Trypanosoma cruzi: evaluation of (−)-cubebin derivatives activity in the messenger RNAs processing

Abstract

No fully effective treatment has been developed since the discovery of Chagas' disease. Since drug-resistant Trypanosoma cruzi strains are occurring and the current therapy is effective in the acute phase but with various adverse side effects, more studies are needed to characterize the susceptibility of T. cruzi to new drugs. Pre-mRNA maturation in trypanosomatids occurs through a process called trans-splicing, which is unusual RNA processing reaction, and it implies the processing of polycistronic transcription units into individual mRNAs; a short transcript spliced leader (SL RNA) is trans-spliced to the acceptor pre-mRNA, giving origin to the mature mRNA. Cubebin derivatives seem to provide treatments with less collateral effects than benznidazole and showed similar or better trypanocidal activities than benznidazole. Therefore, the cubebin derivatives ((-)-6,6'-dinitrohinokinin (DNH) and (-)-hinokinin (HQ)) interference in the mRNA processing was evaluated using T. cruzi permeable cells (Y and BOL (Bolivia) strains) following by RNase protection reaction. These substances seem to intervene in any step of the RNA transcription, promoting alterations in the RNA synthesis, even though the RNA processing mechanism still occurs. Furthermore, HQ presented better activity against the parasites than DNH, meaning that BOL strain seems to be more resistant than Y.

Simplified Derivatives of Dibenzylbutyrolactone Lignans from Hydrocotyle bonariensis as Antitrypanosomal Candidates

“…As part of our continuous studies aiming the discovery on new antitrypanosomal natural products, the crude hexane extract from H. bonariensis demonstrated activity against the trypomastigote forms of T. cruzi and was subjected to bioactivity‐guided fractionation procedures to afford two chemically related dibenzylbutyrolactone lignans ‐ hinokinin ( 1 ) and hibalactone ( 2 ). In a previous work, compound 1 demonstrated activity against T. cruzi parasites of different strains and parasite forms [26–31] . In addition, a previous in vivo efficacy study also revealed a significant reduction of the parasitaemia in T. cruzi ‐infected BALB/c mice after treatment with compound 1 [31] .…”

An Ethnopharmacological, Phytochemical and Pharmacological Review on Lignans from Mexican Bursera spp.

“…Hinokinin has been chosen as a trypanosomicidal marker in P. cubeba [ 58 ]. In order to ascertain the safety of this compound toward mammalian cells, several studies have been performed [ 59 , 60 , 61 ]. The authors found that hinokinin did not increase DNA damage, demonstrating the absence of mutagenic and genotoxic activities.…”

Cubebin and semisynthetic dibenzyl butyrolactone derivatives: Biological activities

“…Hinokinin and 6,6-dinitro hinokinin were evaluated for their interference with the messenger RNA processing in trypanosomatids. The study performed by Silva et al (2011) used T. cruzi epimastigotes strains Y and BOL (Bolivia). The substances seemed to intervene at some RNA transcription stage, promoting changes in their synthesis.…”