scholarly journals Novel Trypanocidal Analogs of 5′-(Methylthio)-Adenosine

2007 ◽  
Vol 52 (1) ◽  
pp. 211-219 ◽  
Author(s):  
Janice R. Sufrin ◽  
Arthur J. Spiess ◽  
Canio J. Marasco ◽  
Donna Rattendi ◽  
Cyrus J. Bacchi
Keyword(s):  
Trypanosoma Brucei ◽  
Clinical Isolate ◽  
In Vitro Cytotoxicity ◽  
Trypanosoma Brucei Rhodesiense ◽  
Absolute Requirement ◽  
A Cell ◽  
Biochemical Mechanisms ◽  
Ongoing Development ◽  
New Compounds

ABSTRACT The purine nucleoside 5′-deoxy-5′-(hydroxyethylthio)-adenosine (HETA) is an analog of the polyamine pathway metabolite 5′-deoxy-5′-(methylthio)-adenosine (MTA). HETA is a lead structure for the ongoing development of selectively targeted trypanocidal agents. Thirteen novel HETA analogs were synthesized and examined for their in vitro trypanocidal activities against bloodstream forms of Trypanosoma brucei brucei LAB 110 EATRO and at least one drug-resistant Trypanosoma brucei rhodesiense clinical isolate. New compounds were also assessed in a cell-free assay for their activities as substrates of trypanosome MTA phosphorylase. The most potent analog in this group was 5′-deoxy-5′-(hydroxyethylthio)-tubercidin, whose in vitro cytotoxicity (50% inhibitory concentration [IC50], 10 nM) is 45 times greater than that of HETA (IC50, 450 nM) against pentamidine-resistant clinical isolate KETRI 269. Structure-activity analyses indicate that the enzymatic cleavage of HETA analogs by trypanosome MTA phosphorylase is not an absolute requirement for trypanocidal activity. This suggests that additional biochemical mechanisms are associated with the trypanocidal effects of HETA and its analogs.

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 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.

scholarly journals In vitro Antiprotozoal Activity of Extracts of five Turkish Lamiaceae Species

2011 ◽  
Vol 6 (11) ◽  
pp. 1934578X1100601 ◽  
Author(s):  
Hasan Kirmizibekmez ◽  
Irem Atay ◽  
Marcel Kaiser ◽  
Erdem Yesilada ◽  
Deniz Tasdemir
Keyword(s):  
Trypanosoma Brucei ◽  
Leishmania Donovani ◽  
Hexane Extract ◽  
Significant Activity ◽  
Trypanosoma Brucei Rhodesiense ◽  
L6 Cells ◽  
Methanolic Extracts ◽  
Aerial Parts ◽  
Organic Extracts

The in vitro antiprotozoal activities of crude methanolic extracts from the aerial parts of five Lamiaceae plants ( Salvia tomentosa, S. sclarea, S. dichroantha, Nepeta nuda subsp. nuda and Marrubium astracanicum subsp. macrodon) were evaluated against four parasitic protozoa, i.e. Trypanosoma brucei rhodesiense, T. cruzi, Leishmania donovani and Plasmodium falciparum. The cytotoxic potentials of the extracts on L6 cells were also evaluated. Melarsoprol, benznidazole, miltefosine, chloroquine and podophyllotoxin were used as reference drugs. All crude MeOH extracts showed antiprotozoal potential against at least three parasites, so they were dispersed in water and partitioned against n-hexane and chloroform to yield three subextracts that were screened in the same test systems. The n-hexane extract of N. nuda was the most active against T. brucei rhodesiense while the CHCl3 extracts of S. tomentosa and S. dichroantha showed significant activity against L. donovani. All organic extracts displayed in vitro antimalarial and moderate trypanocidal activities against T. cruzi with the n-hexane extract of S. sclarea being the most active against the latter. The extracts displayed low or no cytotoxicity towards mammalian L6 cells.

scholarly journals New 2-aminopyrimidine derivatives and their antitrypanosomal and antiplasmodial activities

2020 ◽  
Vol 151 (9) ◽  
pp. 1375-1385
Author(s):  
Michael Hoffelner ◽  
Usama Hassan ◽  
Werner Seebacher ◽  
Johanna Dolensky ◽  
Patrick Hochegger ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Trypanosoma Brucei ◽  
Phenyl Ring ◽  
Ring Closure ◽  
Causative Organism ◽  
Amino Group ◽  
Trypanosoma Brucei Rhodesiense ◽  
Structural Modifications ◽  
Skeletal Myoblasts

Abstract Novel 2-aminopyrimidine derivatives were prepared from acyclic starting materials, benzylidene acetones and ammonium thiocyanates, via 5 steps, including ring closure, aromatization, S-methylation, oxidation to methylsulfonyl compounds, and formation of guanidines with suitable amines. The prepared compounds differ from each other by the substitutions of their amino group and of their phenyl ring. The 2-aminopyrimidines were tested by use of microplate assays for their in vitro activities against a causative organism of sleeping sickness, Trypanosoma brucei rhodesiense, as well as against a causative organism of malaria, Plasmodium falciparum NF54. Their cytotoxic properties were determined with L-6 cells (rat skeletal myoblasts). Some of the compounds exhibited quite good antitrypanosomal activity, and others showed excellent antiplasmodial activity. The influence of the structural modifications on these activities is discussed. Graphic abstract

scholarly journals Glutathione Derivatives Active against Trypanosoma brucei rhodesiense and T.brucei brucei In Vitro

2002 ◽  
Vol 46 (2) ◽  
pp. 434-437 ◽  
Author(s):  
Sylvie Daunes ◽  
Claudius D'Silva
Keyword(s):  
Trypanosoma Brucei ◽  
Species Difference ◽  
Steric Effects ◽  
Quantitative Structure ◽  
Trypanosoma Brucei Rhodesiense ◽  
Structure Activity ◽  
Branched Alcohols ◽  
Linear Alcohols ◽  
Glutathione Derivatives

ABSTRACT Diesters based on N-benzyloxycarbonyl-S-(2,4-dinitrophenyl) GSH (CBzGSDNP) containing linear alcohols 3 to 9, branched alcohols 10 to 20, or heteroatom linear alcohols 21 to 25, were investigated as in vitro inhibitors of pathogenic parasites. Diesters 3 to 25 were better inhibitors of Trypanosoma brucei rhodesiense than of T. brucei brucei and had low cytotoxicities. The most active compound had a 50% effective dose (ED50) of 0.2 μM. A quantitative structure activity regression equation relating the log (1/ED50) versus the hydrophobicity parameter (log P), Taft's steric parameter (Es ), molecular weight (MW), and the WienI descriptor (W) was determined, and the species difference was found to be related to membrane penetration and steric effects.

scholarly journals Specific 12β-Hydroxylation of Cinobufagin by Filamentous Fungi

2004 ◽  
Vol 70 (6) ◽  
pp. 3521-3527 ◽  
Author(s):  
Min Ye ◽  
Guiqin Qu ◽  
Hongzhu Guo ◽  
Dean Guo
Keyword(s):  
Microbial Transformation ◽  
Reversed Phase ◽  
In Vitro Models ◽  
In Vitro Cytotoxicity ◽  
New Drugs ◽  
Hydroxyl Group ◽  
Cytotoxic Activities ◽  
Phase Liquid ◽  
New Compounds

ABSTRACT Biotransformation of natural products has great potential for producing new drugs and could provide in vitro models of mammalian metabolism. Microbial transformation of the cytotoxic steroid cinobufagin was investigated. Cinobufagin could be specifically hydroxylated at the 12β-position by the fungus Alternaria alternata. Six products from a scaled-up fermentation were obtained by silica gel column chromatography and reversed-phase liquid chromatography and were identified as 12β-hydroxyl cinobufagin, 12β-hydroxyl desacetylcinobufagin, 3-oxo-12β-hydroxyl cinobufagin, 3-oxo-12β-hydroxyl desacetylcinobufagin, 12-oxo-cinobufagin, and 3-oxo-12α-hydroxyl cinobufagin. The last five products are new compounds. 12β-Hydroxylation of cinobufagin by A. alternata is a fast catalytic reaction and was complete within 8 h of growth with the substrate. This reaction was followed by dehydrogenation of the 3-hydroxyl group and then deacetylation at C-16. Hydroxylation at C-12β also was the first step in the metabolism of cinobufagin by a variety of fungal strains. In vitro cytotoxicity assays suggest that 12β-hydroxyl cinobufagin and 3-oxo-12α-hydroxyl cinobufagin exhibit somewhat decreased but still significant cytotoxic activities. The 12β-hydroxylated bufadienolides produced by microbial transformation are difficult to obtain by chemical synthesis.

scholarly journals Syntheses and PDT activity of new mono- and di-conjugated derivatives of chlorin e6

2017 ◽  
Vol 21 (04-06) ◽  
pp. 354-363 ◽  
Author(s):  
Hui Chen ◽  
Stewart W. Humble ◽  
R. G. Waruna Jinadasa ◽  
Zehua Zhou ◽  
Alex L. Nguyen ◽  
...  
Keyword(s):  
Amino Acid ◽  
In Vitro Cytotoxicity ◽  
Chlorin E6 ◽  
New Compounds ◽  
Derivatives Of

Syntheses of three new chlorin e6 conjugates for PDT of tumors are reported. One of the new compounds 17 is conjugated with lysine at the 131-position, but the others are mono-conjugated 14 or diconjugated 15 with the non-amino acid species ethanolamine. Cellular experiments with the three new compounds and previously synthesized non-amino acid 152-conjugates (7–10), 131-monoconjugates 14, 16, and a 131,152-diconjugate 12 are reported. In vitro cytotoxicity experiments show that the 131-conjugates are more toxic than the 152-conjugates, and the most toxic derivative (dark- and photo-toxicity) is the 131-ethylenediamine conjugate 11. The most useful PDT photosentitizers appear to be the ethanolamine derivatives, conjugated at the 152- and the 131,152-positions; these show high phototoxicity but relatively low dark toxicity compared with 11, and also the highest dark/photo cytotoxicity ratios.

scholarly journals Synthesis and Cytotoxicity of Thieno[2,3-b]Pyridine Derivatives Toward Sensitive and Multidrug-Resistant Leukemia Cells

2021 ◽  
Vol 68 (2) ◽  
pp. 458-465
Author(s):  
Salah A. Al-Trawneh ◽  
Amer H. Tarawneh ◽  
Anastassiya V. Gadetskaya ◽  
Ean-Jeong Seo ◽  
Mohammad R. Al-Ta’ani ◽  
...  
Keyword(s):  
Multidrug Resistant ◽  
In Vitro Cytotoxicity ◽  
Leukemia Cells ◽  
Growth Inhibitory ◽  
Growth Inhibitory Activity ◽  
Anti Cancer ◽  
Ic50 Values ◽  
New Compounds ◽  
Potential Use

A new series of substituted ethyl 7-cyclopropyl-2-(2-aryloxo)-3-nitro-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylates 3a–e were prepared by utilizing ethyl 2-chloro-7-cyclopropyl-3-nitro-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylate (1) and replacing of the 2-chlorine with anions obtained from phenol (2a), salicylaldehyde derivatives 2b–d or thiophenol (2e), leading to the respective ethyl 7-cyclopropyl-2-(2-aryloxo)-3-nitro-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylates 3a–e. The new compounds were evaluated for their in vitro cytotoxicity towards sensitive CCRF-CEM and multidrug-resistant CEM/ADR5000 leukemia cells. The screening revealed that compounds 3a, 3b, and 3e inhibited the growth of both cell lines. Compound 3b, with a phenol moiety, exhibited the highest growth inhibitory activity against CEM/ADR5000 and CCRF-CEM cells with IC50 values 4.486 ± 0.286 and 2.580 ± 0.550 μM, respectively. Collectively, the presented results demonstrate that the synthesized thieno[2,3-b]pyridines warrant further exploration for potential use as anti-cancer agents.

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