- Incorporation of triphenylphosphonium functionality improves the inhibitory properties of phenothiazine derivatives in Mycobacterium tuberculosis
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Tuberculosis (TB) is a difficult to treat disease caused by the bacterium Mycobacterium tuberculosis. The need for improved therapies is required to kill different M. tuberculosis populations present during infection and to kill drug resistant strains. Protein complexes associated with energy generation, required for the survival of all M. tuberculosis populations, have shown promise as targets for novel therapies (e.g., phenothiazines that target type II NADH dehydrogenase (NDH-2) in the electron transport chain). However, the low efficacy of these compounds and their off-target effects has made the development of phenothiazines as a therapeutic agent for TB limited. This study reports that a series of alkyltriphenylphosphonium (alkylTPP) cations, a known intracellular delivery functionality, improves the localization and effective concentration of phenothiazines at the mycobacterial membrane. AlkylTPP cations were shown to accumulate at biological membranes in a range of bacteria and lipophilicity was revealed as an important feature of the structure-function relationship. Incorporation of the alkylTPP cationic function significantly increased the concentration and potency of a series of phenothiazine derivatives at the mycobacterial membrane (the site of NDH-2), where the lead compound 3a showed inhibition of M. tuberculosis growth at 0.5 μg/mL. Compound 3a was shown to act in a similar manner to that previously published for other active phenothiazines by targeting energetic processes (i.e., NADH oxidation and oxygen consumption), occurring in the mycobacterial membrane. This shows the enormous potential of alkylTPP cations to improve the delivery and therefore efficacy of bioactive agents targeting oxidative phosphorylation in the mycobacterial membrane.
- Dunn, Elyse A.,Roxburgh, Marina,Larsen, Lesley,Smith, Robin A.J.,McLellan, Alexander D.,Heikal, Adam,Murphy, Michael P.,Cook, Gregory M.
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- Repositioning of the antipsychotic trifluoperazine: Synthesis, biological evaluation and in silico study of trifluoperazine analogs as anti-glioblastoma agents
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Repositioning of the antipsychotic drug trifluoperazine for treatment of glioblastoma, an aggressive brain tumor, has been previously suggested. However, trifluoperazine did not increase the survival time in mice models of glioblastoma. In attempt to identify an effective trifluoperazine analog, fourteen compounds have been synthesized and biologically in vitro and in vivo assessed. Using MTT assay, compounds 3dc and 3dd elicited 4–5 times more potent inhibitory activity than trifluoperazine with IC50 = 2.3 and 2.2 μM against U87MG glioblastoma cells, as well as, IC50 = 2.2 and 2.1 μM against GBL28 human glioblastoma patient derived primary cells, respectively. Furthermore, they have shown a reasonable selectivity for glioblastoma cells over NSC normal neural cell. In vivo evaluation of analog 3dc confirmed its advantageous effect on reduction of tumor size and increasing the survival time in brain xenograft mouse model of glioblastoma. Molecular modeling simulation provided a reasonable explanation for the observed variation in the capability of the synthesized analogs to increase the intracellular Ca2+ levels. In summary, this study presents compound 3dc as a proposed new tool for the adjuvant chemotherapy of glioblastoma.
- Kang, Seokmin,Lee, Jung Moo,Jeon, Borami,Elkamhawy, Ahmed,Paik, Sora,Hong, Jinpyo,Oh, Soo-Jin,Paek, Sun Ha,Lee, C. Justin,Hassan, Ahmed H.E.,Kang, Sang Soo,Roh, Eun Joo
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- Conjugates Derived from Lapatinib Derivatives with Cancer Cell Stemness Inhibitors Effectively Reversed Drug Resistance in Triple-Negative Breast Cancer
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Increasing evidence indicates that the cancer stem cell (CSC) subpopulation contributes to the therapeutic resistance and metastasis of tumors, leading to patient recurrence and death. Herein, we designed and synthesized several compounds by conjugating lapatinib derivatives with different CSC inhibitors to treat with lapatinib-induced MDA-MB-231 drug-resistant cells. In vitro biological studies indicated that 3a showed strong cytotoxicity and EGFR enzyme inhibitory activity and effectively reversed lapatinib-mediated resistance of MDA-MB-231 cells via inhibiting triple-negative breast cancer (TNBC) cell stemness and the AKT/ERK signaling pathway. In addition, 3a was capable of strongly suppressing the invasion and migration of TNBC cells by inhibiting the Wnt/β-catenin signaling pathway and MMP-2 and MMP-9 protein expression. In vivo tumorigenicity tests showed that 3a could inhibit the occurrence of TNBC by inhibiting BCSCs, proving 3a is a potential EGFR and CSC dual inhibitor for TNBC treatment.
- Wang, Yuanjiang,Lv, Zhaodan,Chen, Feihong,Wang, Xing,Gou, Shaohua
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supporting information
p. 12877 - 12892
(2021/09/13)
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- An Inhibitor of the Interaction of Survivin with Smac in Mitochondria Promotes Apoptosis
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Herein we report the first small molecule that disrupts the survivin-Smac interaction taking place in mitochondria. The inhibitor, PZ-6-QN, was identified by initially screening a phenothiazine library using a fluorescence anisotropy assay and then conducting a structure–activity relationship study. Mutagenesis and molecular docking studies suggest that PZ-6-QN binds to survivin similarly to the known Smac peptide, AVPI. The results of the effort also show that PZ-6-QN exhibits good anticancer activity against various cancer cells. Moreover, cell-based mechanistic studies provide evidence for the proposal that PZ-6-QN enters mitochondria to inhibit the survivin-Smac interaction and promotes release of Smac and cytochrome c from mitochondria into the cytosol, a process that induces apoptosis in cancer cells. Overall, the present study suggests that PZ-6-QN can serve as a novel chemical probe for study of processes associated with the mitochondrial survivin-Smac interaction and it will aid the discovery of novel anticancer agents.
- Park, Seong-Hyun,Shin, Insu,Park, Sang-Hyun,Kim, Nam Doo,Shin, Injae
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supporting information
p. 4035 - 4041
(2019/08/02)
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- Phenothiazine compound and application thereof
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The invention provides a phenothiazine compound and application thereof to preparation of drugs for curing breast cancer and melanoma. The phenothiazine compound has higher inhibitory activity on thebreast cancer cell MDA- MB- 231, SUM159, MCF- 7, SKBR- 3 and the melanoma cell A375 and B16BL6 than trifluoperazine and thioridazine, and can be applied to curing breast cancer and melanoma. The general formula of the phenothiazine compound is as following (the formula is shown in the description), wherein R1 and R2 are as shown in the description.
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Paragraph 0122-0126
(2019/06/07)
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- PHENOTHIAZINE DERIVATIVES AND USES THEREOF
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The present invention provides phenothiazine compounds, processes for their preparation, pharmaceutical compositions comprising the compounds, and the use of the compounds or the compositions in the treatment of various diseases or conditions, for example ribosomal disorders and ribosomopathies, e.g. Diamond Blackfan anemia (DBA).
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Paragraph 00356; 00410; 00413
(2019/10/29)
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- The phenothiazine compound and its preparation method and application
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The invention relates to a phenothiazine compound and a preparation method thereof. The invention further relates the application of the phenothiazine compound in anti-cancer drug preparation and anti-cancer drugs using the compound as the effective component. The phenothiazine compound has the advantages that the compound with broad-spectrum anti-cancer effect is obtained by modifying phenothiazine ternary interlink parent nucleuses, synthesizing method is simple, and high yield is achieved; the phenothiazine compound has certain restraining effect on human breast cancer cells line MCF-7 and human hepatoma cell line Hep-G2, and a new thought is provided to new drugs satisfying clinic requirements.
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Paragraph 0028-0031
(2018/07/30)
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- TRICYCLIC COMPOUNDS USEFUL AS NEUROGENIC AND NEUROPROTECTIVE AGENTS
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The invention disclosed herein is direct to compounds of Formula I and pharmaceutically acceptable salts thereof, which are useful in treating neurodegenerative diseases and promoting the generation or survival of neurons in the mammalian brain. The invention also comprises pharmaceutical compositions comprising a therapeutically effective amount of compound of Formula I or a pharmaceutically acceptable salt thereof. The invention disclosed herein is also directed to a method of promoting the generation or survival of neurons in a patient in need thereof in neurodegenerative and related diseases.
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Paragraph 00113
(2013/04/10)
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- NOVEL COMPOSITIONS AND METHODS FOR TREATMENT OF DISEASES RELATED TO ACTIVATED LYMPHOCYTES
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The present invention relates to inhibiting proliferation and inducing apoptosis in activated lymphocytes, including T cells and B cells. The invention also provides compositions and methods for inhibiting proliferation and inducing apoptosis in activated lymphocytes, as well methods for treating diseases associated with activated lymphocytes by administering 5-HT receptor antagonists.
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Page/Page column 55
(2008/06/13)
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- Potential CNS antitumor agents - Phenothiazines. II: Fluphenazine analogs
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Fluphenazine was found to possess moderate, reproducible activity against the intraperitoneal L-1210 and P-388 leukemia murine tumor models. Seven ether derivatives of fluphenazine and eight compounds in which the terminal side-chain hydroxyl group was replaced by an amine function were prepared and evaluated in the intraperitoneal L-1210, P-388, and B16 melanoma systems as well as the intracerebral L-1210 and ependymoblastoma brain tumor models. While no substantial intracerebral activity was observed, seven derivatives possessed reproducible activity in the intraperitoneal L-1210 or P-388 system. Several gave T/C [(treated survival/control survival) x 100%] values of 150%. No B16 melanoma activity was observed. These compounds were also tested for their cytototoxic properties in culture against L-1210, P-388, and KB cells. The amine isosteres, while possessing little in vivo activity, were the most cytotoxic of the compounds prepared, with several having ED50 values 1 μg/ml.
- Hirata,Peng,Driscoll
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p. 157 - 162
(2007/10/04)
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