scholarly journals In vivo efficacies of 5'-methylthioadenosine analogs as trypanocides.

1997 ◽  
Vol 41 (10) ◽  
pp. 2108-2112 ◽  
Author(s):  
C J Bacchi ◽  
K Sanabria ◽  
A J Spiess ◽  
M Vargas ◽  
C J Marasco ◽  
...  
Keyword(s):  
Trypanosoma Brucei ◽  
East African ◽  
Trypanosoma Brucei Rhodesiense ◽  
Polyamine Biosynthesis ◽  
Substrate Analogs ◽  
Osmotic Pumps ◽  
Derivatives Of ◽  
Ribose Moiety

5'-Deoxy-5'-(methylthio)adenosine (MTA), a key by-product of polyamine biosynthesis, is cleaved by MTA phosphorylase and is salvaged as adenine and, through conversion of the ribose moiety, methionine. An analog of MTA, 5'-deoxy-5'-(hydroxyethylthio)adenosine (HETA), is a substrate for trypanosome MTA phosphorylase and is active in vitro and in vivo against Trypanosoma brucei brucei, an agent of bovine trypanosomiasis. In this study, HETA and three O-acylated HETA derivatives were examined for their activities against model infections of T. b. brucei and Trypanosoma brucei rhodesiense, the agent of East African sleeping sickness. HETA was curative (>60%) for infections caused by 5 of 11 clinical isolates of T. b. rhodesiense when it was given to mice at 200 mg/kg of body weight for 7 days as a continuous infusion in osmotic pumps. HETA at 150 to 200 mg/kg also extended the life spans of the mice infected with four additional isolates two- to fivefold. Di- and tri-O-acetylated derivatives of HETA also proved curative for the infections, while a tri-O-propionyl derivative, although also curative, was not as effective. This study indicates that substrate analogs of MTA should be given important consideration for development as novel chemotherapies against African trypanosomiasis.

Morphological changes in trypanosoma brucei rhodesiense following inhibition of polyamine biosynthesis in vivo

1984 ◽  
Vol 16 (5) ◽  
pp. 731-738 ◽  
Author(s):  
Antonie L.W. de Gee ◽  
Per H.B. Carstens ◽  
Peter P. McCann ◽  
John M. Mansfield
Keyword(s):  
Trypanosoma Brucei ◽  
Morphological Changes ◽  
Trypanosoma Brucei Rhodesiense ◽  
Polyamine Biosynthesis

scholarly journals Antitrypanosomal Activity of a New Triazine Derivative, SIPI 1029, In Vitro and in Model Infections

1998 ◽  
Vol 42 (10) ◽  
pp. 2718-2721 ◽  
Author(s):  
Cyrus J. Bacchi ◽  
Marcus Vargas ◽  
Donna Rattendi ◽  
Burt Goldberg ◽  
Weicheng Zhou
Keyword(s):  
Trypanosoma Brucei ◽  
Model Systems ◽  
In Vivo Model ◽  
Trypanosoma Brucei Rhodesiense ◽  
Diminazene Aceturate ◽  
African Trypanosomes ◽  
Cure Rates ◽  
Laboratory Models

ABSTRACT A recently developed diaminotriazine derivative [O,O′-bis(1,2-dihydro-2,2-tetramethylene-4,6-diamino-S-triazin-1-yl)-1,6-hexanediol dihydrochloride; T-46; SIPI 1029] was examined for activity against African trypanosomes in in vitro and in vivo model systems. In vitro, SIPI 1029 was 50% inhibitory for growth of bloodstream trypomastigotes of four strains of Trypanosoma brucei brucei and Trypanosoma brucei rhodesiense at 0.15 to 2.15 nM (50% inhibitory concentrations). In in vivo mouse laboratory models of T. b. rhodesiense clinical isolate infections, SIPI 1029 was curative for 12 of 13 isolates at ≤10 mg/kg of body weight/day for 3 days. In eight infections, a single dose was ≥60% curative, and in six of these, a dose of ≤5 mg/kg was sufficient for ≥60% cure rates. A number of these isolates were resistant to the standard trypanocide melarsoprol (Arsobal) and/or the diamidines diminazene aceturate (Berenil) and pentamidine. SIPI 1029 was also curative in combination withdl-α-difluoromethylornithine (Ornidyl) in a T. b. brucei central nervous system model infection. Some evidence of toxicity was found in dosage regimens of 10 mg/kg/day for 2 or 3 days in which deaths were observed in 6 of 65 animals given this dosage regimen. The activity of SIPI 1029 in this study indicates that this class of compounds (diaminotriazines) should be explored as leads for new human and veterinary trypanocides.

In vitro and in vivo activity of cynaropicrin against Trypanosoma brucei rhodesiense

Planta Medica ◽  
2010 ◽  
Vol 76 (12) ◽  
Author(s):  
M Adams ◽  
S Zimmermann ◽  
P Küenzi ◽  
T Julianti ◽  
Y Hata ◽  
...  
Keyword(s):  
Trypanosoma Brucei ◽  
Trypanosoma Brucei Rhodesiense

Alkaloid subfractions of Buxus sempervirens L. leaves with strong in vitro activity against Trypanosoma brucei rhodesiense

Planta Medica ◽  
2014 ◽  
Vol 80 (16) ◽  
Author(s):  
JB Althaus ◽  
G Jerz ◽  
P Winterhalter ◽  
M Kaiser ◽  
R Brun ◽  
...  
Keyword(s):  
Trypanosoma Brucei ◽  
Vitro Activity ◽  
In Vitro Activity ◽  
Trypanosoma Brucei Rhodesiense ◽  
Buxus Sempervirens

Derivatives of Deoxypodophyllotoxin Induce Apoptosis Through Bcl-2/Bax Proteins Expression

2020 ◽  
Vol 20 ◽  
Author(s):  
Ya-Nan Li ◽  
Ni Ning ◽  
Lei Song ◽  
Yun Geng ◽  
Jun-Ting Fan ◽  
...  
Keyword(s):  
Annexin V ◽  
Mtt Method ◽  
Anthriscus Sylvestris ◽  
Anti Tumor Activity ◽  
Derivatives Of ◽  
Toxicity In Vitro ◽  
Ht 29 ◽  
Mcf 7

Background: Deoxypodophyllotoxin, isolated from theTraditional Chinese Medicine Anthriscus sylvestris, is well-known because of its significant antitumor activity with strong toxicity in vitro and in vivo. Objective: In this article, we synthesized a series of deoxypodophyllotoxin derivatives, and evaluated their antitumor effectiveness.Methods:The anti tumor activity of deoxypodophyllotoxin derivatives was investigated by the MTT method. Apoptosis percentage was measured by flow cytometer analysis using Annexin-V-FITC. Results: The derivatives revealed obvious cytotoxicity in the MTT assay by decreasing the number of late cancer cells. The decrease of Bcl-2/Bax could be observed in MCF-7, HepG2, HT-29 andMG-63 using Annexin V-FITC. The ratio of Bcl-2/Bax in the administration group was decreased, which was determined by the ELISA kit. Conclusion: The derivatives of deoxypodophyllotoxin could induce apoptosis in tumor cell lines by influencing Bcl-2/Bax.

scholarly journals Unusual derivatives from Hypericum scabrum

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Sara Soroury ◽  
Mostafa Alilou ◽  
Thomas Gelbrich ◽  
Marzieh Tabefam ◽  
Ombeline Danton ◽  
...  
Keyword(s):  
Trypanosoma Brucei ◽  
2D Nmr ◽  
Moderate Activity ◽  
Trypanosoma Brucei Rhodesiense ◽  
L6 Cells ◽  
Aerial Parts ◽  
Hypericum Scabrum ◽  
New Compounds ◽  
Absolute Structure

AbstractThree new compounds (1–3) with unusual skeletons were isolated from the n-hexane extract of the air-dried aerial parts of Hypericum scabrum. Compound 1 represents the first example of an esterified polycyclic polyprenylated acylphloroglucinol that features a unique tricyclo-[4.3.1.11,4]-undecane skeleton. Compound 2 is a fairly simple MPAP, but with an unexpected cycloheptane ring decorated with prenyl substituents, and compound 3 has an unusual 5,5-spiroketal lactone core. Their structures were determined by extensive spectroscopic and spectrometric techniques (1D and 2D NMR, HRESI-TOFMS). Absolute configurations were established by ECD calculations, and the absolute structure of 2 was confirmed by a single crystal determination. Plausible biogenetic pathways of compounds 1–3 were also proposed. The in vitro antiprotozoal activity of the compounds against Trypanosoma brucei rhodesiense and Plasmodium falciparum and cytotoxicity against rat myoblast (L6) cells were determined. Compound 1 showed a moderate activity against T. brucei and P. falciparum, with IC50 values of 3.07 and 2.25 μM, respectively.

scholarly journals Antitrypanosomal activity of purine nucleosides can be enhanced by their conversion to O-acetylated derivatives.

1996 ◽  
Vol 40 (11) ◽  
pp. 2567-2572 ◽  
Author(s):  
J R Sufrin ◽  
D Rattendi ◽  
A J Spiess ◽  
S Lane ◽  
C J Marasco ◽  
...  
Keyword(s):  
Trypanosoma Brucei ◽  
Parent Compound ◽  
Nucleoside Analogs ◽  
Significant Activity ◽  
Structural Class ◽  
Antitrypanosomal Activity ◽  
Salvage Pathways ◽  
Purine Salvage Pathways

Fifteen purine nucleosides and their O-acetylated ester derivatives were examined for in vitro antitrypanosomal activity against the LAB 110 EATRO isolate of Trypanosoma brucei brucei and two clinical isolates of Trypanosoma brucei rhodesiense. Initial comparisons of activity were made for the LAB 110 EATRO isolate. Three nucleoside analogs exhibited no significant activity (50% inhibitory concentrations [IC50s] of > 100 microM), whether they were O acetylated or unacetylated; three nucleosides showed almost equal activity (IC50s of < 5 microM) for the parent compound and the O-acetylated derivative; nine nucleosides showed significantly improved activity (> or = 3-fold) upon O acetylation; of these nine analogs, six displayed activity at least 10-fold greater than that of their parent nucleosides. The most significant results were those for four apparently inactive compounds which, upon O acetylation, displayed IC50s of < or = 25 microM. When the series of compounds was tested against T. brucei rhodesiense isolates (KETRI 243 and KETRI 269), their antitrypanosomal effects were comparable to those observed for the EATRO 110 strain. Thus, our studies of purine nucleosides have determined that O acetylation consistently improved their in vitro antitrypanosomal activity. This observed phenomenon was independent of their cellular enzyme targets (i.e., S-adenosylmethionine, polyamine, or purine salvage pathways). On the basis of our results, the routine preparation of O-acetylated purine nucleosides for in vitro screening of antitrypanosomal activity is recommended, since O acetylation transformed several inactive nucleosides into compounds with significant activity, presumably by improving uptake characteristics. O-acetylated purine nucleosides may offer in vivo therapeutic advantages compared with their parent nucleosides, and this possibility should be considered in future evaluations of this structural class of trypanocides.

Synthesis, in vitro and in vivo antitumor activity of symmetrical bis-Schiff base derivatives of isatin

2014 ◽  
Vol 74 ◽  
pp. 742-750 ◽  
Author(s):  
Chengyuan Liang ◽  
Juan Xia ◽  
Dong Lei ◽  
Xiang Li ◽  
Qizheng Yao ◽  
...  
Keyword(s):  
Schiff Base ◽  
Antitumor Activity ◽  
Schiff Base Derivatives ◽  
In Vivo Antitumor Activity ◽  
Derivatives Of

scholarly journals Characterization and selective inhibition of myristoyl-CoA:protein N-myristoyltransferase from Trypanosoma brucei and Leishmania major

2006 ◽  
Vol 396 (2) ◽  
pp. 277-285 ◽  
Author(s):  
Chrysoula Panethymitaki ◽  
Paul W. Bowyer ◽  
Helen P. Price ◽  
Robin J. Leatherbarrow ◽  
Katherine A. Brown ◽  
...  
Keyword(s):  
Trypanosoma Brucei ◽  
Leishmania Major ◽  
Homo Sapiens ◽  
Selective Inhibition ◽  
Fungal Species ◽  
Chemotherapeutic Agents ◽  
Human Pathogens ◽  
Ic50 Values

The eukaryotic enzyme NMT (myristoyl-CoA:protein N-myristoyltransferase) has been characterized in a range of species from Saccharomyces cerevisiae to Homo sapiens. NMT is essential for viability in a number of human pathogens, including the fungi Candida albicans and Cryptococcus neoformans, and the parasitic protozoa Leishmania major and Trypanosoma brucei. We have purified the Leishmania and T. brucei NMTs as active recombinant proteins and carried out kinetic analyses with their essential fatty acid donor, myristoyl-CoA and specific peptide substrates. A number of inhibitory compounds that target NMT in fungal species have been tested against the parasite enzymes in vitro and against live parasites in vivo. Two of these compounds inhibit TbNMT with IC50 values of <1 μM and are also active against mammalian parasite stages, with ED50 (the effective dose that allows 50% cell growth) values of 16–66 μM and low toxicity to murine macrophages. These results suggest that targeting NMT could be a valid approach for the development of chemotherapeutic agents against infectious diseases including African sleeping sickness and Nagana.

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