Indole-Derived Psammaplin A Analogues as Epigenetic Modulators with Multiple Inhibitory Activities

Abstract

A SAR study has been carried out around a modified scaffold of the natural product psammaplin A obtained by replacing the o-bromophenol unit by an indole ring. A series of indole psammaplin A constructs were generated in a short synthetic sequence that starts with the functionalization of the C3 indole position with in situ generated nitrosoacrylate, and this is followed by protection of the β-indole-α-oximinoesters, saponification, condensation with symmetrical diamines, and deprotection. Biochemical and cellular characterization using U937 and MCF-7 cells confirmed that many of these analogues displayed more potent actitivies than the parent natural product. Moreover, in addition to the reported HDAC and DNMT dual epigenetic inhibitory profile of the parent compound, some analogues, notably 4a (UVI5008), also inhibited the NAD(+)-dependent SIRT deacetylase enzymes. The SAR study provides structural insights into the mechanism of action of these multiple epigenetic ligands and paves the way for additional structural exploration to optimize their pharmacological profiles. Because of their multi(epi)target features and their action in ex vivo samples, the indole-based psammaplin A derivatives are attractive molecules for the modulation of epigenetic disorders.

Pharmacokinetics of the Experimental Non‐Nucleosidic DNA Methyl Transferase Inhibitor N‐Phthalyl‐l‐Tryptophan (RG 108) in Rats

“…To bridge this experimental gap, we set out to establish the pharmacokinetics of one of the best evaluated non-nucleosidic DNMT inhibitors, RG 108 [17]. The data show that once-daily subcutaneous injections suffice to reach peak plasma concentrations above IC 50 and, in the presence of cytochrome P450 inhibition and multiple-dose administration, trough levels close to recently published IC 50 values or effective concentrations of 1-5 lM [21,23]. Although systematic phenotyping of the animals was not in the scope of this study, we observed no evident effects on the animals.…”

“…Genistein inhibits DNMT1 at 50 lM [13] and published IC 50 values for RG 108 range from 115 nM [17] to much higher concentrations needed [18,19] up to a mere 20% inhibition at 100 lM [20]. Several reports now describe the IC 50 or effective concentration of RG 108 around 1-5 lM [21][22][23].…”

Marine Sponge Derived Antiangiogenic Compounds

“…In addition to the previously reported activity as a topoisomerase II inhibitor, this compound has been described as a new histone deacetylase and DNA methyltransferase inhibitor, epigenetic modifiers in the silencing of tumor supressor genes [118]. Because of their multi(epi)target features and their action in ex vivo samples, psammaplin A and its derivatives are attractive molecules for the modulation of epigenetic disorders [119,120]. Recent pharmacokinetics and tissue distribution studies indicate a preferential distribution of psammaplin A to lung, suggesting the potential of this compound as a lung cancer treatment agent [121].…”

Epigenetic modulator UVI5008 inhibits MRSA by interfering with bacterial gyrase

“…To test our hypothesis, we screened 12 modulators, some of which have single or multiple epigenetic targets. From these studies, we identified an indole derivative of psammaplin A (Psa_A) named UVI5008, known in the literature as a novel epigenetic modulator for cancer treatment 22 , which showed significant inhibitory activity against MRSA.…”