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Keywords = imidazoacridinone

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22 pages, 3969 KB  
Article
The Effect of Conjugation with Octaarginine, a Cell-Penetrating Peptide on Antifungal Activity of Imidazoacridinone Derivative
by Kamila Rząd, Ewa Paluszkiewicz, Damian Neubauer, Mateusz Olszewski, Katarzyna Kozłowska-Tylingo, Wojciech Kamysz and Iwona Gabriel
Int. J. Mol. Sci. 2021, 22(24), 13190; https://doi.org/10.3390/ijms222413190 - 7 Dec 2021
Cited by 10 | Viewed by 3954
Abstract
Acridine cell-penetrating peptide conjugates are an extremely important family of compounds in antitumor chemotherapy. These conjugates are not so widely analysed in antimicrobial therapy, although bioactive peptides could be used as nanocarriers to smuggle antimicrobial compounds. An octaarginine conjugate of an imidazoacridinone derivative [...] Read more.
Acridine cell-penetrating peptide conjugates are an extremely important family of compounds in antitumor chemotherapy. These conjugates are not so widely analysed in antimicrobial therapy, although bioactive peptides could be used as nanocarriers to smuggle antimicrobial compounds. An octaarginine conjugate of an imidazoacridinone derivative (Compound 1-R8) synthetized by us exhibited high antifungal activity against reference and fluconazole-resistant clinical strains (MICs ≤ 4 μg mL−1). Our results clearly demonstrate the qualitative difference in accumulation of the mother compound and Compound 1-R8 conjugate into fungal cells. Only the latter was transported and accumulated effectively. Microscopic and flow cytometry analysis provide some evidence that the killing activity of Compound 1-R8 may be associated with a change in the permeability of the fungal cell membrane. The conjugate exhibited low cytotoxicity against human embryonic kidney (HEK-293) and human liver (HEPG2) cancer cell lines. Nevertheless, the selectivity index value of the conjugate for human pathogenic strains remained favourable and no hemolytic activity was observed. The inhibitory effect of the analysed compound on yeast topoisomerase II activity suggested its molecular target. In summary, conjugation with R8 effectively increased imidazoacridinone derivative ability to enter the fungal cell and achieve a concentration inside the cell that resulted in a high antifungal effect. Full article
(This article belongs to the Special Issue Bioactive Molecules and Health)
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19 pages, 7186 KB  
Article
Anticancer Imidazoacridinone C-1311 is Effective in Androgen-Dependent and Androgen-Independent Prostate Cancer Cells
by Magdalena Niemira, Barbara Borowa-Mazgaj, Samuel B. Bader, Adrianna Moszyńska, Marcin Ratajewski, Kaja Karaś, Mirosław Kwaśniewski, Adam Krętowski, Zofia Mazerska, Ester M. Hammond and Anna Skwarska
Biomedicines 2020, 8(9), 292; https://doi.org/10.3390/biomedicines8090292 - 19 Aug 2020
Cited by 6 | Viewed by 3743
Abstract
The androgen receptor (AR) plays a critical role in prostate cancer (PCa) development and metastasis. Thus, blocking AR activity and its downstream signaling constitutes a major strategy for PCa treatment. Here, we report on the potent anti-PCa activity of a small-molecule imidazoacridinone, C-1311. [...] Read more.
The androgen receptor (AR) plays a critical role in prostate cancer (PCa) development and metastasis. Thus, blocking AR activity and its downstream signaling constitutes a major strategy for PCa treatment. Here, we report on the potent anti-PCa activity of a small-molecule imidazoacridinone, C-1311. In AR-positive PCa cells, C-1311 was found to inhibit the transcriptional activity of AR, uncovering a novel mechanism that may be relevant for its anticancer effect. Mechanistically, C-1311 decreased the AR binding to the prostate-specific antigen (PSA) promoter, reduced the PSA protein level, and, as shown by transcriptome sequencing, downregulated numerous AR target genes. Importantly, AR-negative PCa cells were also sensitive to C-1311, suggesting a promising efficacy in the androgen-independent PCa sub-type. Irrespective of AR status, C-1311 induced DNA damage, arrested cell cycle progression, and induced apoptosis. RNA sequencing indicated significant differences in the transcriptional response to C-1311 between the PCa cells. Gene ontology analysis showed that in AR-dependent PCa cells, C-1311 mainly affected the DNA damage response pathways. In contrast, in AR-independent PCa cells, C-1311 targeted the cellular metabolism and inhibited the genes regulating glycolysis and gluconeogenesis. Together, these results indicate that C-1311 warrants further development for the treatment of PCa. Full article
(This article belongs to the Special Issue Biomarkers and Therapy Targets in Urologic Cancer)
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