Synthesis and activity of a novel inhibitor of nonsense-mediated mRNA decay

During efforts to prepare the known compound , a new tetracyclic compound, called , was prepared in six steps. This compound was found to have good activity as an inhibitor of nonsense-mediated mRNA decay

Sequence-selective binding of an ellipticine derivative to DNA.

The DNA sequence specificity of an ellipticine derivative bearing an aminoalkyl side chain has been determined by a variety of footprinting methods. The drug exhibits sequence selective binding and discriminates against runs of adenines or thymines. Binding is shown to occur at various sequences with a preference for GC rich regions of DNA. A large enhancement of DNAase I and of hydroxyl radical cleavage in regions rich in A's or T's is observed together with hyperreactivity of adenines towards diethylpyrocarbonate in the presence of drug. This indicates the occurrence of drug-induced changes in critical conformational features of DNA. The total absence of hyperreactivity of guanine residues towards diethylpyrocarbonate appears to be related to the sequence selectivity of drug binding. No alteration of the dimethyl sulphate and methylene blue-induced cleavage of DNA is observed. Irradiation of ellipticine derivative-DNA complexes with UV light followed by alkali treatment leads to selective photocleavage at guanine residues, consistent with the deduced degree of selectivity of the binding reaction

Radical chemistry of the antitumor drug pazelliptine (PZE) in aqueous solution or intercalated in poly(dA)-poly(dT)

The effect of 2 ns pulse of 355 nm laser light on aqueous solutions of free pazelliptine (PZE) at different pH and complexed wirth poly(dA)-poly(dT) was investigated. Spectral analysis revealed the occurence of a photoionization process generating PZE radical cation (PZE+), and the formation of PZE triplet state. The absorption spectrum of the radical PZE+ was pH dependent and closely related to the protonated form of PZE in the ground state. Its kinetic evolution appeared very similar for the free drug and for the intercalated complex. By contrast, the triplet state desactivation was different for the free drug and the intercalating complex in deaerated solution. An electron transfer from the poly(dA)-poly(dT) was observed

Oxydation monoélectronique d’un composé antitumoral dérivé de l’ellipticine : le BD84

L’oxydation monoélectronique par les radicaux OH• d’un médicament dérivé de l’ellipticine, le BD84, a été étudiée, en solution aqueuse à pH 7, par radiolyse pulsée. En l’absence d’oxygène, les radicaux R• (λmax ~ 420 à 480 nm) obtenus par l’action des radicaux OH• sur le BD84 [k(OH• + BD84) = (5,0 ± 0,5) × 109 mol-1.dm3.s-1], disparaissent en réagissant sur eux-mêmes [2k = (2,8 ± 0,4) × 108 mol-1.dm3.s-1]. En présence d’oxygène, les radicaux R• réagissent avec O2, en donnant un autre intermédiaire radicalaire RO2• [k = (2,5 ± 0,3) × 108 mol-1.dm3.s-1]. Ces résultats sont comparés à ceux obtenus pour d’autres dérivés de l’ellipticine

Selective modification of alternative splicing by indole derivatives that target serine-arginine-rich protein splicing factors

The prevalence of alternative splicing as a target for alterations leading to human genetic disorders makes it highly relevant for therapy. Here we have used in vitro splicing reactions with different splicing reporter constructs to screen 4,000 chemical compounds for their ability to selectively inhibit spliceosome assembly and splicing. We discovered indole derivatives as potent inhibitors of the splicing reaction. Importantly, compounds of this family specifically inhibit exonic splicing enhancer (ESE)-dependent splicing, because they interact directly and selectively with members of the serine-arginine-rich protein family. Treatment of cells expressing reporter constructs with ESE sequences demonstrated that selected indole derivatives mediate inhibition of ESE usage in vivo and prevent early splicing events required for HIV replication. This discovery opens the exciting possibility of a causal pharmacological treatment of aberrant splicing in human genetic disorders and development of new antiviral therapeutic approaches