scholarly journals Activity of Indenoisoquinolines against African Trypanosomes

2008 ◽  
Vol 53 (1) ◽  
pp. 123-128 ◽  
Author(s):  
Rahul P. Bakshi ◽  
Dongpei Sang ◽  
Andrew Morrell ◽  
Mark Cushman ◽  
Theresa A. Shapiro
Keyword(s):  
Anticancer Agents ◽  
Mammalian Cells ◽  
Sleeping Sickness ◽  
Water Soluble ◽  
African Trypanosomes ◽  
In Vivo Experiments ◽  
Topoisomerase Ib ◽  
Topoisomerase Poisons

ABSTRACT African trypanosomiasis (sleeping sickness), caused by protozoan Trypanosoma brucei species, is a debilitating disease that is lethal if untreated. Available drugs are antiquated, toxic, and compromised by emerging resistance. The indenoisoquinolines are a class of noncamptothecin topoisomerase IB poisons that are under development as anticancer agents. We tested a variety of indenoisoquinolines for their ability to kill T. brucei. Indenoisoquinolines proved trypanocidal at submicromolar concentrations in vitro. Structure-activity analysis yielded motifs that enhanced potency, including alkylamino substitutions on N-6, methoxy groups on C-2 and C-3, and a methylenedioxy bridge between C-8 and C-9. Detailed analysis of eight water-soluble indenoisoquinolines demonstrated that in trypanosomes the compounds inhibited DNA synthesis and acted as topoisomerase poisons. Testing these compounds on L1210 mouse leukemia cells revealed that all eight were more effective against trypanosomes than against mammalian cells. In preliminary in vivo experiments one compound delayed parasitemia and extended survival in mice subjected to a lethal trypanosome challenge. The indenoisoquinolines provide a promising lead for the development of drugs against sleeping sickness.

scholarly journals The activity of superoxide-dismutase in animal cell culture CHO-K1 after treatment with fullerenol and mytomicine C

2009 ◽  
Vol 63 (3) ◽  
pp. 143-149 ◽  
Author(s):  
Visnja Bogdanovic ◽  
Marija Slavic ◽  
Jasminka Mrdjanovic ◽  
Slavica Solajic ◽  
Aleksandar Djordjevic
Keyword(s):  
Superoxide Dismutase ◽  
Mammalian Cells ◽  
Animal Cell ◽  
Water Soluble ◽  
Cytotoxic Agents ◽  
Antioxidant Defenses ◽  
Free Radical Scavengers ◽  
Sod Activity

Eukaryotic cell survives in predominantly reduced conditions. Homeostasis of cellular redox system is an imperative of cell surviving and its normal metabolism. ROS are well recognized for playing a dual role as both deleterious and beneficial species, since they can be either harmful or beneficial to living systems. These species are mutagenic compounds known to lead to DNA damage, favor cell transformation, and contribute to the development of a variety of malignant diseases. All the effects of oxidants are influenced by the cellular antioxidant defenses. This multilayer system consists of low molecular weight components and several antioxidant enzymes. Superoxide dismutases (SODs) are the only enzymes dismuting superoxide radicals. Mitomycin C, a cross-linking agent, demonstrated genotoxicity in all in vitro and in vivo test systems in mammalian cells and animals. Water-soluble fullerenes are well known as cytotoxic agents for many cell lines in vitro. At the other side, fullerenols are good free radical scavengers and antioxidants both in vitro and in vivo. This paper investigates the effects of fullerenol on survival and fullerenol/ /mytomicine (MMC) treatment on superoxide-dismutase (SOD) activity in CHO-K1 cells. Samples were treated 3 and 24 h with fullerenol (C60(OH)24) at concentration range 0.01-0.5 mg/mL and survival was monitored with dye exclusion test (DET). The activity of total SOD was estimated in samples treated with chosen concentrations of fullerenol and MMC (0.5 and 0.1 mg/mL) after 3 and 24 h of cell incubation. Increasing of C60(OH)24 concentration leads to decreasing of percent of surviving cells 3 and 24 h after incubation. The activity of total SOD enhanced with higher concentration of fullerenol, while decreased in the highest concentration at both experimental points. In samples treated with MMC, as well as in samples treated with fullerenol (0.0625 mg/mL) + MMC was noticed boost in total SOD activity in comparison with controls. Treatment with fullerenol decreased SOD activity in rest of samples treated with MMC. Decreased activity of superoxide-dismutase in almost all samples treated with fullerenol and MMC might be contributed to antioxidative properties of fullerenol. Increased enzyme level at concentration of 0.0625 mg/mL may be due to its prooxidative activity.

Development and Characterization of the Neuroregenerative Xanthohumol C/Hydroxypropyl-β-cyclodextrin Complex Suitable for Parenteral Administration

Planta Medica ◽  
2019 ◽  
Vol 85 (16) ◽  
pp. 1233-1241
Author(s):  
Michael Kirchinger ◽  
Lara Bieler ◽  
Julia Tevini ◽  
Michael Vogl ◽  
Elisabeth Haschke-Becher ◽  
...  
Keyword(s):  
Water Solubility ◽  
Pharmaceutical Research ◽  
Water Soluble ◽  
Complexing Agents ◽  
Cyclodextrin Complex ◽  
Scanning Calorimetry ◽  
In Vivo Experiments ◽  
Strong Candidate

AbstractThe chroman-like chalcone Xanthohumol C, originally found in hops, was demonstrated to be a potent neuroregenerative and neuroprotective natural product and therefore constitutes a strong candidate for further pharmaceutical research. The bottleneck for in vivo experiments is the low water solubility of this chalcone. Consequently, we developed and validated a suitable formulation enabling in vivo administration. Cyclodextrins were used as water-soluble and nontoxic complexing agents, and the complex of Xanthohumol C and 2-hydroxypropyl-β-cyclodextrin was characterized using HPLC, HPLC-MS, NMR, and differential scanning calorimetry. The water solubility of Xanthohumol C increases with increasing concentrations of cyclodextrin. Using 50 mM 2-hydroxypropyl-β-cyclodextrin, solubility was increased 650-fold. Furthermore, in vitro bioactivity of Xanthohumol C in free and complexed form did not significantly differ, suggesting the release of Xanthohumol C from 2-hydroxypropyl-β-cyclodextrin. Finally, a small-scaled in vivo experiment in a rat model showed that after i. p. administration of the complex, Xanthohumol C can be detected in serum, the brain, and the cerebrospinal fluid at 1 and 6 h post-administration. Mean (± SD) Xanthohumol C serum concentrations after 1, 6, and 12 h were determined as 463.5 (± 120.9), 61.9 (± 13.4), and 9.3 (± 0.8) ng/mL upon i. v., and 294.3 (± 22.4), 45.5 (± 0.7), and 13 (± 1.0) ng/mL after i. p. application, respectively. Accordingly, the formulation of Xanthohumol C/2-hydroxypropyl-β-cyclodextrin is suitable for further in vivo experiments and further pharmaceutical research aiming for the determination of its neuroregenerative potential in animal disease models.

scholarly journals New Treatment Option for Second-Stage African Sleeping Sickness: In Vitro and In Vivo Efficacy of Aza Analogs of DB289

2009 ◽  
Vol 53 (10) ◽  
pp. 4185-4192 ◽  
Author(s):  
Tanja Wenzler ◽  
David W. Boykin ◽  
Mohamed A. Ismail ◽  
James Edwin Hall ◽  
Richard R. Tidwell ◽  
...  
Keyword(s):  
Sleeping Sickness ◽  
African Sleeping Sickness ◽  
African Trypanosomes ◽  
Second Stage ◽  
Resistant Lines ◽  
New Treatment ◽  
Toxic Drugs ◽  
Further Development

ABSTRACT African sleeping sickness is a fatal parasitic disease, and all drugs currently in use for treatment have strong liabilities. It is essential to find new, effective, and less toxic drugs, ideally with oral application, to control the disease. In this study, the aromatic diamidine DB75 (furamidine) and two aza analogs, DB820 and DB829 (CPD-0801), as well as their methoxyamidine prodrugs and amidoxime metabolites, were evaluated against African trypanosomes. The active parent diamidines showed similar in vitro profiles against different Trypanosoma brucei strains, melarsoprol- and pentamidine-resistant lines, and a P2 transporter knockout strain (AT1KO), with DB75 as the most trypanocidal molecule. In the T. b. rhodesiense strain STIB900 acute mouse model, the aza analogs DB820 and DB829 demonstrated activities superior to that of DB75. The aza prodrugs DB844 and DB868, as well as two metabolites of DB844, were orally more potent in the T. b. brucei strain GVR35 mouse central nervous system (CNS) model than DB289 (pafuramidine maleate). Unexpectedly, the parent diamidine DB829 showed high activity in the mouse CNS model by the intraperitoneal route. In conclusion, DB868 with oral and DB829 with parenteral application are potential candidates for further development of a second-stage African sleeping sickness drug.

scholarly journals PLANT-DERIVED CHEMOTHERAPEUTICS DRUGS FOR CANCER CHEMOTHERAPY

2021 ◽  
Vol 1 (1) ◽  
pp. 28-37
Author(s):  
Alexandra Dragoi ◽  
Oana Alexandru
Keyword(s):  
Anticancer Agents ◽  
Natural Compounds ◽  
Clinical Use ◽  
Vinca Alkaloids ◽  
Chemotherapeutic Drugs ◽  
Malignant Cells ◽  
In Vivo Experiments ◽  
Whole Plant

Cancer chemotherapeutic drugs acts in different manner to kill malignant cells. Most of the anticancer drugs available in clinical practice to treat cancer patients, are natural products including whole plant extract, crude plant extracts, isolated constituents, plant –based drug formulations etc. These natural compounds have been a basis for the development of several drugs against cancer. Agents such as topotecan, taxol, vinca alkaloids (vincristine, vinblastine, vinorelbine and vindesine), are important anticancer agents in widespread clinical use. Other agents, such as combretastatin, flavopiridol, betulinic acid were shown to have anti-tumor effects in both in vitro and in vivo experiments. In this review, we aim to make a brief description of classical plant-derived chemotherapeutics drugs and also to highlight the importance of these natural compounds in the development of new potential drugs in cancer treatment.

scholarly journals Efficacious Treatment of Experimental Leishmaniasis with Amphotericin B-Arabinogalactan Water-Soluble Derivatives

1999 ◽  
Vol 43 (9) ◽  
pp. 2209-2214 ◽  
Author(s):  
Jacob Golenser ◽  
Shoshana Frankenburg ◽  
Tirtsa Ehrenfreund ◽  
Abraham J. Domb
Keyword(s):  
Amphotericin B ◽  
Leishmania Major ◽  
Water Soluble ◽  
In Vivo Experiments ◽  
Drug Concentrations ◽  
Efficacious Treatment ◽  
Lipid Formulations ◽  
Established Infection

ABSTRACT In this study, we tested the efficacy of amphotericin B (AmB)-arabinogalactan (AmB-AG) conjugates for the treatment of experimental leishmaniasis. Chemical conjugation of AmB to a water-soluble, biodegradable, and biocompatible polymer could present many advantages over presently available AmB formulations. Two conjugates were tested, a reduced (rAmB-AG) form and an unreduced (uAmB-AG) form. In vitro, the drug concentrations which lower the values of parasites (for promastigotes) or infected macrophages (for amastigotes) to 50% of the untreated values (ED50s) of uAmB-AG and rAmB-AG were 0.19 and 0.34 μg/ml, respectively, forLeishmania major promastigotes and 0.17 and 0.31 μg/ml, respectively, for amastigotes. The effect on Leishmania infantum-infected macrophages was more marked, with ED50s of 0.035 μg/ml for rAmB-AG and 0.027 μg/ml for uAmB-AG. In in vivo experiments, BALB/c mice injected with L. major were treated from day 2 onwards on alternate days for 2 weeks. Both conjugates, as well as liposomal AmB (all at 6 mg/kg of body weight) and Fungizone (1 mg/kg), significantly delayed the appearance of lesions compared to that in untreated mice. In addition, both conjugates, but not liposomal AmB, were significantly more effective than Fungizone. Subcutaneous injection of the conjugates (6 mg/kg) was significantly more effective than liposomal AmB in delaying the appearance of lesions. Higher AmB concentrations of up to 12 mg/kg could be administered by this route. When an established infection was treated, uAmB-AG was somewhat more effective than liposomal AmB. In summary, water-soluble polymeric AmB derivatives were found effective and safe for the treatment of leishmanial infections. The conjugates, which are stable and can be produced relatively cheaply (compared to lipid formulations), can be used in the future for the treatment of leishmaniasis infections.

scholarly journals Organometallic iron complexes as potential cancer therapeutics.

2014 ◽  
Vol 61 (4) ◽  
Author(s):  
Gabriela Mojžišová ◽  
Ján Mojžiš ◽  
Janka Vašková
Keyword(s):  
Anticancer Agents ◽  
Acquired Resistance ◽  
Cancer Therapeutics ◽  
Iron Complexes ◽  
Cytotoxic Agents ◽  
In Vitro Tests ◽  
Clinical Use ◽  
In Vivo Experiments

Metal-containing drugs have long been used for medicinal purposes in more or less empirical way. The potential of these anticancer agents has only been fully realised and explored since the discovery of the biological activity of cisplatin. Cisplatin and carboplatin have been two of the most successful anti-cancer agents ever developed, and are currently used to treat ovarian, lung and testicular cancers. They share certain side effects, so their clinical use is severely limited by dose-limiting toxicity. Inherent or acquired resistance is a second problem often associated with platinum-based drugs, with further limits of their clinical use. These problems have prompted chemists to employ different strategies in development of the new metal-based anticancer agents with different mechanisms of action. There are various metal complexes still under development and investigation for the future cancer treatment use. In the search for novel bio-organometallic molecules, iron containing anti-tumoral agents are enjoying an increasing interest and appear very promising as the potential drug candidates. Iron, as an essential cofactor in a number of enzymes and physiological processes, may be less toxic than non essential metals, such as platinum. Up to now, some of iron complexes have been tested as cytotoxic agents and found to be endowed with an antitumor activity in several in vitro tests (on cultured cancer cell lines) and few in vivo experiments (e. g. on Ehrlich's ascites carcinoma). Although the precise molecular mechanism is yet to be defined, a number of observations suggest that the reactive oxygen species can play important role in iron-induced cytotoxicty. This review covers some relevant examples of research on the novel iron complexes.

scholarly journals In vitro Cytotoxicity Studies of Industrially Used Common Nanomaterials on L929 and 3T3 Fibroblast Cells

2020 ◽  
Vol 1 (5) ◽  
pp. 192-200
Author(s):  
Madhulika Srikanth ◽  
Waseem S Khan ◽  
Ramazan Asmatulu ◽  
Heath E Misak ◽  
Shang-You Yang ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Cell Types ◽  
In Vitro Cytotoxicity ◽  
In Vitro Tests ◽  
Fibroblast Cells ◽  
In Vivo Experiments ◽  
Cytotoxicity Studies ◽  
Biomedical Electronics

The unique structures and properties of nanomaterials have attracted many engineers and scientists to these resources for different applications, including biomedical, electronics, manufacturing, transportation, energy, and defense. The increasing applications of nanomaterials have also caused some concern among the scientific community about their safety and cytotoxicity. To successfully use nanomaterials in different fields, their interaction with mammalian cells in vitro must be addressed before in vivo experiments can be carried out successfully. In this study, the cytotoxicity values of commonly known nanomaterials, such as 100-ply Carbon Nanotube (CNT) wires, graphene, CNTs, nanoclay, and fullerene, were investigated through in vitro tests on human L929 and mice 3T3 fibroblast cells and compared with each other. The effects of cytotoxicity on both cell types were similar in many ways, but not closely identical due to structural and morphological differences. Compared to mice fibroblast cells, human fibroblast cells have a larger surface area; therefore, the viability values of L929 cells at different dilutions and time durations vary over a larger range. Pristine 100-ply CNT wires were found to be the least cytotoxic, with an average viability of 86.9%, whereas materials with high aspect ratio (e.g., CNTs and graphene) had higher cytotoxicity values due to their potential to pierce through cell membranes.

scholarly journals In Vitro Assessment of Fluoropyrimidine-Metabolizing Enzymes: Dihydropyrimidine Dehydrogenase, Dihydropyrimidinase, and β-Ureidopropionase

2020 ◽  
Vol 9 (8) ◽  
pp. 2342
Author(s):  
Eiji Hishinuma ◽  
Evelyn Gutiérrez Rico ◽  
Masahiro Hiratsuka
Keyword(s):  
Anticancer Agents ◽  
Mammalian Cells ◽  
Dihydropyrimidine Dehydrogenase ◽  
In Vitro Tests ◽  
Severe Toxicity ◽  
Metabolizing Enzymes ◽  
Underlying Mechanisms ◽  
Enzyme Metabolism

Fluoropyrimidine drugs (FPs), including 5-fluorouracil, tegafur, capecitabine, and doxifluridine, are among the most widely used anticancer agents in the treatment of solid tumors. However, severe toxicity occurs in approximately 30% of patients following FP administration, emphasizing the importance of predicting the risk of acute toxicity before treatment. Three metabolic enzymes, dihydropyrimidine dehydrogenase (DPD), dihydropyrimidinase (DHP), and β-ureidopropionase (β-UP), degrade FPs; hence, deficiencies in these enzymes, arising from genetic polymorphisms, are involved in severe FP-related toxicity, although the effect of these polymorphisms on in vivo enzymatic activity has not been clarified. Furthermore, the clinical usefulness of current methods for predicting in vivo activity, such as pyrimidine concentrations in blood or urine, is unknown. In vitro tests have been established as advantageous for predicting the in vivo activity of enzyme variants. This is due to several studies that evaluated FP activities after enzyme metabolism using transient expression systems in Escherichia coli or mammalian cells; however, there are no comparative reports of these results. Thus, in this review, we summarized the results of in vitro analyses involving DPD, DHP, and β-UP in an attempt to encourage further comparative studies using these drug types and to aid in the elucidation of their underlying mechanisms.

scholarly journals In Vitro and In Vivo Trypanocidal Efficacy of Synthesized Nitrofurantoin Analogs

Molecules ◽  
2021 ◽  
Vol 26 (11) ◽  
pp. 3372
Author(s):  
Linous Munsimbwe ◽  
Anna Seetsi ◽  
Boniface Namangala ◽  
David D. N’Da ◽  
Noboru Inoue ◽  
...  
Keyword(s):  
Treatment Efficacy ◽  
Oral Treatment ◽  
Aliphatic Chain ◽  
African Trypanosomes ◽  
Trypanocidal Activity ◽  
Relationship Analysis ◽  
In Vivo Experiments ◽  
Trypanocidal Drugs

African trypanosomes cause diseases in humans and livestock. Human African trypanosomiasis is caused by Trypanosoma brucei rhodesiense and T. b. gambiense. Animal trypanosomoses have major effects on livestock production and the economy in developing countries, with disease management depending mainly on chemotherapy. Moreover, only few drugs are available and these have adverse effects on patients, are costly, show poor accessibility, and parasites develop drug resistance to them. Therefore, novel trypanocidal drugs are urgently needed. Here, the effects of synthesized nitrofurantoin analogs were evaluated against six species/strains of animal and human trypanosomes, and the treatment efficacy of the selected compounds was assessed in vivo. Analogs 11 and 12, containing 11- and 12-carbon aliphatic chains, respectively, showed the highest trypanocidal activity (IC50 < 0.34 µM) and the lowest cytotoxicity (IC50 > 246.02 µM) in vitro. Structure-activity relationship analysis suggested that the trypanocidal activity and cytotoxicity were related to the number of carbons in the aliphatic chain and electronegativity. In vivo experiments, involving oral treatment with nitrofurantoin, showed partial efficacy, whereas the selected analogs showed no treatment efficacy. These results indicate that nitrofurantoin analogs with high hydrophilicity are required for in vivo assessment to determine if they are promising leads for developing trypanocidal drugs.

In vitro and in vivo evaluation of organometallic gold(i) derivatives as anticancer agents

2016 ◽  
Vol 45 (6) ◽  
pp. 2462-2475 ◽  
Author(s):  
Elena García-Moreno ◽  
Alejandro Tomás ◽  
Elena Atrián-Blasco ◽  
Sonia Gascón ◽  
Eduardo Romanos ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cell Line ◽  
Anticancer Agents ◽  
Cancer Cell Line ◽  
Colon Cancer Cell Line ◽  
Colon Cancer Cell ◽  
Water Soluble ◽  
In Vivo Evaluation

Alkyne gold(i) derivatives with the water soluble phosphanes PTA and DAPTA were described and their anticancer potential against the colon cancer cell line Caco-2 (PD7 and TC7 clones) was studied.

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