17431-90-2Relevant articles and documents
Novel therapeutic compound acridine–retrotuftsin action on biological forms of melanoma and neuroblastoma
Cichorek, Miroslawa,Ronowska, Anna,Gensicka-Kowalewska, Monika,Deptula, Milena,Pelikant-Malecka, Iwona,Dzierzbicka, Krystyna
, p. 165 - 179 (2019)
Purpose: As a continuation of our search for anticancer agents, we have synthesized a new acridine-retrotuftsin analog HClx9-[Arg(NO2)-Pro-Lys-Thr-OCH3]-1-nitroacridine (named ART) and have evaluated its activity against melanoma and neuroblastoma lines. Both tumors develop from cells (melanocytes, neurons) of neuroectodermal origin, and both are tumors with high heterogeneity and unsatisfactory susceptibility to chemotherapies. Thus, we analyzed the action of ART on pairs of biological forms of melanoma (amelanotic and melanotic) and neuroblastoma (dopaminergic and cholinergic) with regard to proliferation, mechanism of cell death, and effect on the activity of tricarboxylic acid cycle (TAC) enzymes. Methods: The cytotoxicity of ART was evaluated by XTT and trypan blue tests. Cell death was estimated by plasma membrane structure changes (phosphatidylserine and calreticulin externalization), caspase activation, presence of ROS (reactive oxygen species), activity of tricarboxylic acid cycle enzymes (pyruvate dehydrogenase complex, aconitase, and isocitrate dehydrogenase), NAD level, and ATP level. Results: ART influences the biological forms of melanoma and neuroblastoma in different ways. Amelanotic (Ab) melanoma (with the inhibited melanogenesis, higher malignancy) and SHSY5Y neuroblastoma (with cholinergic DC cells) were especially sensitive to ART action. The Ab melanoma cells died through apoptosis, while, with SH-SY5Y-DC neuroblastoma, the number of cells decreased but not as a result of apoptosis. With Ab melanoma and SH-SY5Y-DC cells, a diminished activity of TAC enzymes was noticed, along with ATP/NAD depletion. Conclusion: Our data show that the biological forms of certain tumors responded in different ways to the action of ART. As a combination of retrotuftsin and acridine, the compound can be an inducer of apoptotic cell death of melanoma, especially the amelanotic form. Although the mechanism of the interrelationships between energy metabolism and cell death is not fully understood, interference of ART with TAC enzymes could encourage the further investigation of its anticancer action.
NOVEL NUCLEIC ACID MODIFIERS
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, (2019/07/20)
The present inventions generally relate to site-specific delivery of nucleic acid modifiers and includes novel DNA-binding proteins and effectors that can be rapidly programmed to make site-specific DNA modifications. The present inventions also provide a synthetic all-in-one genome editor (SAGE) systems comprising designer DNA sequence readers and a set of small molecules that induce double-strand breaks, enhance cellular permeability, inhibit NHEJ and activate HDR, as well as methods of using and delivering such systems.
Hypoxia-Selective Antitumor Agents. 4. Relationships between Structure, Physicochemical Properties, and Hypoxia-Selective Cytotoxicity for Nitracrine Analogues with Varying Side Chains: The "Iminoacridan Hypothesis"
Denny, William A.,Atwell, Graham J.,Anderson, Robert F.,Wilson, William R.
, p. 1288 - 1295 (2007/10/02)
The nitroacridine derivative nitracrine is a potent hypoxia-selective cytotoxin for mammalian cells in culture.In an attempt to modulate the degree of hypoxia selectivity among this class of compounds, we have studied a series of side-chain analogues of nitracrine.Both the electronic and steric properties of the side chain are shown to be important in determining the hypoxia selectivity of the compounds, by controlling the degree of aminoacridine/iminoacridan tautomerism.Studies with the repair-defective Chinese hamster cell line UV4 indicate that the cytotoxicity ofall the compounds is due to nitro group reduction and subsequent macromolecular adduct formation.However, compounds such as the 9-amino derivative, which exist totally as the aminoacridine tautomer, form much less lethal lesions than the 9-alkylamino derivatives, which exist to varying degrees in the iminoacridan conformation.For the whole set of compounds, the degree of hypoxia-selective cytotoxicity correlates well with the proportion of iminoacridan tautomer present.
