Studies on phenothiazines: New microtubule-interacting compounds with phenothiazine A-ring as potent antineoplastic agents

Ghinet, Alina; Moise, Iuliana-Monica; Rigo, Benoı̂t; Homerin, Germain; Farce, Amaury; Dubois, Joëlle; Bîcu, Elena

doi:10.1016/j.bmc.2016.04.001

Cited by 25 publications

(19 citation statements)

References 31 publications

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“…Indeed, novel phenothiazine derivatives have been shown to have many potential anticancer activities aside from the established activities with respect to calmodulin, dopamine receptors, and other known psychiatrically relevant targets. These include antioxidant ability, inhibition of tubulin polymerization, and inhibition of farnesyl transferase (Prinz et al, 2011;Baciu-Atudosie et al, 2012;Engwa et al, 2016;Ghinet et al, 2016). We recognize how our hypothesis, which runs counter to a voluminous literature, could be interpreted, but we believe it would be useful if this generates controversy that leads to hypothesis-driven studies using orthogonal approaches and varying structural series of D 2 R antagonists.…”

Section: Critical Interpretation and Future Directionsmentioning

confidence: 83%

Cancer and the Dopamine D2 Receptor: A Pharmacological Perspective

Weissenrieder

Neighbors

Mailman

et al. 2019

The Journal of Pharmacology and Experimental Therapeutics

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The dopamine D 2 receptor (D 2 R) family is upregulated in many cancers and tied to stemness. Reduced cancer risk has been correlated with disorders such as schizophrenia and Parkinson's disease, in which dopaminergic drugs are used. D 2 R antagonists are reported to have anticancer efficacy in cell culture and animal models where they have reduced tumor growth, induced autophagy, affected lipid metabolism, and caused apoptosis, among other effects. This has led to several hypotheses, the most prevalent being that D 2 R ligands may be a novel approach to cancer chemotherapy. This hypothesis is appealing because

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Section: Critical Interpretation and Future Directionsmentioning

confidence: 83%

Cancer and the Dopamine D2 Receptor: A Pharmacological Perspective

Weissenrieder

Neighbors

Mailman

et al. 2019

The Journal of Pharmacology and Experimental Therapeutics

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“…It also displayed antiproliferative activity by inducing autophagic cell death . Furthermore, phenothiazine derivative IV exhibited in ‐ vitro tubulin polymerization inhibition and antiproliferative activity against human colon Duke's type D, colorectal adenocarcinoma COLO 205 and human kidney adenocarcinoma A498 cancer cell lines …”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis and Characterisation of Novel Phenothiazine‐Based Triazolopyridine Derivatives: Evaluation of Anti‐Breast Cancer Activity on Human Breast Carcinoma

Sachdeva

Low

et al. 2019

ChemistrySelect

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A series of novel phenothiazine based [1,2,4]triazolo[4, 3‐a]pyridine scaffolds were designed and synthesized in good yields by the oxidative cyclisation of phenothiazine pyridylhydrazones. Biological responses of all compounds toward a panel of human breast cancer cells (MDA‐MB‐231, MDA‐MB‐468, MCF7, SKBR3 and T47D) and human non‐tumorigenic epithelial breast cells (MCF10 A) were evaluated. Structure‐activity relationship revealed that compound with pendant phenyl ring on phenothiazine exhibited significant cytotoxic activity and apoptotic induction effects against breast cancer cell line with IC50 value 10.2 to 17.6 μM. Notably, the cytotoxic effect was 3.5 fold higher on cancer than non‐cancer cells, indicating potential control of breast cancer with lower side effects. Molecular docking studies confirmed the presence of hydrophobic contacts between appended phenyl ring, triazolopyridine and phenothiazine moieties with adjacent residues within the binding pocket of tubulin. One of the nitrogen in the triazolo ring also showed hydrogen bonding with tubulin. These tubulin interactions were also found with the taxane ring of paclitaxel. Cell cycle analysis confirmed the G2/M arrest induced by this compound on human breast cancer cells. Therefore, the potential anti‐cancer, pro‐apoptotic, and cell cycle arrest warrant further development of this molecule as a new class of anticancer agent.

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“…Recently, many phenothiazine derivatives were designed as novel anticancer agents. For example, phenothiazine derivative 1 ( Figure 1 ) proved to be a microtubule-interacting agent with great cell growth inhibition profile (GI 50 in the nanomolar range on human melanoma-adenocarcinoma MDA-MB-435 cells) [ 6 ]. Phenothiazine derivative 2 could arrest tumor cell cycle in the G2/M phase [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

Antiproliferative Phenothiazine Hybrids as Novel Apoptosis Inducers against MCF-7 Breast Cancer

et al. 2018

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We designed a series of novel phenothiazine-1,2,3-triazole hybrids by the molecular hybridization strategy and evaluated their antiproliferative activity against three cancer cell lines (MDA-MB-231, MDA-MB-468 and MCF-7). For the structure-activity relationships, the importance of 1,2,3-triazole and substituents on phenyl ring was explored. Among these phenothiazine-1,2,3-triazole hybrids, compound 9f showed the most potent inhibitory effect against MCF-7 cells, with an IC50 value of 0.8 μM. Importantly, compound 9f could induce apoptosis against MCF-7 cells by regulating apoptosis-related proteins (Bcl-2, Bax, Bad, Parp, and DR5). These potent phenothiazine-1,2,3-triazole hybrids as novel apoptosis inducers might be used as antitumor agents in the future.

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Studies on phenothiazines: New microtubule-interacting compounds with phenothiazine A-ring as potent antineoplastic agents

Cited by 25 publications

References 31 publications

Cancer and the Dopamine D2 Receptor: A Pharmacological Perspective

Cancer and the Dopamine D2 Receptor: A Pharmacological Perspective

Design, Synthesis and Characterisation of Novel Phenothiazine‐Based Triazolopyridine Derivatives: Evaluation of Anti‐Breast Cancer Activity on Human Breast Carcinoma

Antiproliferative Phenothiazine Hybrids as Novel Apoptosis Inducers against MCF-7 Breast Cancer

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