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1.
Eur J Med Chem ; 204: 112599, 2020 Oct 15.
Article in English | MEDLINE | ID: mdl-32736230

ABSTRACT

New promising unsymmetrical bisacridine derivatives (UAs), have been developed. Three groups including 36 compounds were synthesized by the condensation of 4-nitro or 4-methylacridinone, imidazoacridinone and triazoloacridinone derivatives with 1-nitroacridine compounds linked with an aminoalkyl chain. Cytotoxicity screening revealed the high potency of these compounds against several tumor cell lines. Particularly, imidazoacridinone-1-nitroacridine dimers strongly inhibited pancreatic Panc-1, Mia-Pa-Ca-2, Capan-2 and prostate cancer DU-145 cell growth. The studied compounds showed very strong antitumor activity (T/C> 300%) against Walker 256 rat adenocarcinoma. The selected 26 UAs were tested against 12 human tumor xenografts in nude mice, including colon, breast, prostate and pancreatic cancers. The studies on the molecular mechanism of action demonstrated that these unsymmetrical dimers significantly responded to the presence of G-quadruplex not to dsDNA. Structure-activity relationships for UAs potency to G-quadruplex stabilization indicated that thermal stability of this drug-G-quadruplex complex depended not only on the structure of heterocyclic rings, but also on the properties of dialkylamino chains of the ring linkers. In conclusion, the presented studies identified the new group of effective antitumor agents against solid human tumors, particularly pancreatic Panc-1, BxPC-3 and Mia-Pa-Ca-2 and strongly indicated their distinctive interactions with DNA. In contrast to monomers, G-quadruplex not dsDNA is proposed to be the first molecular target for these compounds.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , DNA/chemistry , Drug Design , G-Quadruplexes/drug effects , Pancreatic Neoplasms/pathology , Animals , Antineoplastic Agents/chemistry , Cell Line, Tumor , Chemistry Techniques, Synthetic , Drug Screening Assays, Antitumor , Humans , Mice , Structure-Activity Relationship
2.
J Am Assoc Lab Anim Sci ; 54(5): 507-15, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26424248

ABSTRACT

Autoclaving diminishes the nutritional value of rat diets, depending on the duration and temperature of the process and the type of dietary protein. We evaluated in vivo and in vitro the effects of autoclaving on the protein and energy values of soy-free and soy-containing rat diets. The true digestibility and biological value of the dietary protein were determined in a 10-d experiment involving 28-d-old Wistar Crl:WI(Han) male rats fed casein- or soy-containing diet that was autoclaved for 20 min at 121 °C (T1), 10 min at 134 °C (T2), or not autoclaved (T0). The apparent protein digestibility and metabolizable energy concentration of experimental diets were assayed during an 18-d trial involving 6-wk-old Wistar-Crl:WI(Han) male rats and compared with a commercial diet. The neutral detergent fiber (NDF) content, amount of protein bound to NDF, protein solubility, and in vitro ileal protein digestibility were determined. Autoclaving decreased protein solubility, with the T2 condition having a greater effect than that of T1, and decreased the protein parameters determined in vivo, except for the apparent digestibility of the standard rat diet. Autoclaving decreased metabolizable energy slightly. The Atwater formula yielded higher values than those determined in rats, in vitro, and calculated according to the pig equation. We conclude that autoclaving diets according to the T1 program was less detrimental to dietary protein than was T2 and that the NDF content and protein solubility may be helpful in assessing the effect of autoclaving. The pig formula and in vitro method appear to be valid for estimating the metabolizable energy of rat diets.


Subject(s)
Animal Feed/analysis , Animals, Laboratory , Rats , Animals , Dietary Fiber , Dietary Proteins/metabolism , Energy Metabolism , Male , Mice , Rats, Wistar , Solubility
3.
J Sci Food Agric ; 94(3): 544-51, 2014 Feb.
Article in English | MEDLINE | ID: mdl-23801189

ABSTRACT

BACKGROUND: Simultaneous quantification of liposoluble vitamins is not a new area of interest, since these compounds co-determine the nutritional quality of food and feed, a field widely explored in the human and animal diet. However, the development of appropriate methods is still a matter of concern, especially when the vitamin composition is highly complex, as is the case with feed designated for laboratory animals, representing a higher health and microbiological status. RESULTS: A method combining microemulsion electrokinetic chromatography (MEEKC) with liquid-liquid extraction was developed for the determination of four fat-soluble vitamins in animal feed. A separation medium consisting of 25 mmol L⁻¹ phosphate buffer (pH 2.5), 2-propanol, 1-butanol, sodium dodecyl sulfate and octane allowed the simultaneous determination of vitamins A, D, E and K within a reasonable time of 25 min. The polarity of the separation voltage was reversed in view of the strongly suppressed electro-osmotic flow, and the applied voltage was set at 12 kV. The fat-soluble vitamins were separated in the order of decreasing hydrophobicity. CONCLUSION: It was proved that the proposed MEEKC method was sufficiently specific and sensitive for screening fat-soluble vitamins in animal feed samples after their sterilization.


Subject(s)
Animal Feed/analysis , Chromatography/methods , Nutritive Value , Vitamins/analysis , Animals , Humans , Hydrophobic and Hydrophilic Interactions , Solubility , Vitamin A/analysis , Vitamin D/analysis , Vitamin E/analysis , Vitamin K/analysis , Vitamins/classification
4.
Int J Mol Sci ; 14(3): 6157-69, 2013 Mar 18.
Article in English | MEDLINE | ID: mdl-23507752

ABSTRACT

Isoprostanes are stable products of arachidonic acid peroxidation and are regarded as the most reliable markers of oxidative stress in vivo. Here we describe the LC-MS/MS procedure enabling simultaneous determination of four regioisomers (8-iso prostaglandin F2α, 8-iso-15(R)-prostaglandin F2α, 11ß-prostaglandin F2α, 15(R)-prostaglandin F2α) in plasma samples collected from mice. The four plasma isoprostanes are determined by LC-ESI-MS/MS with deuterated 8-iso-PGF2α-d4 as an internal standard (I.S.). For plasma samples spiked with the isoprostanes at a level of 200 pg/mL each, the method imprecision has been below 7.1% and mean inaccuracy equaled 8.7%. The applicability of the proposed approach has been verified by the assessment of changes in isoprostane levels in plasma samples derived from mice exposed to tert-butyl hydroperoxide (TBHP), a model inducer of oxidative stress, or to antitumor drug doxorubicin (DOX) known for potent stimulation of redox cycling. Compared to the control group of mice, both oxidative stress inducers tested increased the levels of three out of four isoprostanes in exposed animals; 11ß-prostaglandin F2α being the exception. The greatest rise was observed in the case of 15(R)-prostaglandin F2α, by about 50% and 70% in plasma samples derived from mice exposed to DOX and TBHP, respectively.

5.
Cancer Biol Ther ; 12(7): 586-97, 2011 Oct 01.
Article in English | MEDLINE | ID: mdl-21775820

ABSTRACT

Antitumor imidazoacridinone C-1311 is a DNA-reactive topoisomerase II and FLT3 receptor tyrosine kinase inhibitor. Here, we demonstrate the mechanism of C-1311 inhibitory action on novel targets: hypoxia-inducible factor-1α (HIF-1α), vascular-endothelial growth factor (VEGF), and angiogenesis. In a cell-free system, C-1311 prevented HIF-1α binding to an oligonucleotide encompassing a canonical hypoxia-responsive element (HRE), but did not directly interfere with HIF-1α protein. Whereas C-1311 did not affect HIF-1α transcription, at higher concentrations (10 µM), it decreased HIF-1α protein accumulation. Furthermore, C-1311 potently reduced the transcription of HIF-1-dependent reporter gene as well as endogenous HIF-1 target gene encoding vascular endothelial growth factor. In colon cancer HCT116 and murine melanoma B16/F10 cells, C-1311-induced down-regulation of VEGF, resulted in decreased VEGF protein expression. C-1311 did not alter normoxic VEGF secretion. Consistent with VEGF depletion, C-1311 significantly affected angiogenesis in vivo. A single dose of C-1311 (40 mg/kg), inhibited angiogenesis by 70%, as measured by vascularization of Matrigel plugs in mice. Continuous low C-1311 dosing (8 mg/kg/day for 5 days) gave similar inhibition of angiogenesis (80%), suggesting that low-dose, frequent C-1311 administration may be more effective in terms of reducing toxicity. Anti-angiogenic activity of C-1311 was further demonstrated in an experimental model in which B16/F10 cells were encapsulated in alginate beads and implanted into mice. C-1311 (8 mg/kg/day for 9 days), completely abrogated vascularization of the alginate implants. Our findings indicate that C-1311 is an effective inhibitor of HIF-1α, VEGF, and angiogenesis and provide new perspectives into the mechanism of its anticancer activity.


Subject(s)
Aminoacridines/pharmacology , Angiogenesis Inhibitors/pharmacology , Antineoplastic Agents/pharmacology , Hypoxia-Inducible Factor 1, alpha Subunit/antagonists & inhibitors , Neovascularization, Pathologic/drug therapy , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Animals , Binding Sites , Cell Line, Tumor , Cell-Free System , Colonic Neoplasms/drug therapy , Colonic Neoplasms/metabolism , Colonic Neoplasms/pathology , Dose-Response Relationship, Drug , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Melanoma/drug therapy , Melanoma/metabolism , Melanoma/pathology , Mice , Mice, Inbred C57BL , Response Elements , Tumor Suppressor Protein p53/genetics , Vascular Endothelial Growth Factor A/genetics , Vascular Endothelial Growth Factor A/metabolism
6.
Bioorg Med Chem ; 11(3): 399-405, 2003 Feb 06.
Article in English | MEDLINE | ID: mdl-12517435

ABSTRACT

A series of potential DNA-binding antitumor agents, 3-[omega-(alkylamino)alkyl]-6-nitro-thiadiazino[3,4,5-kl]acridines 12 and 1,3-di[omega-(alkylamino)alkyl]-6-nitro-thiadiazino[3,4,5-kl]acridines 13, has been prepared by cyclization with SOCl(2) of 1-[[omega-(alkylamino)alkyl]amino]-9-imino-4-nitro-9,10-dihydroacridines 16 or 1-[[omega-(alkylamino)alkyl]amino]-9-[omega-(alkylamino)alkyl]imino-4-nitro-9,10-dihydroacridines 17, respectively. The non-covalent DNA-binding properties of 12, 13 have been examined using a fluorometric technique. In vitro cytotoxic potencies of these derivatives toward six tumor cell lines, including human colon adenocarcinoma (HT29) and human ovarian carcinoma (A2780 sensitive, A2780cisR cisplatin-resistant, CH1, CH1cisR cisplatin-resistant, and SKOV-3) cells, are described and compared to that of reference drugs. In vivo antitumor activity of some selected derivatives, endowed with relevant cytotoxic activity against murine leukemia P388 are reported. The 3-[2-(dimethylamino)ethyl]-6-nitro-2,7-dihydro-3H-2 lambda(4)-thiadiazino[3,4,5-kl]acridin-2-one (12d) has been identified as a new lead in the development of anticancer tetracyclic acridine derivatives.


Subject(s)
Acridines/chemistry , Acridines/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Thiadiazines/chemistry , Thiadiazines/pharmacology , Acridines/chemical synthesis , Animals , Antineoplastic Agents/chemical synthesis , Binding Sites , Cattle , Cyclization , DNA/drug effects , DNA/metabolism , Drug Design , Drug Screening Assays, Antitumor , HT29 Cells , Humans , Inhibitory Concentration 50 , Intercalating Agents/chemical synthesis , Intercalating Agents/chemistry , Intercalating Agents/pharmacology , Leukemia P388 , Mice , Structure-Activity Relationship , Thiadiazines/chemical synthesis , Tumor Cells, Cultured
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