Triptolide is a diterpene triepoxide isolated from Tripterygium wilfordii, a Chinese medicinal plant and possessing a wealth of biological activities. In order to produce more soluble derivatives of triptolide, its 14-amino analogue was prepared. Initial attempts at its preparation using classical displacements led to rearranged compounds and success was finally met using carefully controlled Borch conditions. 14-Deoxy-14-aminotriptolide was thus prepared for the first time and it was found 10 times less cytotoxic than the parent compound. (C) 2016 Published by Elsevier Ltd.

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.

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 compoundsnamely the derivatives 12, 16, 31 and 32exhibited 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.

AbstractAnnulated diaminopyrimidines are prepared via Thorpe—Ziegler cyclization of various dinitriles followed by in situ reaction with cyanamides (II) in a one‐pot manner.

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.

Annulated diaminopyrimidines are prepared via Thorpe—Ziegler cyclization of various dinitriles followed by in situ reaction with cyanamides (II) in a one-pot manner.

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.

Thirty new cycloartane derivatives (1-3, 5-12, 14-32) have been isolated from the leaves of Neoboutonia melleri. Their novelty stems from the loss of one of the C-4 methyl groups (1-3, 5-12, 14-25, and 32) and from the presence of an "extra" carbon atom in the side chain (1-3, 5-12, 14-20, 26-29, and 30-32). Furthermore, compound 32 possesses a rare triterpene skeleton with the cyclopropane ring fused onto C-1 and C-10, instead of C-9 and C-10. The structures were determined by spectrometric means, chemical correlations, and X-ray crystallography of derivative 1c. The substitution pattern in ring A, with a cyclopropyl ring conjugated with an α,β-unsaturated carbonyl moiety, confers to the molecule a particular reactivity, giving rise to a formal inversion of the stereochemistry of the cyclopropane ring under UV irradiation. These compounds showed an interesting level of activity on the proteasome pathway, thus motivating their evaluation as possible anticancer agents. The large number of isolated compounds permitted a structure-activity relationship analysis, which showed that the presence of the two enone functions was a requirement for the activity.

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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.

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.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

The preparation of new enantiopure cyclic nitrones based on the 1-oxy-2,3-dihydro-imidazol-4-one ring is described. The addition of arylmagnesium or alkynylzinc reagents to these nitrones can be achieved with total enantio- and diastereoselectivity, leading to α,α-disubstituted amino-acid precursors.

A new enantiopure cyclic nitrone, a potential electrophilic alanine synthon, has been prepared. Its reaction with alkynylzinc reagents led to a tandem addition/cyclization reaction with complete regio- and stereoselectivity. The adducts are potential precursors of quaternary a-amino acids. ((c) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005).

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.

Bis(trimethylsilyl) ketene acetals react successively with allylic acetates, in the presence of Pd(0) then with H2O2, in the presence of methyltrioxorhenium, to give δ-hydroxy-γ-lactones via γ-unsaturated carboxylic acids.