Solid phase synthesis and antiprotozoal evaluation of di- and trisubstituted 5′-carboxamidoadenosine analogues

Rodenko, Boris; Detz, Remko J.; Pinas, Victorine A.; Lambertucci, Catia; Brun, Reto; Wanner, Martin J.; Koomen, Gerrit‐Jan

doi:10.1016/j.bmc.2005.10.011

Cited by 22 publications

(17 citation statements)

References 30 publications

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“…The classical antimalarial quinolines, quinine and chloroquine, are also believed to act via complexation to heme molecules (14,15,29), as are diamidines, such as pentamidine (33). Other studies by us (30) and others (20) on the antiplasmodial activities of adenosine derivatives also revealed that substitution of the parent adenosine structure with groups rich in electrons favored their antimalarial activity. The targeting of the unique hemoglobin degradation pathways of Plasmodium would also be consistent with the relatively low levels of activity of these aromatically substituted compounds against Trypanosoma and Leishmania spp.…”

Section: Discussionmentioning

confidence: 97%

“…Evaluation of the compounds for their cytotoxicities for L6 mouse fibroblast cells and for their activities against the chloroquine-and pyrimethamine-resistant line Plasmodium falciparum K1, Trypanosoma brucei rhodesiense strain STIB 900, T. b. brucei strain BS221, the tbat1 Ϫ/Ϫ clone derived from BS221 (23), trypomastigotes of Trypanosoma cruzi strain Tulahuen C4, and amastigotes of Leishmania donovani strain MHOM-ET-67/L82 in primary mouse macrophages was performed at the Swiss Tropical Institute, exactly as described previously (24,30). Additional drug sensitivity assays with culture-adapted bloodstream T. b. brucei s427, Leishmania major promastigotes, and Leishmania mexicana amastigotes were performed at the University of Glasgow, as described previously (1,26,36).…”

Section: Synthesis Of 2nmentioning

confidence: 99%

“…In previous work we have described the synthesis of a library of di-and trisubstituted 5Ј-carboxamidoadenosine analogs and evaluated their antiprotozoal activities (30). Here, we report on the antiprotozoal activities of a library of 2,N 6 -disubstituted adenosine analogs (31).…”

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confidence: 97%

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2,N ⁶ -Disubstituted Adenosine Analogs with Antitrypanosomal and Antimalarial Activities

Rodenko

Burg

Wanner

et al. 2007

Antimicrob Agents Chemother

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A library of 2,N 6 -disubstituted adenosine analogs was synthesized and the analogs were tested for their antiprotozoal activities. It was found that 2-methoxy and 2-histamino and N 6 -m-iodobenzyl substitutions generally produced analogs with low levels of antiprotozoal activity. The best antiplasmodial activity was achieved with large aromatic substitutions, such as N 6 -2,2-diphenylethyl and naphthylmethyl, which could indicate a mechanism of action through aromatic stacking with heme in the digestive vacuole of Plasmodium spp. The activities against Trypanosoma cruzi trypomastigotes and Leishmania donovani amastigotes were generally low; but several analogs, particularly those with cyclopentylamino substitutions, displayed potent activities against Trypanosoma brucei rhodesiense and T. b. brucei bloodstream forms in vitro. The most active were 2-cyclopentylamino-N 6 -cyclopentyladenosine (compound NA42) and 2-cyclopentylamino-N 6 -cyclopentyladenine (compound NA134), with the nucleobase an order of magnitude more potent than the nucleoside, at 26 ؎ 4 nM. It was determined that the mode of action of these purines was trypanostatic, with the compounds becoming trypanocidal only at much higher concentrations. Those 2,N 6 -disubstituted purines tested for their effects on purine transport in T. b. brucei displayed at best a moderate affinity for the transporters. It is highly probable that the large hydrophobic substitutions, which bestow high calculated octanol-water coefficient values on the analogs, allow them to diffuse across the membrane. Consistent with this view, the analogs were as effective against a T. b. brucei strain lacking the P2 nucleoside transporter as they were against the parental strain. As the analogs were not toxic to human cell lines, the purine analogs are likely to act on a trypanosomespecific target.

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Section: Discussionmentioning

confidence: 97%

Section: Synthesis Of 2nmentioning

confidence: 99%

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2,N ⁶ -Disubstituted Adenosine Analogs with Antitrypanosomal and Antimalarial Activities

Rodenko

Burg

Wanner

et al. 2007

Antimicrob Agents Chemother

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“…55 Immobilization of the purine nucleoside 185 via the modified ribose scaffold was also described by Koomen using Kenner's linker or safety-catch arylhydrazide linker 184 (Scheme 29). 56 The safety-catch concept relies on the fact that the linker is acid and base stable and can be activated under oxidative conditions to generate the reactive acyldiazene. Subsequent attack by a nucleophile releases nitrogen gas and produces carboxylic acids, esters or amides, when water, alcohols or amines are used as nucleophiles.…”

Section: ■ Immobilization Via the N 9 Positionmentioning

confidence: 99%

Solid-Phase Synthetic Strategies for the Preparation of Purine Derivatives

Krajčovičová

Soural

2016

ACS Comb. Sci.

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“…More recently, Rodenko et al used the same linker for the solid phase synthesis of several di-and trisubstituted 5'-carboxamidoadenosine analogues in very good yields (Rodenko et al, 2006). It is interesting to note that the authors initially used Kenner's benzenesulfonamide linker for the production of the 5'-carboxyadenosine libraries.…”

Section: Miscellaneous Reactionsmentioning

confidence: 99%

The Use of Aryl Hydrazide Linkers for the Solid‐Phase Synthesis of Chemically Modified Peptides

2007

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Since Merrifield introduced the concept of solid phase synthesis in 1963 for the rapid preparation of peptides, a large variety of different supports and resin-linkers have been developed that improve the efficiency of peptide assembly and expand the myriad of synthetically feasible peptides. The aryl hydrazide is one of the most useful resin-linkers for the synthesis of chemically modified peptides. This linker is completely stable during Boc-and Fmoc-based solid phase synthesis and yet it can be cleaved under very mild oxidative conditions. The present article reviews the use of this valuable linker for the rapid and efficient synthesis of C-terminal modified peptides, head-to-tail cyclic peptides and lipidated peptides.

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Solid phase synthesis and antiprotozoal evaluation of di- and trisubstituted 5′-carboxamidoadenosine analogues

Cited by 22 publications

References 30 publications

2,N ⁶ -Disubstituted Adenosine Analogs with Antitrypanosomal and Antimalarial Activities

2,N ⁶ -Disubstituted Adenosine Analogs with Antitrypanosomal and Antimalarial Activities

Solid-Phase Synthetic Strategies for the Preparation of Purine Derivatives

The Use of Aryl Hydrazide Linkers for the Solid‐Phase Synthesis of Chemically Modified Peptides

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Solid phase synthesis and antiprotozoal evaluation of di- and trisubstituted 5′-carboxamidoadenosine analogues

Cited by 22 publications

References 30 publications

2,N 6 -Disubstituted Adenosine Analogs with Antitrypanosomal and Antimalarial Activities

2,N 6 -Disubstituted Adenosine Analogs with Antitrypanosomal and Antimalarial Activities

Solid-Phase Synthetic Strategies for the Preparation of Purine Derivatives

The Use of Aryl Hydrazide Linkers for the Solid‐Phase Synthesis of Chemically Modified Peptides

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2,N ⁶ -Disubstituted Adenosine Analogs with Antitrypanosomal and Antimalarial Activities

2,N ⁶ -Disubstituted Adenosine Analogs with Antitrypanosomal and Antimalarial Activities