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Design, Synthesis and Evaluation of Novel Anticancer Agents

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

Deadline for manuscript submissions: closed (31 August 2023) | Viewed by 25581

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Special Issue Editor

Dr. Anna Mrozek-Wilczkiewicz

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Chełkowski Institute of Physics, Faculty of Science and Technology, University of Silesia in Katowice, 75 Pułku Piechoty 1, 41-500 Chorzów, Poland
Interests: molecular biology of cancer; anticancer drugs; pharmacology; synthesis; drug design
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The design and development of new anticancer agents with selectivity for tumors and their metastases is a very broad and popular topic in the new approach to medicinal chemistry. The aim of this Special Issue is to provide a wide spectrum of the newest strategies in drug development explored in research teams. First, we want to identify the most popular structures present in many anticancer compounds known as privileged structures. Additionally, we want to collect the most important molecular targets (signaling pathways, proteins involved, receptors, etc.) which are of interest to researchers focused on anticancer therapy.

Dr. Anna Mrozek-Wilczkiewicz
Guest Editor

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Keywords

metal complexes
iron chelators
oxidative stress
anticancer agents
reactive oxygen species

Published Papers (12 papers)

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Research

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42 pages, 11187 KiB

Open AccessArticle

Synthesis and Pro-Apoptotic Effects of Nitrovinylanthracenes and Related Compounds in Chronic Lymphocytic Leukaemia (CLL) and Burkitt’s Lymphoma (BL)

by Andrew J. Byrne, Sandra A. Bright, James. P. McKeown, Adam Bergin, Brendan Twamley, Anthony M. McElligott, Sara Noorani, Shubhangi Kandwal, Darren Fayne, Niamh M. O’Boyle, D. Clive Williams and Mary J. Meegan

Molecules 2023, 28(24), 8095; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules28248095 - 14 Dec 2023

Viewed by 1522

Abstract

Chronic lymphocytic leukaemia (CLL) is a malignancy of the immune B lymphocyte cells and is the most common leukaemia diagnosed in developed countries. In this paper, we report the synthesis and antiproliferative effects of a series of (E)-9-(2-nitrovinyl)anthracenes and related nitrostyrene compounds in CLL cell lines and also in Burkitt’s lymphoma (BL) cell lines, a rare form of non-Hodgkin’s immune B-cell lymphoma. The nitrostyrene scaffold was identified as a lead structure for the development of effective compounds targeting BL and CLL. The series of structurally diverse nitrostyrenes was synthesised via Henry–Knoevenagel condensation reactions. Single-crystal X-ray analysis confirmed the structure of (E)-9-chloro-10-(2-nitrobut-1-en-1-yl)anthracene (19f) and the related 4-(anthracen-9-yl)-1H-1,2,3-triazole (30a). The (E)-9-(2-nitrovinyl)anthracenes 19a, 19g and 19i–19m were found to elicit potent antiproliferative effects in both BL cell lines EBV⁻MUTU-1 (chemosensitive) and EBV⁺ DG-75 (chemoresistant) with >90% inhibition at 10 μM. Selected (E)-9-(2-nitrovinyl)anthracenes demonstrated potent antiproliferative activity in CLL cell lines, with IC₅₀ values of 0.17 μM (HG-3) and 1.3 μM (PGA-1) for compound 19g. The pro-apoptotic effects of the most potent compounds 19a, 19g, 19i, 19l and 19m were demonstrated in both CLL cell lines HG-3 and PGA-1. The (E)-nitrostyrene and (E)-9-(2-nitrovinyl)anthracene series of compounds offer potential for further development as novel chemotherapeutics for CLL. Full article

(This article belongs to the Special Issue Design, Synthesis and Evaluation of Novel Anticancer Agents)

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13 pages, 2491 KiB

Open AccessArticle

Proliferation, Migration and Invasion of Breast Cancer Cell Lines Are Inhibited by 1,5-Disubstituted Tetrazol-1,2,3-triazole Hybrids through Interaction with p53

by Marisol Moreno-Perea, Abel Suárez-Castro, Ixamail Fraire-Soto, Jessica Lizbeth Sifuentes-Padilla, Rosalinda Gutiérrez-Hernández, Claudia Araceli Reyes-Estrada, Yamilé López-Hernández, Carlos J. Cortés-García, Luis Chacón-García, Angelica Judith Granados-López and Jesús Adrián López

Molecules 2023, 28(22), 7600; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules28227600 - 15 Nov 2023

Viewed by 1084

Abstract

The anticarcinogenic potential of a series of 1,5-disubstituted tetrazole-1,2,3-triazole hybrids (T-THs) was evaluated in the breast cancer (BC)-derived cell lines MCF-7 (ER+, PR+, and HER2−), CAMA-1 (ER+, PR+/−, and HER2−), SKBR-3 (ER+, PR+, and HER2+), and HCC1954 (ER+, PR+, and HER2+). The T-THs 7f, 7l, and 7g inhibited the proliferation of MCF-7 and CAMA-1, HCC1954, and SKBR-3 cells, respectively. The compounds with stronger effect in terms of migration and invasion inhibition were 7o, 7b, 7n, and 7k for the CAMA-1, MCF-7, HCC1954, and SKBR-3 cells respectively. Interestingly, these T-THs were the compounds with a fluorine present in their structures. To discover a possible target protein, a molecular docking analysis was performed for p53, p38, p58, and JNK1. The T-THs presented a higher affinity for p53, followed by JNK1, p58, and lastly p38. The best-predicted affinity for p53 showed interactions between the T-THs and both the DNA fragment and the protein. These results provide an opportunity for these compounds to be studied as potential drug candidates for breast cancer treatment. Full article

(This article belongs to the Special Issue Design, Synthesis and Evaluation of Novel Anticancer Agents)

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10 pages, 993 KiB

Open AccessArticle

May 1,2-Dithiolane-4-carboxylic Acid and Its Derivatives Serve as a Specific Thioredoxin Reductase 1 Inhibitor?

by Anna Nikitjuka, Kristaps Krims-Davis, Iveta Kaņepe-Lapsa, Melita Ozola and Raivis Žalubovskis

Molecules 2023, 28(18), 6647; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules28186647 - 15 Sep 2023

Viewed by 818

Abstract

Thioredoxin reductase is an essential enzyme that plays a crucial role in maintaining cellular redox homeostasis by catalyzing the reduction of thioredoxin, which is involved in several vital cellular processes. The overexpression of TrxR is often associated with cancer development. A series of 1,2-dithiolane-4-carboxylic acid analogs were obtained to verify the selectivity of 1,2-dithiolane moiety toward TrxR. Asparagusic acid analogs and their bioisoters remain inactive toward TrxR, which proves the inability of the 1,2-dithiolane moiety to serve as a pharmacophore during the interaction with TrxR. It was found that the Michael acceptor functionality-containing analogs exhibit higher inhibitory effects against TrxR compared to other compounds of the series. The most potent representatives exhibited micromolar TrxR1 inhibition activity (IC₅₀ varied from 5.3 to 186.0 μM) and were further examined with in vitro cell-based assays to assess the cytotoxic effects on various cancer cell lines and cell death mechanisms. Full article

(This article belongs to the Special Issue Design, Synthesis and Evaluation of Novel Anticancer Agents)

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21 pages, 1235 KiB

Open AccessArticle

Design, Synthesis, and Evaluation of Novel Indole Hybrid Chalcones and Their Antiproliferative and Antioxidant Activity

by Zuzana Kudličková, Radka Michalková, Aneta Salayová, Marián Ksiažek, Mária Vilková, Slávka Bekešová and Ján Mojžiš

Molecules 2023, 28(18), 6583; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules28186583 - 12 Sep 2023

Cited by 4 | Viewed by 1418

Abstract

The synthesis, anticancer, and antioxidant activities of a series of indole-derived hybrid chalcones are reported here. First, using the well-known Claisen–Schmidt condensation method, a set of 29 chalcones has been designed, synthesized, and consequently characterized. Subsequently, screening for the antiproliferative activity of the synthesized hybrid chalcones was performed on five cancer cell lines (HCT116, HeLa, Jurkat, MDA-MB-231, and MCF7) and two non-cancer cell lines (MCF-10A and Bj-5ta). Chalcone 18c, bearing 1-methoxyindole and catechol structural features, exhibited selective activity against cancer cell lines with IC₅₀ values of 8.0 ± 1.4 µM (Jurkat) and 18.2 ± 2.9 µM (HCT116) and showed no toxicity to non-cancer cells. Furthermore, antioxidant activity was evaluated using three different methods. The in vitro studies of radical scavenging activity utilizing DPPH radicals as well as the FRAP method demonstrated the strong activity of catechol derivatives 18a–c. According to the ABTS radical scavenging assay, the 3-methoxy-4-hydroxy-substituted chalcones 19a–c were slightly more favorable. In general, a series of 3,4-dihydroxychalcone derivatives showed properties as a lead compound for both antioxidant and antiproliferative activity. Full article

(This article belongs to the Special Issue Design, Synthesis and Evaluation of Novel Anticancer Agents)

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24 pages, 8826 KiB

Open AccessArticle

Exploring the Potential of Lapatinib, Fulvestrant, and Paclitaxel Conjugated with Glycidylated PAMAM G4 Dendrimers for Cancer and Parasite Treatment

by Łukasz Uram, Konrad Wróbel, Małgorzata Walczak, Żaneta Szymaszek, Magdalena Twardowska and Stanisław Wołowiec

Molecules 2023, 28(17), 6334; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules28176334 - 30 Aug 2023

Cited by 1 | Viewed by 1526

Abstract

Fulvestrant (F), lapatinib (L), and paclitaxel (P) are hydrophobic, anticancer drugs used in the treatment of estrogen receptor (ER) and epidermal growth factor receptor (EGFR)-positive breast cancer. In this study, glycidylated PAMAM G4 dendrimers, substituted with F, L, and/or P and targeting tumor cells, were synthesized and characterized, and their antitumor activity against glioma U-118 MG and non-small cell lung cancer A549 cells was tested comparatively with human non-tumorogenic keratinocytes (HaCaT). All cell lines were ER+ and EGFR+. In addition, the described drugs were tested in the context of antinematode therapy on C. elegans. The results show that the water-soluble conjugates of G4P, G4F, G4L, and G4PFL actively entered the tested cells via endocytosis due to the positive zeta potential (between 13.57–40.29 mV) and the nanoparticle diameter of 99–138 nm. The conjugates of G4P and G4PFL at nanomolar concentrations were the most active, and the least active conjugate was G4F. The tested conjugates inhibited the proliferation of HaCaT and A549 cells; in glioma cells, cytotoxicity was associated mainly with cell damage (mitochondria and membrane transport). The toxicity of the conjugates was proportional to the number of drug residues attached, with the exception of G4L; its action was two- and eight-fold stronger against glioma and keratinocytes, respectively, than the equivalent of lapatinib alone. Unfortunately, non-cancer HaCaT cells were the most sensitive to the tested constructs, which forced a change in the approach to the use of ER and EGFR receptors as a goal in cancer therapy. In vivo studies on C. elegans have shown that all compounds, most notably G4PFL, may be potentially useful in anthelmintic therapy. Full article

(This article belongs to the Special Issue Design, Synthesis and Evaluation of Novel Anticancer Agents)

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11 pages, 860 KiB

Open AccessArticle

Palladium and Platinum Complexes of the Antimetabolite Fludarabine with Vastly Enhanced Selectivity for Tumour over Non-Malignant Cells

by Sebastian W. Schleser, Oleksandr Krytovych, Tim Ziegelmeier, Elisabeth Groß, Jana Kasparkova, Viktor Brabec, Thomas Weber, Rainer Schobert and Thomas Mueller

Molecules 2023, 28(13), 5173; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules28135173 - 2 Jul 2023

Cited by 1 | Viewed by 1549

Abstract

The purine derivative fludarabine is part of frontline therapy for chronic lymphocytic leukaemia (CLL). It has shown positive effects on solid tumours such as melanoma, breast, and colon carcinoma in clinical phase I studies. As the treatment of CLL cells with combinations of fludarabine and metal complexes of antitumoural natural products, e.g., illudin M ferrocene, has led to synergistically enhanced apoptosis, in this research study different complexes of fludarabine itself. Four complexes bearing a trans-[Br(PPh₃)₂]Pt/Pd fragment attached to atom C-8 via formal η¹-sigma or η²-carbene bonds were synthesised in two or three steps without protecting polar groups on the arabinose or adenine. The platinum complexes were more cytotoxic than their palladium analogues, with low single-digit micromolar IC₅₀ values against cells of various solid tumour entities, including cisplatin-resistant ones and certain B-cell lymphoma and CLL, presumably due to the ten-fold higher cellular uptake of the platinum complexes. However, the palladium complexes interacted more readily with isolated Calf thymus DNA. Interestingly, the platinum complexes showed vastly greater selectivity for cancer over non-malignant cells when compared with fludarabine. Full article

(This article belongs to the Special Issue Design, Synthesis and Evaluation of Novel Anticancer Agents)

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16 pages, 1880 KiB

Open AccessArticle

Novel Arylsulfonylhydrazones as Breast Anticancer Agents Discovered by Quantitative Structure-Activity Relationships

by Violina T. Angelova, Teodora Tatarova, Rositsa Mihaylova, Nikolay Vassilev, Boris Petrov, Zvetanka Zhivkova and Irini Doytchinova

Molecules 2023, 28(5), 2058; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules28052058 - 22 Feb 2023

Cited by 4 | Viewed by 1254

Abstract

Breast cancer (BC) is the second leading cause of cancer death in women, with more than 600,000 deaths annually. Despite the progress that has been made in early diagnosis and treatment of this disease, there is still a significant need for more effective drugs with fewer side effects. In the present study, we derive QSAR models with good predictive ability based on data from the literature and reveal the relationships between the chemical structures of a set of arylsulfonylhydrazones and their anticancer activity on human ER+ breast adenocarcinoma and triple-negative breast (TNBC) adenocarcinoma. Applying the derived knowledge, we design nine novel arylsulfonylhydrazones and screen them in silico for drug likeness. All nine molecules show suitable drug and lead properties. They are synthesized and tested in vitro for anticancer activity on MCF-7 and MDA-MB-231 cell lines. Most of the compounds are more active than predicted and show stronger activity on MCF-7 than on MDA-MB-231. Four of the compounds (1a, 1b, 1c, and 1e) show IC₅₀ values below 1 μM on MCF-7 and one (1e) on MDA-MB-231. The presence of an indole ring bearing 5-Cl, 5-OCH₃, or 1-COCH₃ has the most pronounced positive effect on the cytotoxic activity of the arylsulfonylhydrazones designed in the present study. Full article

(This article belongs to the Special Issue Design, Synthesis and Evaluation of Novel Anticancer Agents)

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16 pages, 11443 KiB

Open AccessArticle

Synthesis, Characterization, and Antiproliferative Properties of New Bio-Inspired Xanthylium Derivatives

by Claudia Koch, Diana-Maria Dreavă, Anamaria Todea, Francisc Péter, Mihai Medeleanu, Iulia Păușescu, Corina Samoilă and Ioan Ovidiu Sîrbu

Molecules 2023, 28(3), 1102; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules28031102 - 22 Jan 2023

Cited by 1 | Viewed by 1496

Abstract

Xanthylium derivatives are curcumin analogs showing photochromic properties. Similarly, to anthocyanins, they follow the same multistate network of chemical species that are reversibly interconverted by external stimuli. In the present work, two new asymmetric monocarbonyl analogues of curcumin, 4-(4-hydroxy-3-metoxybenzylidene)-1,2,3,4-tetrahydroxanthylium chloride (compound 3) and 4-(4-hydroxybenzylidene)-6-methoxy-1,2,3,4-tetrahydroxanthylium chloride (compound 4) were synthesized, and their photochromic and biological properties were investigated. The UV-Vis spectroscopy and the direct and reverse pH-jumps studies confirmed the halochromic properties and the existence of different molecular species. A network of chemical reactions of these species was proposed. Furthermore, the antiproliferative properties of both compounds were evaluated using P19 murine embryocarcinoma cells and compared with each other. The results demonstrate that both new xanthylium derivatives modify the progression through the cell cycle of P19 cells, which translates into a significant antiproliferative effect. The effect of the methoxy group position is discussed and several checkpoint proteins are advanced as putative targets. Full article

(This article belongs to the Special Issue Design, Synthesis and Evaluation of Novel Anticancer Agents)

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19 pages, 6928 KiB

Open AccessArticle

Studies on 1,4-Quinone Derivatives Exhibiting Anti-Leukemic Activity along with Anti-Colorectal and Anti-Breast Cancer Effects

by Halilibrahim Ciftci, Belgin Sever, Nusret Kaya, Nilüfer Bayrak, Mahmut Yıldız, Hatice Yıldırım, Hiroshi Tateishi, Masami Otsuka, Mikako Fujita and Amaç Fatih TuYuN

Molecules 2023, 28(1), 77; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules28010077 - 22 Dec 2022

Cited by 1 | Viewed by 1737

Abstract

Colorectal cancer (CRC), breast cancer, and chronic myeloid leukemia (CML) are life-threatening malignancies worldwide. Although potent therapeutic and screening strategies have been developed so far, these cancer types are still major public health problems. Therefore, the exploration of more potent and selective new agents is urgently required for the treatment of these cancers. Quinones represent one of the most important structures in anticancer drug discovery. We have previously identified a series of quinone-based compounds (ABQ-1-17) as anti-CML agents. In the current work, ABQ-3 was taken to the National Cancer Institute (NCI) for screening to determine its in vitro antiproliferative effects against a large panel of human tumor cell lines at five doses. ABQ-3 revealed significant growth inhibition against HCT-116 CRC and MCF-7 breast cancer cells with 2.00 µM and 2.35 µM GI₅₀ values, respectively. The MTT test also showed that ABQ-3 possessed anticancer effects towards HCT-116 and MCF-7 cells with IC₅₀ values of 5.22 ± 2.41 μM and 7.46 ± 2.76 μM, respectively. Further experiments indicated that ABQ-3 induced apoptosis in both cell lines, and molecular docking studies explicitly suggested that ABQ-3 exhibited DNA binding in a similar fashion to previously reported compounds. Based on in silico pharmacokinetic prediction, ABQ-3 might display drug-like features enabling this compound to become a lead molecule for future studies. Full article

(This article belongs to the Special Issue Design, Synthesis and Evaluation of Novel Anticancer Agents)

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16 pages, 2670 KiB

Open AccessArticle

Facile Synthesis of Some Coumarin Derivatives and Their Cytotoxicity through VEGFR2 and Topoisomerase II Inhibition

by Mohamed S. Gomaa, Ibrahim A. I. Ali, Gaber El Enany, El Sayed H. El Ashry, Samir M. El Rayes, Walid Fathalla, Abdulghany H. A. Ahmed, Samar A. Abubshait, Haya A. Abubshait and Mohamed S. Nafie

Molecules 2022, 27(23), 8279; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27238279 - 28 Nov 2022

Cited by 6 | Viewed by 1829

Abstract

Novel semisynthetic coumarin derivatives were synthesized to be developed as chemotherapeutic anticancer agents through topoisomerase II, VEGFR2 inhibition that leads to apoptotic cancer cell death. The coumarin amino acids and dipeptides derivatives were prepared by the reaction of coumarin-3-carboxylic acid with amino acid methyl esters following the N,N-dicyclohexylcarbodiimide (DCC) method and 1-hydroxy-benzotriazole (HOBt), as coupling reagents. The synthesized compounds were screened towards VEGFR2, and topoisomerase IIα proteins to highlight their binding affinities and virtual mechanism of binding. Interestingly, compounds 4k (Tyr) and 6c (β-Ala-L-Met) shared the activity towards the three proteins by forming the same interactions with the key amino acids, such as the co-crystallized ligands. Both compounds 4k and 6c exhibited potent cytotoxic activities against MCF-7 cells with IC₅₀ values of 4.98 and 5.85 µM, respectively causing cell death by 97.82 and 97.35%, respectively. Validating the molecular docking studies, both compounds demonstrated promising VEGFR-2 inhibition with IC₅₀ values of 23.6 and 34.2 µM, compared to Sorafenib (30 µM) and topoisomerase-II inhibition with IC₅₀ values of 4.1 and 8.6 µM compared to Doxorubicin (9.65 µM). Hence, these two promising compounds could be further tested as effective and selective target-oriented active agents against cancer. Full article

(This article belongs to the Special Issue Design, Synthesis and Evaluation of Novel Anticancer Agents)

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Review

Jump to: Research

20 pages, 1622 KiB

Open AccessReview

Bruton’s Tyrosine Kinase Inhibitors (BTKIs): Review of Preclinical Studies and Evaluation of Clinical Trials

by Dariusz Rozkiewicz, Justyna Magdalena Hermanowicz, Iwona Kwiatkowska, Anna Krupa and Dariusz Pawlak

Molecules 2023, 28(5), 2400; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules28052400 - 6 Mar 2023

Cited by 14 | Viewed by 6347

Abstract

In the last few decades, there has been a growing interest in Bruton’s tyrosine kinase (BTK) and the compounds that target it. BTK is a downstream mediator of the B-cell receptor (BCR) signaling pathway and affects B-cell proliferation and differentiation. Evidence demonstrating the expression of BTK on the majority of hematological cells has led to the hypothesis that BTK inhibitors (BTKIs) such as ibrutinib can be an effective treatment for leukemias and lymphomas. However, a growing body of experimental and clinical data has demonstrated the significance of BTK, not just in B-cell malignancies, but also in solid tumors, such as breast, ovarian, colorectal, and prostate cancers. In addition, enhanced BTK activity is correlated with autoimmune disease. This gave rise to the hypothesis that BTK inhibitors can be beneficial in the therapy of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), Sjögren’s syndrome (SS), allergies, and asthma. In this review article, we summarize the most recent findings regarding this kinase as well as the most advanced BTK inhibitors that have been developed to date and their clinical applications mainly in cancer and chronic inflammatory disease patients. Full article

(This article belongs to the Special Issue Design, Synthesis and Evaluation of Novel Anticancer Agents)

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42 pages, 34933 KiB

Open AccessReview

Acridine as an Anti-Tumour Agent: A Critical Review

by Potlapati Varakumar, Kalirajan Rajagopal, Baliwada Aparna, Kannan Raman, Gowramma Byran, Clara Mariana Gonçalves Lima, Salma Rashid, Mohammed H. Nafady, Talha Bin Emran and Sławomir Wybraniec

Molecules 2023, 28(1), 193; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules28010193 - 26 Dec 2022

Cited by 20 | Viewed by 4174

Abstract

This review summarized the current breakthroughs in the chemistry of acridines as anti-cancer agents, including new structural and biologically active acridine attributes. Acridine derivatives are a class of compounds that are being extensively researched as potential anti-cancer drugs. Acridines are well-known for their high cytotoxic activity; however, their clinical application is restricted or even excluded as a result of side effects. The photocytotoxicity of propyl acridine acts against leukaemia cell lines, with C1748 being a promising anti-tumour drug against UDP-UGT’s. CK0403 is reported in breast cancer treatment and is more potent than CK0402 against estrogen receptor-negative HER2. Acridine platinum (Pt) complexes have shown specificity on the evaluated DNA sequences; 9-anilinoacridine core, which intercalates DNA, and a methyl triazene DNA-methylating moiety were also studied. Acridine thiourea gold and acridinone derivatives act against cell lines such as MDA-MB-231, SK-BR-3, and MCF-7. Benzimidazole acridine compounds demonstrated cytotoxic activity against Dual Topo and PARP-1. Quinacrine, thiazacridine, and azacridine are reported as anti-cancer agents, which have been reported in the previous decade and were addressed in this review article. Full article

(This article belongs to the Special Issue Design, Synthesis and Evaluation of Novel Anticancer Agents)

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