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24 pages, 1729 KiB

Open AccessArticle

The Finally Rewarding Search for A Cytotoxic Isosteviol Derivative

by Julia Heisig, Niels V. Heise, Sophie Hoenke, Dieter Ströhl and René Csuk

Molecules 2023, 28(13), 4951; https://doi.org/10.3390/molecules28134951 - 23 Jun 2023

Cited by 2 | Viewed by 923

Abstract

Acid hydrolysis of stevioside resulted in a 63% yield of isosteviol (1), which served as a starting material for the preparation of numerous amides. These compounds were tested for cytotoxic activity, employing a panel of human tumor cell lines, and almost [...] Read more.

Acid hydrolysis of stevioside resulted in a 63% yield of isosteviol (1), which served as a starting material for the preparation of numerous amides. These compounds were tested for cytotoxic activity, employing a panel of human tumor cell lines, and almost all amides were found to be non-cytotoxic. Only the combination of isosteviol, a (homo)-piperazinyl spacer and rhodamine B or rhodamine 101 unit proved to be particularly suitable. These spacered rhodamine conjugates exhibited cytotoxic activity in the sub-micromolar concentration range. In this regard, the homopiperazinyl-spacered derivatives were found to be better than those compounds with piperazinyl spacers, and rhodamine 101 conjugates were more cytotoxic than rhodamine B hybrids. Full article

(This article belongs to the Special Issue Recent Advances in Development of Small Molecules to Fight Cancer)

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23 pages, 5532 KiB

Open AccessArticle

Anticancer Activities of Novel Nicotinamide Phosphoribosyltransferase Inhibitors in Hematological Malignancies

by Paulina Biniecka, Saki Matsumoto, Axel Belotti, Jessie Joussot, Jian Fei Bai, Somi Reddy Majjigapu, Paul Thoueille, Dany Spaggiari, Vincent Desfontaine, Francesco Piacente, Santina Bruzzone, Michele Cea, Laurent A. Decosterd, Pierre Vogel, Alessio Nencioni, Michel A. Duchosal and Aimable Nahimana

Molecules 2023, 28(4), 1897; https://doi.org/10.3390/molecules28041897 - 16 Feb 2023

Cited by 1 | Viewed by 2158

Abstract

Targeting cancer cells that are highly dependent on the nicotinamide adenine dinucleotide (NAD+) metabolite is a promising therapeutic strategy. Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme catalyzing NAD⁺ production. Despite the high efficacy of several developed NAMPT inhibitors (i.e., FK866 (APO866)) in [...] Read more.

Targeting cancer cells that are highly dependent on the nicotinamide adenine dinucleotide (NAD+) metabolite is a promising therapeutic strategy. Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme catalyzing NAD⁺ production. Despite the high efficacy of several developed NAMPT inhibitors (i.e., FK866 (APO866)) in preclinical studies, their clinical activity was proven to be limited. Here, we report the synthesis of new NAMPT Inhibitors, JJ08, FEI191 and FEI199, which exhibit a broad anticancer activity in vitro. Results show that these compounds are potent NAMPT inhibitors that deplete NAD⁺ and NADP(H) after 24 h of drug treatment, followed by an increase in reactive oxygen species (ROS) accumulation. The latter event leads to ATP loss and mitochondrial depolarization with induction of apoptosis and necrosis. Supplementation with exogenous NAD⁺ precursors or catalase (ROS scavenger) abrogates the cell death induced by the new compounds. Finally, in vivo administration of the new NAMPT inhibitors in a mouse xenograft model of human Burkitt lymphoma delays tumor growth and significantly prolongs mouse survival. The most promising results are collected with JJ08, which completely eradicates tumor growth. Collectively, our findings demonstrate the efficient anticancer activity of the new NAMPT inhibitor JJ08 and highlight a strong interest for further evaluation of this compound in hematological malignancies. Full article

(This article belongs to the Special Issue Recent Advances in Development of Small Molecules to Fight Cancer)

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13 pages, 2543 KiB

Open AccessArticle

2′-Fucosyllactose Suppresses Angiogenesis and Alleviates Toxic Effects of 5-Fu in a HCT116 Colon Tumor-Bearing Model

by Huiying Li, Bingyuan Wang and Yang Wang

Molecules 2022, 27(21), 7255; https://doi.org/10.3390/molecules27217255 - 26 Oct 2022

Cited by 2 | Viewed by 1384

Abstract

The present study was aimed at examining the anti-tumor effects and molecular mechanisms of 2′-fucosyllactose (2′-FL). At the beginning, the viabilities of four types of colon cancer cells were analyzed after exposure to increasing concentrations of 2′-FL, and HCT116 cells were selected as [...] Read more.

The present study was aimed at examining the anti-tumor effects and molecular mechanisms of 2′-fucosyllactose (2′-FL). At the beginning, the viabilities of four types of colon cancer cells were analyzed after exposure to increasing concentrations of 2′-FL, and HCT116 cells were selected as the sensitive ones, which were applied in the further experiments; then, interestingly, 2′-FL (102.35 µM) was found to induce apoptosis of HCT116 cells, which coincides with significant changes in VEGFA/VEGFR2/p-PI3K/p-Akt/cleaved Caspase3 proteins. Next, in a tumor-bearing nude mouse model, HCT116 was chosen as the sensitive cell line, and 5-fluorouracil (5-Fu) was chosen as the positive medicine. It was noteworthy that both 2′-FL group (2.41 ± 0.57 g) and 2′FL/5-Fu group (1.22 ± 0.35 g) had a significantly lower tumor weight compared with the control (3.87 ± 0.79 g), suggesting 2′-FL could inhibit colon cancer. Since 2′-FL reduced the number of new blood vessels and the malignancy of tumors, we confirmed that 2′-FL effectively inhibited HCT116 tumors, and its mechanism was achieved by regulating the VEGFA/VEGFR2/PI3K/Akt/Caspase3 pathway. Moreover, though HE staining and organ index measurement, 2′-FL was validated to alleviate toxic effects on liver and kidney tissue when combining with 5-Fu. In conclusion, 2′-FL had certain anti-tumor and detoxification effects. Full article

(This article belongs to the Special Issue Recent Advances in Development of Small Molecules to Fight Cancer)

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Review

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43 pages, 6645 KiB

Open AccessReview

The Benzoylpiperidine Fragment as a Privileged Structure in Medicinal Chemistry: A Comprehensive Review

by Giulia Bononi, Chiara Lonzi, Tiziano Tuccinardi, Filippo Minutolo and Carlotta Granchi

Molecules 2024, 29(9), 1930; https://doi.org/10.3390/molecules29091930 - 23 Apr 2024

Viewed by 696

Abstract

The phenyl(piperidin-4-yl)methanone fragment (here referred to as the benzoylpiperidine fragment) is a privileged structure in the development of new drugs considering its presence in many bioactive small molecules with both therapeutic (such as anti-cancer, anti-psychotic, anti-thrombotic, anti-arrhythmic, anti-tubercular, anti-parasitic, anti-diabetic, and neuroprotective agents) [...] Read more.

The phenyl(piperidin-4-yl)methanone fragment (here referred to as the benzoylpiperidine fragment) is a privileged structure in the development of new drugs considering its presence in many bioactive small molecules with both therapeutic (such as anti-cancer, anti-psychotic, anti-thrombotic, anti-arrhythmic, anti-tubercular, anti-parasitic, anti-diabetic, and neuroprotective agents) and diagnostic properties. The benzoylpiperidine fragment is metabolically stable, and it is also considered a potential bioisostere of the piperazine ring, thus making it a feasible and reliable chemical frame to be exploited in drug design. Herein, we discuss the main therapeutic and diagnostic agents presenting the benzoylpiperidine motif in their structure, covering articles reported in the literature since 2000. A specific section is focused on the synthetic strategies adopted to obtain this versatile chemical portion. Full article

(This article belongs to the Special Issue Recent Advances in Development of Small Molecules to Fight Cancer)

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24 pages, 8068 KiB

Open AccessReview

Inhibitors of Cyclophilin A: Current and Anticipated Pharmaceutical Agents for Inflammatory Diseases and Cancers

by Xuemei Zhao, Xin Zhao, Weihua Di and Chang Wang

Molecules 2024, 29(6), 1235; https://doi.org/10.3390/molecules29061235 - 11 Mar 2024

Viewed by 1249

Abstract

Cyclophilin A, a widely prevalent cellular protein, exhibits peptidyl-prolyl cis-trans isomerase activity. This protein is predominantly located in the cytosol; additionally, it can be secreted by the cells in response to inflammatory stimuli. Cyclophilin A has been identified to be a [...] Read more.

Cyclophilin A, a widely prevalent cellular protein, exhibits peptidyl-prolyl cis-trans isomerase activity. This protein is predominantly located in the cytosol; additionally, it can be secreted by the cells in response to inflammatory stimuli. Cyclophilin A has been identified to be a key player in many of the biological events and is therefore involved in several diseases, including vascular and inflammatory diseases, immune disorders, aging, and cancers. It represents an attractive target for therapeutic intervention with small molecule inhibitors such as cyclosporin A. Recently, a number of novel inhibitors of cyclophilin A have emerged. However, it remains elusive whether and how many cyclophilin A inhibitors function in the inflammatory diseases and cancers. In this review, we discuss current available data about cyclophilin A inhibitors, including cyclosporin A and its derivatives, quinoxaline derivatives, and peptide analogues, and outline the most recent advances in clinical trials of these agents. Inhibitors of cyclophilin A are poised to enhance our comprehension of the molecular mechanisms that underpin inflammatory diseases and cancers associated with cyclophilin A. This advancement will aid in the development of innovative pharmaceutical treatments in the future. Full article

(This article belongs to the Special Issue Recent Advances in Development of Small Molecules to Fight Cancer)

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16 pages, 2184 KiB

Open AccessReview

Mushroom-Derived Compounds as Metabolic Modulators in Cancer

by Bhoomika Dowaraka-Persad and Vidushi Shradha Neergheen

Molecules 2023, 28(3), 1441; https://doi.org/10.3390/molecules28031441 - 2 Feb 2023

Cited by 1 | Viewed by 2775

Abstract

Cancer is responsible for lifelong disability and decreased quality of life. Cancer-associated changes in metabolism, in particular carbohydrate, lipid, and protein, offer a new paradigm of metabolic hits. Hence, targeting the latter, as well as related cross-linked signalling pathways, can reverse the malignant [...] Read more.

Cancer is responsible for lifelong disability and decreased quality of life. Cancer-associated changes in metabolism, in particular carbohydrate, lipid, and protein, offer a new paradigm of metabolic hits. Hence, targeting the latter, as well as related cross-linked signalling pathways, can reverse the malignant phenotype of transformed cells. The systemic toxicity and pharmacokinetic limitations of existing drugs prompt the discovery of multi-targeted and safe compounds from natural products. Mushrooms possess biological activities relevant to disease-fighting and to the prevention of cancer. They have a long-standing tradition of use in ethnomedicine and have been included as an adjunct therapy during and after oncological care. Mushroom-derived compounds have also been reported to target the key signature of cancer cells in in vitro and in vivo studies. The identification of metabolic pathways whose inhibition selectively affects cancer cells appears as an interesting approach to halting cell proliferation. For instance, panepoxydone exerted protective mechanisms against breast cancer initiation and progression by suppressing lactate dehydrogenase A expression levels and reinducing lactate dehydrogenase B expression levels. This further led to the accumulation of pyruvate, the activation of the electron transport chain, and increased levels of reactive oxygen species, which eventually triggered mitochondrial apoptosis in the breast cancer cells. Furthermore, the inhibition of hexokinase 2 by neoalbaconol induced selective cytotoxicity against nasopharyngeal carcinoma cell lines, and these effects were also observed in mouse models. Finally, GL22 inhibited hepatic tumour growth by downregulating the mRNA levels of fatty acid-binding proteins and blocking fatty acid transport and impairing cardiolipin biosynthesis. The present review, therefore, will highlight how the metabolites isolated from mushrooms can target potential biomarkers in metabolic reprogramming. Full article

(This article belongs to the Special Issue Recent Advances in Development of Small Molecules to Fight Cancer)

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14 pages, 1771 KiB

Open AccessReview

Emerging Roles of RNF168 in Tumor Progression

by Tianyuan Xie, Hai Qin, Zhengdong Yuan, Yiwen Zhang, Xiaoman Li and Lufeng Zheng

Molecules 2023, 28(3), 1417; https://doi.org/10.3390/molecules28031417 - 2 Feb 2023

Cited by 4 | Viewed by 2346

Abstract

RING finger protein 168 (RNF168) is an E3 ubiquitin ligase with the RING finger domain. It is an important protein contributing to the DNA double-strand damage repair pathway. Recent studies have found that RNF168 is significantly implicated in the occurrence and development of [...] Read more.

RING finger protein 168 (RNF168) is an E3 ubiquitin ligase with the RING finger domain. It is an important protein contributing to the DNA double-strand damage repair pathway. Recent studies have found that RNF168 is significantly implicated in the occurrence and development of various cancers. Additionally, RNF168 contributes to the drug resistance of tumor cells by enhancing their DNA repair ability or regulating the degradation of target proteins. This paper summarizes and prospects the research progress of the structure and main functions of RNF168, especially its roles and the underlying mechanisms in tumorigenesis. Full article

(This article belongs to the Special Issue Recent Advances in Development of Small Molecules to Fight Cancer)

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14 pages, 1599 KiB

Open AccessReview

Targeting Nrf2 and NF-κB Signaling Pathways in Cancer Prevention: The Role of Apple Phytochemicals

by Francesca Gado, Giulio Ferrario, Larissa Della Vedova, Beatrice Zoanni, Alessandra Altomare, Marina Carini, Giancarlo Aldini, Alfonsina D’Amato and Giovanna Baron

Molecules 2023, 28(3), 1356; https://doi.org/10.3390/molecules28031356 - 31 Jan 2023

Cited by 8 | Viewed by 2119

Abstract

Plant secondary metabolites, known as phytochemicals, have recently gained much attention in light of the “circular economy”, to reutilize waste products deriving from agriculture and food industry. Phytochemicals are known for their onco-preventive and chemoprotective effects, among several other beneficial properties. Apple phytochemicals [...] Read more.

Plant secondary metabolites, known as phytochemicals, have recently gained much attention in light of the “circular economy”, to reutilize waste products deriving from agriculture and food industry. Phytochemicals are known for their onco-preventive and chemoprotective effects, among several other beneficial properties. Apple phytochemicals have been extensively studied for their effectiveness in a wide range of diseases, cancer included. This review aims to provide a thorough overview of the main studies reported in the literature concerning apple phytochemicals, mostly polyphenols, in cancer prevention. Although there are many different mechanisms targeted by phytochemicals, the Nrf2 and NF-κB signaling pathways are the ones this review will be focused on, highlighting also the existing crosstalk between these two systems. Full article

(This article belongs to the Special Issue Recent Advances in Development of Small Molecules to Fight Cancer)

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