Frédéric Cantagrel

Design, Synthesis and Biological Evaluation of 4-Amino-N-(4-aminophenyl)benzamide Analogues of Quinoline-Based SGI-1027 as Inhibitors of DNA Methylation

Quinoline derivative SGI‐1027 (N‐(4‐(2‐amino‐6‐methylpyrimidin‐4‐ylamino)phenyl)‐4‐(quinolin‐4‐ylamino)benzamide) was first described in 2009 as a potent inhibitor of DNA methyltransferase (DNMT) 1, 3A and 3B. Based on molecular modeling studies, performed using the crystal structure of Haemophilus haemolyticus cytosine‐5 DNA methyltransferase (MHhaI C5 DNMT), which suggested that the quinoline and the aminopyridimine moieties of SGI‐1027 are important for interaction with the substrates and protein, we designed and synthesized 25 derivatives. Among them, four compounds—namely the derivatives 12, 16, 31 and 32—exhibited activities comparable to that of the parent compound. Further evaluation revealed that these compounds were more potent against human DNMT3A than against human DNMT1 and induced the re‐expression of a reporter gene, controlled by a methylated cytomegalovirus (CMV) promoter, in leukemia KG‐1 cells. These compounds possessed cytotoxicity against leukemia KG‐1 cells in the micromolar range, comparable with the cytotoxicity of the reference compound, SGI‐1027. Structure–activity relationships were elucidated from the results. First, the presence of a methylene or carbonyl group to conjugate the quinoline moiety decreased the activity. Second, the size and nature of the aromatic or heterocycle subsitutents effects inhibition activity: tricyclic moieties, such as acridine, were found to decrease activity, while bicyclic substituents, such as quinoline, were well tolerated. The best combination was found to be a bicyclic substituent on one side of the compound, and a one‐ring moiety on the other side. Finally, the orientation of the central amide bond was found to have little effect on the biological activity. This study provides new insights in to the structure–activity relationships of SGI‐1027 and its derivative.

Transition-metal catalyzed synthesis of δ-hydroxy-γ-lactones from bis(trimethylsilyl) ketene acetals and allylic acetates via γ-unsaturated carboxylic acids. Comments on the formation of α-cyclopropyl carboxylic acids

Abstract Bis(trimethylsilyl)ketene acetals react with allylic acetates in the presence of Pd(0) complexes to give γ-unsaturated carboxylic acids together with α-cyclopropyl carboxylic acids. The unsaturated acids can be converted catalytically to δ-hydroxy-γ-lactones by the H2O2/MTO system (methyltrioxorhenium) and to butenolides by Pd(II) catalyzed intramolecular cyclization reactions. The structure of two of these lactones has been established by X-ray analysis. The mechanism of the formation of the cyclopropanic acids will be discussed.

New insights on the mechanism of quinoline-based DNA methyltransferase inhibitors

Background: 4-Aminoquinoline SGI-1027 and analogs inhibit DNA methylation, which is deregulated in cancers. Results: These compounds induce deviations from Michaelis-Menten equations in DNA competition experiments and interact with DNA. Conclusion: They are competitive inhibitors for the DNA substrate of the DNA methyltransferase and non-competitive for the methyl group donor, S-adenosyl-l-methionine. Significance: These findings suggest a mechanism of inhibition for these 4-aminoquinoline-based DNMT inhibitors. Among the epigenetic marks, DNA methylation is one of the most studied. It is highly deregulated in numerous diseases, including cancer. Indeed, it has been shown that hypermethylation of tumor suppressor genes promoters is a common feature of cancer cells. Because DNA methylation is reversible, the DNA methyltransferases (DNMTs), responsible for this epigenetic mark, are considered promising therapeutic targets. Several molecules have been identified as DNMT inhibitors and, among the non-nucleoside inhibitors, 4-aminoquinoline-based inhibitors, such as SGI-1027 and its analogs, showed potent inhibitory activity. Here we characterized the in vitro mechanism of action of SGI-1027 and two analogs. Enzymatic competition studies with the DNA substrate and the methyl donor cofactor, S-adenosyl-l-methionine (AdoMet), displayed AdoMet non-competitive and DNA competitive behavior. In addition, deviations from the Michaelis-Menten model in DNA competition experiments suggested an interaction with DNA. Thus their ability to interact with DNA was established; although SGI-1027 was a weak DNA ligand, analog 5, the most potent inhibitor, strongly interacted with DNA. Finally, as 5 interacted with DNMT only when the DNA duplex was present, we hypothesize that this class of chemical compounds inhibit DNMTs by interacting with the DNA substrate.

The Ether Lipid Inositol-C2-PAF is a Potent Inhibitor of Cell Proliferation in HaCaT Cells

The search for specific anticancer drugs that do not interfere with DNA synthesis or influence the cytoskeleton has led to the development of modified phospholipids with antiproliferative properties. These compounds cause remodeling of the structure and function of plasma membranes. Recently, we described novel compounds, the glycosidated phospholipids, that surprisingly inhibit cell proliferation. These compounds contain α‐D‐glucose in the sn‐2 position of the glycerol backbone of phosphatidylcholine (PC) and platelet‐activating factor (PAF), which gives rise to 2‐glucophosphatidylcholine (Glc‐PC) and 1‐O‐octadecyl‐2‐O‐α‐d‐glucopyranosyl‐sn‐2‐glycero‐3‐phosphatidylcholine (Glc‐PAF), respectively. Glc‐PC and Glc‐PAF inhibit the growth of HaCaT cells at nontoxic concentrations. Here we report the introduction of myo‐inositol, in place of α‐D‐glucose, in the sn‐2 position of the glycerol backbone; this leads to two diastereomeric 1‐O‐octadecyl‐2‐O‐(2‐(myo‐inositolyl)‐ethyl)‐sn‐glycero‐3‐(R/S)‐phosphatidylcholines (Ino‐C2‐PAF). The inositol‐containing PAF enhances the antiproliferative capacity (IC50=1.8 μM) and reduces the cytotoxicity relative to Glc‐PAF (LC50=15 μM). Through biological assays, we showed that, in HaCaT cells, Ino‐C2‐PAF causes upregulation of the keratinocyte‐specific differentiation marker involucrin, increases the activity of the differentiation marker transglutaminase, and induces apoptosis at nontoxic concentrations. Ino‐C2‐PAF therefore seems to be a promising candidate for development as an antiproliferative drug for the treatment of hyperproliferative diseases of the skin.

A stereodivergent synthesis of beta-hydroxy-alpha-methylene lactones via vinyl epoxides.

A catalytic diastereoselective sulfonium ylide epoxidation of aldehydes furnished original vinyl epoxides, having an MBH backbone. These highly functionalized building blocks were used for a formal synthesis of the antibiotic conocandin, and opened up a stereodivergent route towards beta-hydroxy-alpha-methylene lactones, core units of naturally occurring compounds. Under acidic conditions, the oxiranes were mainly transformed, with moderate to good yields, into trans beta-hydroxy-alpha-methylene lactones. On the other hand, a user-friendly palladium-catalysed CO2 insertion and cyclisation sequence gave the cis beta-hydroxy-alpha-methylene lactone counterparts along with an interesting cis-trans equilibration of the pi-allyl intermediates.

Cobalt-Catalyzed Reductive Multicomponent Synthesis of β-Hydroxy- and β-Aminocarbonyl Compounds under Mild Conditions.

The cobalt-catalyzed multicomponent reaction between sp2 -hybridized organic halides, Michael acceptors, and unsaturated electrophiles has been developed. The reaction proceeds through a formal conjugate addition/aldol or aza-aldol (Mannich) tandem reaction initiated by the in situ metalation of the organic halide by cobalt catalysis. The essentially new reaction conditions that have been developed are very mild and atom-economic. Under these conditions, a broad range of β-hydroxy- and β-aminocarbonyl compounds are obtained in good to high yields.

Semisynthetic neoboutomellerone derivatives as ubiquitin-proteasome pathway inhibitors

The interesting pharmacological properties of neoboutomellerones 1 and 2 were the basis for the assembly of a small library of analogues consisting of natural products isolated from the plant Neoboutonia melleri and of semisynthetic derivatives. As the two enone systems (C23-C24a and C1-C3) and the two hydroxyls groups (C22 and C26) of neoboutomellerones are required for activity, modifications were focused on these functional groups. Biological evaluation by using a cellular assay for proteasome activity provided clues regarding the mechanism of action of these natural products and synthetic derivatives. Certain neoboutomellerone derivatives inhibited the proliferation of human WM-266-4 melanoma tumor cells at submicromolar concentration and warrant evaluation as anticancer agents.

A two-step, catalytic synthesis of δ-hydroxy-γ-lactones from allylic acetates and bis(trimethylsilyl)ketene acetals

Bis(trimethylsilyl) ketene acetals react successively with nallylic acetates, in the presence of Pd(0) then with nH2O2, in the presence of methyltrioxorhenium, to give nδ-hydroxy-γ-lactones via γ-unsaturated ncarboxylic acids.