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Molecules (Basel, Switzerland) Nov 2022Proflavine is an acridine derivative which was discovered as one of the earliest antibacterial agents, and it has been proven to have potential application to fields...
Proflavine is an acridine derivative which was discovered as one of the earliest antibacterial agents, and it has been proven to have potential application to fields such as chemotherapy, photobiology and solar-energy conversion. In particular, it is well known that proflavine can bind to DNA with different modes, and this may open addition photochemical-reaction channels in DNA. Herein, the excited-state dynamics of proflavine after intercalation into DNA duplex is studied using femtosecond time-resolved spectroscopy, and compared with that in solution. It is demonstrated that both fluorescence and the triplet excited-state generation of proflavine were quenched after intercalation into DNA, due to ultrafast non-radiative channels. A static-quenching mechanism was identified for the proflavine-DNA complex, in line with the spectroscopy data, and the excited-state deactivation mechanism was proposed.
Topics: Proflavine; Intercalating Agents; DNA; Acridines
PubMed: 36500248
DOI: 10.3390/molecules27238157 -
European Journal of Pharmaceutics and... Jan 2022Larotrectinib is an FDA-approved oral small-molecule inhibitor for neurotrophic tropomyosin receptor kinase (NTRK) fusion-positive cancer treatment. Here larotrectinib...
INTRODUCTION
Larotrectinib is an FDA-approved oral small-molecule inhibitor for neurotrophic tropomyosin receptor kinase (NTRK) fusion-positive cancer treatment. Here larotrectinib pharmacokinetic behavior upon co-administration with prototypical inhibitors of the efflux transporters ABCB1/ABCG2 (elacridar), the SLCO1A/1B (OATP1A/1B) uptake transporters (rifampin), and the drug-metabolizing enzyme CYP3A (ritonavir), respectively, was investigated.
METHODS
Inhibitors were orally administered prior to oral larotrectinib (10 mg/kg) to relevant genetically modified mouse models. Larotrectinib plasma and tissue homogenate concentrations were measured by a liquid chromatography-tandem mass spectrometric assay.
RESULTS
Elacridar increased oral availability (2.7-fold) and markedly improved brain-to-plasma ratios (5.0-fold) of larotrectinib in wild-type mice. Mouse (m)Oatp1a/1b but not hepatic transgenic human (h)OATP1B1 or -1B3 restricted larotrectinib oral availability and affected its tissue distribution. Rifampin enhanced larotrectinib oral availability not only in wild-type mice (1.9-fold), but surprisingly also in Slco1a/1b mice (1.7-fold). Similarly, ritonavir increased the larotrectinib plasma exposure in both wild-type (1.5-fold) and Cyp3a mice (1.7-fold). Intriguingly, both rifampin and ritonavir decreased liver and/or intestinal larotrectinib levels in all related experimental groups, suggesting additional inhibition of enterohepatic Abcb1a/1b activity.
CONCLUSIONS
Elacridar enhances both larotrectinib plasma and tissue exposure and especially relative brain penetration, which might be therapeutically relevant. Hepatic mOatp1a/1b but not hOATP1B1 or -1B3 transported larotrectinib. Additionally, rifampin enhances larotrectinib systemic exposure, most likely by inhibiting mOatp1a/1b, but probably also hepatic and/or intestinal mAbcb1. Similar to rifampin, dual-inhibition functions of ritonavir affecting both CYP3A enzymes and enterohepatic Abcb1 transporters enhanced larotrectinib oral availability. The obtained insights may be used to further optimize the clinical-therapeutic application of larotrectinib.
Topics: Acridines; Administration, Oral; Animals; Biological Availability; Brain; Chromatography, Liquid; Drug Synergism; Male; Mice; Mice, Inbred Strains; Pyrazoles; Pyrimidines; Rifampin; Ritonavir; Tandem Mass Spectrometry; Tetrahydroisoquinolines
PubMed: 34952136
DOI: 10.1016/j.ejpb.2021.12.007 -
Current Organic Synthesis Oct 2021In this study, the synthesis of azo-linked acridine by the reaction of dimedone and synthesized diazoaryl-(2-amino-5-(phenyl)methanone using Ag2S/RHA-MCM-41nanocomposite...
INTRODUCTION
In this study, the synthesis of azo-linked acridine by the reaction of dimedone and synthesized diazoaryl-(2-amino-5-(phenyl)methanone using Ag2S/RHA-MCM-41nanocomposite is reported.
MATERIALS AND METHODS
The synthesized catalyst was characterized by FT-IR, XRD, and SEM. According to the obtained results, AgS/RHA-MCM-41 nanocomposite exhibited high activity in the synthesis of azo-acridine derivatives based on desirable yields and reaction time. Products were prepared in 1.5-2 h and with 88-93% yield. In all the reactions, the catalyst could be easily removed and reused, and its catalytic activity was maintained after five uses and did not decrease significantly. The structures of all newly synthesized products were characterized by spectroscopic spectra (FT-IR, H NMR, C NMR) and elemental analyses.
RESULTS AND DISCUSSION
The results of the study showed that ionic liquid [DBU]OAc (entry 8) and MCM- 41/Ag2S-RHA nanocomposite (entry 8) possessed better efficiency and shorter time than other reaction conditions.
CONCLUSION
In this study, new azo-linked acridine derivatives were synthesized by the reaction of different azo derivatives and dimedone using MCM-41/Ag2S-RHA nanocomposite, and the reaction products were obtained in 1.5-2 h with an efficiency of 88-93%. The short reaction time and high efficiency of the obtained products indicated the high efficiency of this method. In all the reactions, MCM-41/Ag2S-RHA nanocomposite could be easily removed and reused. Its catalytic activity was maintained in the sample reaction after five runs and did not decrease significantly.
Topics: Acridines; Nanocomposites; Silicon Dioxide; Spectroscopy, Fourier Transform Infrared
PubMed: 34465279
DOI: 10.2174/1570179418666210628150938 -
RNA Biology Dec 2021Telomere is a specialized DNA-protein complex that plays an important role in maintaining chromosomal integrity. Shelterin is a protein complex formed by six different...
Telomere is a specialized DNA-protein complex that plays an important role in maintaining chromosomal integrity. Shelterin is a protein complex formed by six different proteins, with telomeric repeat factors 1 (TRF1) and 2 (TRF2) binding to double-strand telomeric DNA. Telomeric DNA consists of complementary G-rich and C-rich repeats, which could form G-quadruplex and intercalated motif (i-motif), respectively, during cell cycle. Its G-rich transcription product, telomeric repeat-containing RNA (TERRA), is essential for telomere stability and heterochromatin formation. After extensive screening, we found that acridine derivative and acridine dimer could selectively interact with TRF1 and telomeric i-motif, respectively. Compound blocked the binding of TRF1 with telomeric duplex DNA, resulting in up-regulation of TERRA. Accumulated TERRA could bind with TRF1 at its allosteric site and further destabilize its binding with telomeric DNA. In contrast, could destabilize telomeric i-motif, resulting in down-regulation of TERRA. Both compounds exhibited anti-tumour activity for A549 cells, but induced different DNA damage pathways. Compound significantly suppressed tumour growth in A549 xenograft mouse model. The function of telomeric i-motif structure was first studied with a selective binding ligand, which could play an important role in regulating TERRA transcription. Our results showed that appropriate level of TERRA transcript could be important for stability of telomere, and acridine derivatives could be further developed as anti-cancer agents targeting telomere. This research increased understanding for biological roles of telomeric i-motif, TRF1 and TERRA, as potential anti-cancer drug targets.
Topics: A549 Cells; Acridines; Animals; Binding Sites; Cell Proliferation; Cell Survival; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Mice; Molecular Structure; Neoplasm Transplantation; Protein Binding; RNA, Long Noncoding; Small Molecule Libraries; Telomeric Repeat Binding Protein 1; Telomeric Repeat Binding Protein 2; Transcription, Genetic
PubMed: 33749516
DOI: 10.1080/15476286.2021.1899652 -
Life Sciences Feb 2022Epithelial ovarian carcinoma is the most lethal female reproductive malignancy in the world. Paclitaxel and carboplatin are generally the first-line treatment drugs for...
AIMS
Epithelial ovarian carcinoma is the most lethal female reproductive malignancy in the world. Paclitaxel and carboplatin are generally the first-line treatment drugs for ovarian cancer patients, but numerous patients may develop chemotherapy resistance. Thus, it is urgent to identify novel drugs for ovarian cancer treatment. Arborinine has been known as a broad-spectrum anti-tumor agent due to it possesses a potent cytotoxic effect on various cancer cells.
MATERIALS AND METHODS
This study aimed to evaluate its anti-tumor effect and the potential underlying mechanism on ovarian cancer cell line SKOV3. The effect of arborinine on SKOV3 cell proliferation and movement were evaluated by MTT assay and cell migration and invasion assays, respectively. The RT-qPCR and Western Blot assays were employed to determine target gene expression. The tumor-bearing mouse model was applied to assess the anti-tumor effect of arborinine in vivo.
KEY FINDINGS
Our results demonstrated that arborinine treatment significantly inhibited the cell proliferation and tumor growth of SKOV3 in a dose-dependent manner. Arborinine treatment dose-dependently reduced LSD1 expression, resulting in increased H3K4m1 expression. Importantly, arborinine also potently suppressed cell migration and invasion of SKOV3 via reducing epithelial-mesenchymal transition (EMT) of SKOV3.
SIGNIFICANCE
Arborinine may serve as a potential drug candidate for developing new strategies for ovarian cancer treatment.
Topics: Acridines; Animals; Antineoplastic Agents; Carcinoma, Ovarian Epithelial; Cell Line, Tumor; Cell Movement; Cell Proliferation; China; Cisplatin; Epithelial-Mesenchymal Transition; Female; Histone Demethylases; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Invasiveness; Ovarian Neoplasms; Ovary; Paclitaxel; Xenograft Model Antitumor Assays
PubMed: 34979197
DOI: 10.1016/j.lfs.2021.120275 -
Biomolecules Dec 2020This study aims to determine the anticancer efficacy of diosgenin encapsulated poly-glycerol malate co-dodecanedioate (PGMD) nanoparticles. Diosgenin loaded PGMD...
This study aims to determine the anticancer efficacy of diosgenin encapsulated poly-glycerol malate co-dodecanedioate (PGMD) nanoparticles. Diosgenin loaded PGMD nanoparticles (variants 7:3 and 6:4) were synthesized by the nanoprecipitation method. The synthesis of PGMD nanoparticles was systematically optimized employing the Box-Behnken design and taking into account the influence of various independent variables such as concentrations of each PGMD, diosgenin and PF-68 on the responses such as size and PDI of the particles. Mathematical modeling was done using the Quadratic second order modeling method and response surface analysis was undertaken to elucidate the factor-response relationship. The obtained size of PGMD 7:3 and PGMD 6:4 nanoparticles were 133.6 nm and 121.4 nm, respectively, as measured through dynamic light scattering (DLS). The entrapment efficiency was in the range of 77-83%. The in vitro drug release studies showed diffusion and dissolution controlled drug release pattern following Korsmeyer-Peppas kinetic model. Furthermore, in vitro morphological and cytotoxic studies were performed to evaluate the toxicity of synthesized drug loaded nanoparticles in model cell lines. The IC after 48 h was observed to be 27.14 µM, 15.15 µM and 13.91 µM for free diosgenin, PGMD 7:3 and PGMD 6:4 nanoparticles, respectively, when administered in A549 lung carcinoma cell lines.
Topics: A549 Cells; Acridine Orange; Antineoplastic Agents; Apoptosis; Cell Survival; Diosgenin; Drug Carriers; Drug Delivery Systems; Drug Liberation; Dynamic Light Scattering; Ethidium; Glycerol; Humans; In Vitro Techniques; Inhibitory Concentration 50; Kinetics; Light; Malates; Models, Theoretical; Nanoparticles; Particle Size; Polymers; Scattering, Radiation
PubMed: 33339083
DOI: 10.3390/biom10121679 -
Investigational New Drugs Jun 2020Background Lapatinib is a small-molecule tyrosine kinase inhibitor of human epidermal receptor 2 (HER2) and EGFR that has currently been approved for the treatment of...
The influence of the coadministration of the p-glycoprotein modulator elacridar on the pharmacokinetics of lapatinib and its distribution in the brain and cerebrospinal fluid.
Background Lapatinib is a small-molecule tyrosine kinase inhibitor of human epidermal receptor 2 (HER2) and EGFR that has currently been approved for the treatment of HER2-positive advanced and metastatic breast cancer (BC). The ATP-binding cassette (ABC) family of transporters includes P-glycoprotein (P-gp; ABCB1) and breast cancer resistance protein (BCRP; ABCG2), which substantially restrict the penetration of drugs, including chemotherapeutics, through the blood-brain barrier and blood-cerebrospinal fluid barrier. The aim of this study was to investigate the effects of elacridar, an ABCB1 and ABCG2 inhibitor, on the brain and cerebrospinal fluid uptake of lapatinib. Methods Rats were divided into two groups: one group received 5 mg/kg elacridar and 100 mg/kg lapatinib (an experimental group), and the other group received 100 mg/kg lapatinib (a control group). Lapatinib concentrations in the blood plasma (BP), cerebrospinal fluid (CSF) and brain tissue (BT) were measured by liquid chromatography coupled with tandem mass spectrometry. Results Elacridar significantly increased lapatinib penetration into the CSF and BT (C increase of 136.4% and 54.7% and AUC increase of 53.7% and 86.5%, respectively). The C of lapatinib in BP was similar in both experimental groups (3057.5 vs. 3257.5 ng/mL, respectively). Conclusion This study showed that elacridar influenced the pharmacokinetics of lapatinib. The inhibition of ABCB1 and ABCG2 transporters by elacridar substantially enhanced the penetration of lapatinib into the CSF and BT. The blocking of protein transporters could become indispensable in the treatment of patients with breast cancer and brain metastases.
Topics: ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; Acridines; Animals; Biological Transport; Blood-Brain Barrier; Brain; Cerebrospinal Fluid; Lapatinib; Male; Protein Transport; Rats; Rats, Wistar; Tetrahydroisoquinolines
PubMed: 31177402
DOI: 10.1007/s10637-019-00806-3 -
International Journal of Molecular... Jan 2021In Alzheimer's disease (AD), several studies have reported blood-brain barrier (BBB) breakdown with compromised function. P-glycoprotein (P-gp) and breast cancer...
In Alzheimer's disease (AD), several studies have reported blood-brain barrier (BBB) breakdown with compromised function. P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are transport proteins localized at the BBB luminal membrane and play an important role in the clearance of amyloid-β (Aβ). The purpose of this study was to investigate the effect of pharmacological inhibition of Aβ efflux transporters on BBB function and Aβ accumulation and related pathology. Recently, we have developed an in vitro high-throughput screening assay to screen for compounds that modulate the integrity of a cell-based BBB model, which identified elacridar as a disruptor of the monolayer integrity. Elacridar, an investigational compound known for its P-gp and BCRP inhibitory effect and widely used in cancer research. Therefore, it was used as a model compound for further evaluation in a mouse model of AD, namely TgSwDI. TgSwDI mouse is also used as a model for cerebral amyloid angiopathy (CAA). Results showed that P-gp and BCRP inhibition by elacridar disrupted the BBB integrity as measured by increased IgG extravasation and reduced expression of tight junction proteins, increased amyloid deposition due to P-gp, and BCRP downregulation and receptor for advanced glycation end products (RAGE) upregulation, increased CAA and astrogliosis. Further studies revealed the effect was mediated by activation of NF-κB pathway. In conclusion, results suggest that BBB disruption by inhibiting P-gp and BCRP exacerbates AD pathology in a mouse model of AD, and indicate that therapeutic drugs that inhibit P-gp and BCRP could increase the risk for AD.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; Acridines; Alzheimer Disease; Amyloid beta-Peptides; Animals; Astrocytes; Blood-Brain Barrier; Brain; Cell Line; Disease Models, Animal; Immunoglobulin G; Immunohistochemistry; Male; Matrix Metalloproteinase 9; Mice; Mice, Transgenic; NF-kappa B; Signal Transduction; Synapses; Tetrahydroisoquinolines; Tight Junctions
PubMed: 33513818
DOI: 10.3390/ijms22031231 -
Journal of Travel Medicine Jan 2022Giardiasis is one of the most common human protozoal infections worldwide. First-line therapy of giardiasis includes nitroimidazole antibiotics. However, treatment...
RATIONALE FOR REVIEW
Giardiasis is one of the most common human protozoal infections worldwide. First-line therapy of giardiasis includes nitroimidazole antibiotics. However, treatment failure with nitroimidazoles is increasingly reported, with up to 45% of patients not responding to initial treatment. There is no clear consensus on the approach to the management of nitroimidazole-refractory giardiasis. This systematic review aims to summarize the literature on pharmacotherapy for nitroimidazole-refractory giardiasis.
METHODS
We conducted a systematic review of the literature to determine the optimal management strategies for nitroimidazole-refractory giardiasis. We searched Pubmed/MEDLINE, Embase and Cochrane library using the following search terms 'Giardia' AND 'treatment failure' OR 'refractory giardia' OR 'resistant giardia' with date limits of 1 January 1970 to 30 June 2021. We included all reports on humans, which described clinical outcomes of individuals with treatment refractory giardiasis, including case series and case reports. A descriptive synthesis of the data was conducted with pooling of data for interventions.
KEY FINDINGS
Included in this review were five prospective studies, three retrospective studies, seven case series and nine case reports. Across these reports, a wide heterogeneity of treatment regimens was employed, including retreatment with an alternative nitroimidazole, combination therapy with a nitroimidazole and another agent and monotherapy with non-nitroimidazole regimens, including quinacrine, paromomycin and nitazoxanide. Retreatment with a nitroimidazole was not an effective therapy for refractory giardiasis. However, treatment with a nitroimidazole in combination with albendazole had a cure rate of 66.9%. In the included studies, quinacrine monotherapy was administered to a total of 179 patients, with a clinical cure rate of 88.8%. Overall, quinacrine was fairly well tolerated.
CONCLUSIONS
Reports on the treatment of nitroimidazole-refractory giardiasis demonstrate a heterogeneous approach to treatment. Of these, quinacrine appeared to be highly effective, though more data on its safety are needed.
Topics: Antiprotozoal Agents; Giardia lamblia; Giardiasis; Humans; Metronidazole; Nitroimidazoles; Prospective Studies; Quinacrine; Retrospective Studies
PubMed: 34350966
DOI: 10.1093/jtm/taab120 -
Biochimica Et Biophysica Acta.... Jun 2023The efficiency of methylene blue (MB) and acridine orange (AO) for photodynamic therapy (PDT) is increased if encapsulated in liposomes. In this paper we determine the...
The efficiency of methylene blue (MB) and acridine orange (AO) for photodynamic therapy (PDT) is increased if encapsulated in liposomes. In this paper we determine the molecular-level interactions between MB or AO and mixed monolayers of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-dipalmitoyl-sn-glycero-3-phospho-(1'-rac-glycerol) (DPPG) and cholesterol (CHOL) using surface pressure isotherms and polarization-modulated infrared reflection absorption spectroscopy (PM-IRRAS). To increase liposome stability, the effects from adding the surfactants Span® 80 and sodium cholate were also studied. Both MB and AO induce an expansion in the mixed monolayer, but this expansion is less significant in the presence of either Span® 80 or sodium cholate. The action of AO and MB occurred via coupling with phosphate groups of DPPC or DPPG. However, the levels of chain ordering and hydration of carbonyl and phosphate in headgroups depended on the photosensitizer and on the presence of Span® 80 or sodium cholate. From the PM-IRRAS spectra, we inferred that incorporation of MB and AO increased hydration of the monolayer headgroup, except for the case of the monolayer containing sodium cholate. This variability in behaviour offers an opportunity to tune the incorporation of AO and MB into liposomes which could be exploited in the release necessary for PDT.
Topics: Methylene Blue; Acridine Orange; Liposomes; Sodium Cholate; Spectrophotometry, Infrared
PubMed: 37031871
DOI: 10.1016/j.bbamem.2023.184156