Design, Synthesis and Biological Activity of Novel Antitumor Drugs)

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Review

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21 pages, 5487 KiB

Open AccessReview

Targeting the CXCR4/CXCL12 Axis in Cancer Therapy: Analysis of Recent Advances in the Development of Potential Anticancer Agents

by Gerardina Smaldone, Francesca Di Matteo, Roberta Castelluccio, Valeria Napolitano, Maria Rosaria Miranda, Michele Manfra, Pietro Campiglia and Vincenzo Vestuto

Molecules 2025, 30(6), 1380; https://doi.org/10.3390/molecules30061380 - 20 Mar 2025

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Abstract

Cancer, a leading cause of premature death, arises from genetic and epigenetic mutations that transform normal cells into tumor cells, enabling them to proliferate, evade cell death, and stimulate angiogenesis. Recent evidence indicates that chemokines are essential in tumor development, activating receptors that [...] Read more.

Cancer, a leading cause of premature death, arises from genetic and epigenetic mutations that transform normal cells into tumor cells, enabling them to proliferate, evade cell death, and stimulate angiogenesis. Recent evidence indicates that chemokines are essential in tumor development, activating receptors that promote proliferation, invasion, and metastasis. The CXCR4/CXCL12 signaling pathway is gaining attention as a promising target for cancer therapy. CXCR4, a chemokine receptor, is often overexpressed in various types of cancer, including kidney, lung, brain, prostate, breast, pancreas, ovarian, and melanomas. When it binds to its endogenous ligand, CXCL12, it promotes cell survival, proliferation, and migration, crucial mechanisms for the retention of hematopoietic stem cells in the bone marrow and the movement of lymphocytes. The extensive expression of CXCR4 in cancer, coupled with the constant presence of CXCL12 in various organs, drives the activation of this axis, which in turn facilitates angiogenesis, tumor progression, and metastasis. Given the detrimental role of the CXCR4/CXCL12 axis, the search for drugs acting selectively against this protein represents an open challenge. This review aims to summarize the recent advancements in the design and development of CXCR4 antagonists as potential anticancer agents. Full article

(This article belongs to the Special Issue Design, Synthesis and Biological Activity of Novel Antitumor Drugs)

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30 pages, 39322 KiB

Open AccessReview

Recent Advances in the Development of Immunoproteasome Inhibitors as Anti-Cancer Agents: The Past 5 Years

by Francesca Mancuso, Carla Di Chio, Francesca Di Matteo, Gerardina Smaldone, Nunzio Iraci and Salvatore Vincenzo Giofrè

Molecules 2025, 30(3), 755; https://doi.org/10.3390/molecules30030755 - 6 Feb 2025

Cited by 2 | Viewed by 774

Abstract

The immunoproteasome (iCP) is an isoform of the 20S proteasome that is expressed in response to cellular stress or inflammatory stimuli. The primary role of the iCP is to hydrolyze proteins into peptides that can be loaded into the MHC-I complex. Beyond its [...] Read more.

The immunoproteasome (iCP) is an isoform of the 20S proteasome that is expressed in response to cellular stress or inflammatory stimuli. The primary role of the iCP is to hydrolyze proteins into peptides that can be loaded into the MHC-I complex. Beyond its primary role in the adaptive immune response, it is also involved in the pathogenic mechanism of numerous disease states such as inflammatory conditions and cancer. In the last decade, a huge number of immunoproteasome-specific inhibitors have been described, allowing researchers to elucidate the role of the immunoproteasome as a potential therapeutic target for these diseases. The present manuscript summarizes the latest advances regarding immunoproteasome inhibitors tested against different cancer models. Specifically, it will focus on peptide and non-peptide analogs that have been reported in the last five years, together with their structure–activity relationship (SAR) studies. It aims to provide structural insights into this class of compounds pertaining to their favorable applicability as selective iCP inhibitors in the treatment of cancer. Full article

(This article belongs to the Special Issue Design, Synthesis and Biological Activity of Novel Antitumor Drugs)

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