ABSTRACT
Twelve new hydroquinones and quinones (4a-c to 7a-c) derived from free or peracetylated bile acids were prepared by a Barton decarboxylation reaction, with subsequent trapping of the resulting free radical by benzoquinone. All new compounds were completely characterized by 2D NMR techniques and screened for antifungal and cytotoxic activity. One of the new hydroquinones (7b) showed promising results against the human pancreatic ductal carcinoma cell line PANC1, with similar cytotoxic activity as the commercial chemotherapy drug doxorubicin.
Subject(s)
Antifungal Agents/chemical synthesis , Antineoplastic Agents/chemical synthesis , Bile Acids and Salts/chemistry , Hydroquinones/chemical synthesis , Quinones/chemical synthesis , Steroids/chemical synthesis , Animals , Antifungal Agents/isolation & purification , Antifungal Agents/pharmacology , Antineoplastic Agents/isolation & purification , Antineoplastic Agents/pharmacology , Benzoquinones/chemistry , Candida albicans/drug effects , Candida albicans/growth & development , Carcinoma, Pancreatic Ductal , Cell Line, Tumor , Cell Survival/drug effects , Decarboxylation , Doxorubicin/pharmacology , Drug Design , Free Radicals/chemistry , Humans , Hydroquinones/isolation & purification , Hydroquinones/pharmacology , Magnetic Resonance Spectroscopy , Molecular Structure , Pancreatic Neoplasms , Quinones/isolation & purification , Quinones/pharmacology , Steroids/isolation & purification , Steroids/pharmacology , Structure-Activity RelationshipABSTRACT
Heterogeneous nuclear ribonucleoproteins A and B (hnRNPs A/B), cellular RNA-binding proteins that participate in splicing, trafficking, translation and turnover of mRNAs, have been implicated in the life cycles of several cytoplasmic RNA viruses. Here, we demonstrate that silencing of hnRNPs A1 and A2 significantly reduces the replication of the arenavirus Junín virus (JUNV), the aetiological agent of Argentine haemorrhagic fever. While acute JUNV infection did not modify total levels of expression of hnRNPs A/B in comparison with uninfected cells, non-cytopathic persistent infection exhibited low levels of these cell proteins. Furthermore, acutely infected cells showed a cytoplasmic relocalization of overexpressed hnRNP A1, probably related to the involvement of this protein in virus replicative cycle. This cytoplasmic accumulation was also observed in cells expressing viral nucleoprotein (N), and co-immunoprecipitation studies revealed the interaction between hnRNP A1 and N protein. By contrast, a predominantly nuclear distribution of overexpressed hnRNP A1 was found during persistent infection, even in the presence of endogenous or overexpressed N protein, indicating a differential modulation of nucleo-cytoplasmic trafficking in acute and persistent JUNV infections.