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Pharmacological Reports : PR Jun 2022Acridine compounds have been described as promising anticancer agents. Previous studies showed that...
BACKGROUND
Acridine compounds have been described as promising anticancer agents. Previous studies showed that (E)-1'-((4-chlorobenzylidene)amino)-5'-oxo-1',5'-dihydro-10H-spiro[acridine-9,2'-pyrrole]-4'-carbonitrile (AMTAC-06), a spiro-acridine compound, has antitumor activity on Ehrlich tumor and low toxicity. Herein, we investigated its antitumor effect against human cells in vitro.
METHODS
MTT assay was used to assess cytotoxicity of AMTAC-06 (3.125-200 µM) against tumor and non-tumor cells, and the half-maximal inhibitory concentration (IC) and the selectivity index (SI) were calculated. The effects on the cell cycle (propidium iodide-PI-staining), apoptosis (Annexin V-FITC/PI double staining by flow cytometry), and production of reactive oxygen species, ROS (DCFH assay) were also evaluated. Statistical analysis was achieved using ANOVA followed by Tukey's post-test.
RESULTS
AMTAC-06 showed higher cytotoxicity against colorectal carcinoma HCT-116 cells (IC: 12.62 µM). The SI showed that AMTAC-06 was more selective for HCT-116 cells (HaCaT SI: 1.41; PBMC SI: 0.62) than doxorubicin (HaCaT SI: 0.10; PBMC SI: 0.01). AMTAC-06 (15 and 30 µM) induced an increase in the sub-G1 peak (p < 0.000001) and cell cycle arrest in S phase (p = 0.003547). Moreover, treatment with this compound (15 and 30 µM) resulted in increased early (p < 0.000001) and late apoptotic cells (p < 0.000001). In addition, there was a reduction on ROS production (p < 0.000001).
CONCLUSIONS
AMTAC-06 presents anticancer activity against HCT-116 cells by regulating the cell cycle, inducing apoptosis and an antioxidant action.
Topics: Acridines; Antineoplastic Agents; Antioxidants; Apoptosis; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; HCT116 Cells; Humans; Leukocytes, Mononuclear; Reactive Oxygen Species; Spiro Compounds
PubMed: 35297003
DOI: 10.1007/s43440-022-00357-0 -
Spectrochimica Acta. Part A, Molecular... Jun 2017This paper describes the synthesis of a novel series of acridine thiosemicarbazones through a two-step reaction between various isothiocyanates and hydrazine followed by...
This paper describes the synthesis of a novel series of acridine thiosemicarbazones through a two-step reaction between various isothiocyanates and hydrazine followed by treatment with acridin-9-carbaldehyde. The properties of this series of seven new derivatives are studied using NMR and biochemical techniques, and the DNA-binding properties of the compounds are determined using spectrophotometric studies (UV-vis absorption, fluorescence, and circular/linear dichroism) and viscometry. The binding constants K are estimated as being in the range of 2.2 to 7.8×10M and the percentage of hypochromism was found to be 22.11-49.75% (from UV-vis spectral titration). Electrophoretic experiments prove that the novel compounds demonstrate moderate inhibitory effects against Topo I activity at a concentration of 60×10M.
Topics: Acridines; Circular Dichroism; DNA; DNA Topoisomerases, Type I; Magnetic Resonance Spectroscopy; Models, Molecular; Spectrophotometry, Ultraviolet; Thiosemicarbazones; Thiourea; Topoisomerase I Inhibitors
PubMed: 28315620
DOI: 10.1016/j.saa.2017.03.014 -
Bioorganic Chemistry May 2022Dual inhibition of topoisomerase (topo) II and FLT3 kinase, as in the case of C-1311, was shown to overcome the shortcomings of using topo II inhibitors solely. In the...
Dual inhibition of topoisomerase (topo) II and FLT3 kinase, as in the case of C-1311, was shown to overcome the shortcomings of using topo II inhibitors solely. In the present study, we designed and synthesized two series of pyrido-dipyrimidine- and pseudo-pyrido-acridone-containing compounds. The two series were evaluated against topo II and FLT3 as well as the HL-60 promyelocytic leukemia cell line in vitro. Compounds 6, 7, and 20 showed higher potency against topo II than the standard amsacrine (AMSA), whereas compounds 19 and 20 were stronger FLT3 inhibitors than the standard DACA. Compounds 19 and 20 showed to be dual inhibitors of both enzymes. Compounds 6, 7, 19, and 20 were more potent inhibitors of the HL-60 cell line than the standard AMSA. The results of the in vitro DNA flow cytometry analysis assay and Annexin V-FITC apoptosis analysis showed that 19 and 20 induced cell cycle arrest at the G2/M phase, significantly higher total percentage of apoptosis, and late-stage apoptosis in HL-60 cell lines than AMSA. Furthermore, 19 and 20 upregulated several apoptosis biomarkers such as p53, TNFα, caspase 3/7 and increased the Bax/Bcl-2 ratio. These results showed that 19 and 20 deserve further evaluation of their antiproliferative activities, particularly in leukemia. Molecular docking studies were performed for selected compounds against topo II and FLT3 enzymes to investigate their binding patterns. Compound 19 exerted dual fitting inside the active site of both enzymes.
Topics: Amsacrine; Antineoplastic Agents; Apoptosis; Cell Proliferation; DNA Topoisomerases, Type II; Humans; Leukemia, Promyelocytic, Acute; Molecular Docking Simulation; Topoisomerase II Inhibitors; fms-Like Tyrosine Kinase 3
PubMed: 35339926
DOI: 10.1016/j.bioorg.2022.105752 -
Acta Tropica Mar 2023Pathogenic A. castellanii and N. fowleri are opportunistic free-living amoebae. Acanthamoeba spp. are the causative agents of granulomatous amebic encephalitis (GAE) and...
Pathogenic A. castellanii and N. fowleri are opportunistic free-living amoebae. Acanthamoeba spp. are the causative agents of granulomatous amebic encephalitis (GAE) and amebic keratitis (AK), whereas Naegleria fowleri causes a very rare but severe brain infection called primary amebic meningoencephalitis (PAM). Acridinone is an important heterocyclic scaffold and both synthetic and naturally occurring derivatives have shown various valuable biological properties. In the present study, ten synthetic Acridinone derivatives (I-X) were synthesized and assessed against both amoebae for anti-amoebic and cysticidal activities in vitro. In addition, excystation, encystation, cytotoxicity, host cell pathogenicity was also performed in-vitro. Furthermore, molecular docking studies of these compounds with three cathepsin B paralogous enzymes of N. fowleri were performed in order to predict the possible docking mode with pathogen. Compound VII showed potent anti-amoebic activity against A. castellanii with IC 53.46 µg/mL, while compound IX showed strong activity against N. fowleri in vitro with IC 72.41 µg/mL. Compounds II and VII showed a significant inhibition of phenotypic alteration of A. castellanii, while compound VIII significantly inhibited N. fowleri cysts. Cytotoxicity assessment showed that these compounds caused minimum damage to human keratinocyte cells (HaCaT cells) at 100 µg/mL, while also effectively reduced the cytopathogenicity of Acanthamoeba to HaCaT cells. Moreover, Cathepsin B protease was investigated in-silico as a new molecular therapeutic target for these compounds. All compounds showed potential interactions with the catalytic residues. These results showed that acridine-9(10H)-one derivatives, in particular compounds II, VII, VIII and IX hold promise in the development of therapeutic agents against these free-living amoebae.
Topics: Humans; Naegleria fowleri; Cathepsin B; Acridines; Molecular Docking Simulation; Acanthamoeba; Amoeba; Amebiasis; Brain
PubMed: 36610529
DOI: 10.1016/j.actatropica.2023.106824 -
Animal Biotechnology Dec 2023Theileriosis is a hemoprotozoan illness of cattle in tropical regions that poses a severe economic loss to dairy farmers in the form of production loss and mortality. We...
Theileriosis is a hemoprotozoan illness of cattle in tropical regions that poses a severe economic loss to dairy farmers in the form of production loss and mortality. We designed and optimized a multiplex real-time PCR by using Taq-Man probe for detection and quantification of and simultaneously by targeting 18 s rRna and MPSP (surface merozoite protein) genes, respectively. Fifty-five EDTA blood samples from clinically -suspected cows of three -endemic districts of Odisha were processed using acridine dye based fluorescent microscopy, Giemsa staining, and PCR. PCR revealed and in 11/42 (26.11%) and 24/42 (57.14%) cases, respectively. Mixed infection due to both the spp. was recorded in 7/42 (16.66%). On comparison with gold standard test (PCR), the accuracy, sensitivity, and specificity were 92.72, 95.12, and 85.71% for Giemsa staining and 96.36, 97.56, and 92.85% for acridine orange dye. Multiplex real time PCR using Taq-Man probe detected two species of and simultaneously. Acridine dye based fluorescent microscopy is comparatively easy and rapid method in detection of spp.
Topics: Humans; Female; Cattle; Animals; Theileriasis; Theileria annulata; Cattle Diseases; RNA, Ribosomal; Membrane Proteins; Acridines
PubMed: 36695009
DOI: 10.1080/10495398.2023.2168197 -
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 -
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