Triazole‐tethered boswellic acid derivatives against breast cancer: Synthesis, in vitro, and in‐silico studies

Avula, Satya Kumar; Rehman, Najeeb Ur; Khan, Farman Ali; Ullah, Obaid; Halim, Sobia Ahsan; Khan, Ajmal; Anwar, Muhammad U.; Rahman, Shaikh Mizanoor; Csük, René; Al‐Harrasi, Ahmed

doi:10.1016/j.molstruc.2023.135181

Cited by 9 publications

(4 citation statements)

References 56 publications

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“…Besides modulating channel activity, the protective effect of urea may in part be related to sphingomyelinase inhibition [29]. Of note, structural modifications may potentially reduce the toxicity of ERN to off-target tissue while preserving or enhancing its anticancer properties [44]. Interestingly, oncolytic viruses may also be exploited as vehicles of chemotherapeutic agents, which augments their anticancer potential to overcome chemoresistance [45].…”

Section: Discussionmentioning

confidence: 99%

Eriocitrin Disrupts Erythrocyte Membrane Asymmetry through Oxidative Stress and Calcium Signaling and the Activation of Casein Kinase 1α and Rac1 GTPase

Alghareeb,

Alsughayyir,

Alfhili

2023

Pharmaceuticals

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Background: Hemolysis and eryptosis result in the premature elimination of circulating erythrocytes and thus contribute to chemotherapy-related anemia, which is extremely prevalent in cancer patients. Eriocitrin (ERN), a flavanone glycoside in citrus fruits, has shown great promise as an anticancer agent, but the potential toxicity of ERN to human erythrocytes remains unstudied. Methods: Erythrocytes were exposed to anticancer concentrations of ERN (10–100 μM) for 24 h at 37 °C, and hemolysis and associated markers were quantified using colorimetric assays. Eryptosis was assessed by flow cytometric analysis to detect phosphatidylserine (PS) exposure by annexin-V-FITC, intracellular Ca2+ using Fluo4/AM, and oxidative stress with 2-,7-dichlorodihydrofluorescin diacetate (H2DCFDA). ERN was also tested against specific signaling inhibitors and anti-hemolytic agents. Results: ERN caused significant, concentration-dependent hemolysis at 20–100 μM. ERN also significantly increased the percentage of eryptotic cells characterized by Ca2+ elevation and oxidative stress. Furthermore, the hemolytic activity of ERN was significantly ameliorated in the presence of D4476, NSC23766, isosmotic urea and sucrose, and polyethylene glycol 8000 (PEG). In whole blood, ERN significantly elevated MCV and ESR, with no appreciable effects on other peripheral blood cells. Conclusions: ERN promotes premature erythrocyte death through hemolysis and eryptosis characterized by PS externalization, Ca2+ accumulation, membrane blebbing, loss of cellular volume, and oxidative stress. These toxic effects, mediated through casein kinase 1α and Rac1 GTPase, can be ameliorated by urea, sucrose, and PEG. Altogether, these novel findings are relevant to the further development of ERN as an anticancer therapeutic.

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Section: Discussionmentioning

confidence: 99%

Eriocitrin Disrupts Erythrocyte Membrane Asymmetry through Oxidative Stress and Calcium Signaling and the Activation of Casein Kinase 1α and Rac1 GTPase

Alghareeb,

Alsughayyir,

Alfhili

2023

Pharmaceuticals

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“…triazole moiety increased the activity to some extent. [118] Among was not inferior to doxorubicin (IC 50 : 4.17 µM) against MCF-7 breast cancer cells, [119] whereas 1,2,3-triazole-indole-forskolin hybrid 94…”

Section: Indole-pyridine/quinoline Hybridsmentioning

confidence: 90%

“…1,2,3‐Triazole‐boswellic acid hybrids 92 (Figure 13; IC 50 : 4.45–6.65 µM, MTT assay) were more potent than acetyl‐11‐keto‐β‐boswellic acid (β‐AKBA; IC 50 : 17.27 µM) against MDA‐MB‐231 breast cancer cells, and the SAR illustrated that introduction of electron‐withdrawing group into phenyl ring at N‐1 position of 1,2,3‐triazole moiety increased the activity to some extent. [ 118 ] Among them, hybrids 92a,b (IC 50 : 4.45 and 5.01 µM) which were found to be most active against MDA‐MB‐231 breast cancer cells displayed low cytotoxicity (IC 50 : >20 µM) toward normal MCF‐10A breast cells. 1,2,3‐Triazole‐levonorgestrel hybrid 93 (IC 50 : 7.48 µM, MTT assay) was not inferior to doxorubicin (IC 50 : 4.17 µM) against MCF‐7 breast cancer cells, [ 119 ] whereas 1,2,3‐triazole‐indole‐forskolin hybrid 94 (IC 50 : 9.93 and 6.00 µM, MTT assay) was comparable to doxorubicin (IC 50 : 1.65 and 1.97 µM) against MCF‐7 and MDA‐MB‐231 breast cancer cell lines, [ 120 ] demonstrating their potential as novel lead compounds for the exploitation of novel anti‐breast cancer candidates.…”

Section: 23‐triazole‐steroid Hybridsmentioning

confidence: 99%

The anti‐breast cancer therapeutic potential of 1,2,3‐triazole‐containing hybrids

Song,

Zhang,

Zhang

et al. 2023

Archiv der Pharmazie

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Breast cancer, as one of the most common invasive malignancies and the leading cause of cancer‐related deaths in women globally, poses a significant challenge in the world health system. Substantial advances in diagnosis and treatment have significantly improved the survival rate of breast cancer patients, but the number of incidences and deaths of breast cancer are projected to increase by 40% and 50%, respectively, by 2040. Chemotherapy is one of the principal treatments for breast cancer therapy, but multidrug resistance and severe side effects remain the major obstacles to the success of treatment. Hence, there is a vital need to develop novel chemotherapeutic agents to combat this deadly disease. 1,2,3‐Triazole, which can be effectively constructed by click chemistry, not only can serve as a linker to connect different anti‐breast cancer pharmacophores but also is a valuable pharmacophore with anti‐breast cancer potential and favorable properties such as hydrogen bonding, moderate dipole moment, and enhanced water solubility. Particularly, 1,2,3‐triazole‐containing hybrids have demonstrated promising in vitro and in vivo anti‐breast cancer potential against both drug‐sensitive and drug‐resistant forms and possessed excellent selectivity by targeting different biological pathways associated with breast cancer, representing privileged scaffolds for the discovery of novel anti‐breast cancer candidates. This review concentrates on the latest advancements of 1,2,3‐triazole‐containing hybrids with anti‐breast cancer potential, including work published between 2020 and the present. The structure–activity relationships (SARs) and mechanisms of action are also reviewed to shed light on the development of more effective and multitargeted candidates.

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“…In our lab, we attempted new approaches to explore and modify bioactive natural products using molecular biology tools, in silico investigations, derivatization strategies, and pharmaceutical formulations. − So, the successful stories of hybridization of boswellic acids as anti-inflammatory, cytotoxic agents, and antidiabetic agents − encouraged us to pursue novel new hybrids based on AKBA and other anti-inflammatory and antioxidant natural products; these hybrids will be evaluated for their ability to mitigate APAP toxicity in vitro . Furthermore, gene enrichment for the elucidation of potential targets of the compounds would be addressed and supported by molecular docking studies.…”

Section: Introductionmentioning

confidence: 99%

3-Acetyl-11-keto-β-boswellic Acid-Based Hybrids Alleviate Acetaminophen-Induced Hepatotoxicity in HepG2 by the Regulation of Inflammatory and Oxidative Stress Pathways: An Integrated Approach

Elgazar,

El-Domany,

Eldehna

et al. 2023

ACS Omega

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In an effort to develop new compounds for managing drug-induced liver injury, we prepared 23 novel hybrids based on 3-acetyl-11-keto-β-boswellic acid (AKBA) using various biocompatible linkers. A bioguided approach was employed to identify the most promising hybrid. Eight compounds exhibited superior anti-inflammatory activity compared to the parent compound. Two of these hybrids (5b and 18) were able to reduce gene expression of TNF-α in LPS-induced inflammation in RAW 264.7 cells, similar to dexamethasone. Subsequently, the hepatoprotective potential of these hybrids was evaluated against acetaminophen (APAP) toxicity in HepG2 cells at doses of 1 and 10 μM. Both hybrids effectively restored cytokine levels, which had been elevated by APAP, to normal levels. Furthermore, they normalized depleted superoxide dismutase and reduced glutathione levels while significantly reducing malondialdehyde (MDA) levels. Network pharmacology analysis suggested that AKBA-based hybrids exert their action by regulating PI3K and EGFR pathways, activating anti-inflammatory mechanisms, and initiating tissue repair and regeneration. Molecular docking studies provided insights into the interaction of the hybrids with PI3K. Additionally, the hybrids demonstrated good stability at different pH levels, following first-order kinetics, with relatively long half-lives, suggesting potential for absorption into circulation without significant degradation.

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Triazole‐tethered boswellic acid derivatives against breast cancer: Synthesis, in vitro, and in‐silico studies

Cited by 9 publications

References 56 publications

Eriocitrin Disrupts Erythrocyte Membrane Asymmetry through Oxidative Stress and Calcium Signaling and the Activation of Casein Kinase 1α and Rac1 GTPase

Eriocitrin Disrupts Erythrocyte Membrane Asymmetry through Oxidative Stress and Calcium Signaling and the Activation of Casein Kinase 1α and Rac1 GTPase

The anti‐breast cancer therapeutic potential of 1,2,3‐triazole‐containing hybrids

3-Acetyl-11-keto-β-boswellic Acid-Based Hybrids Alleviate Acetaminophen-Induced Hepatotoxicity in HepG2 by the Regulation of Inflammatory and Oxidative Stress Pathways: An Integrated Approach

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