Synthesis and Biological Activity of a New Indenoisoquinoline Copper Derivative as a Topoisomerase I Inhibitor.

Topoisomerases are interesting targets in cancer chemotherapy. Here, we describe the design and synthesis of a novel copper(II) indenoisoquinoline complex, WN198. The new organometallic compound exhibits a cytotoxic effect on five adenocarcinoma cell lines (MCF-7, MDA-MB-231, HeLa, HT-29, and DU-145) with the lowest IC50 (0.37 ± 0.04 µM) for the triple-negative MDA-MB-231 breast cancer cell line. Below 5 µM, WN198 was ineffective on non-tumorigenic epithelial breast MCF-10A cells and Xenopus oocyte G2/M transition or embryonic development. Moreover, cancer cell lines showed autophagy markers including Beclin-1 accumulation and LC3-II formation. The DNA interaction of this new compound was evaluated and the dose-dependent topoisomerase I activity starting at 1 µM was confirmed using in vitro tests and has intercalation properties into DNA shown by melting curves and fluorescence measurements. Molecular modeling showed that the main interaction occurs with the aromatic ring but copper stabilizes the molecule before binding and so can putatively increase the potency as well. In this way, copper-derived indenoisoquinoline topoisomerase I inhibitor WN198 is a promising antitumorigenic agent for the development of future DNA-damaging treatments.

A Novel Copper(II) Indenoisoquinoline Complex Inhibits Topoisomerase I, Induces G2 Phase Arrest, and Autophagy in Three Adenocarcinomas.

Topoisomerases, targets of inhibitors used in chemotherapy, induce DNA breaks accumulation leading to cancer cell death. A newly synthesized copper(II) indenoisoquinoline complex WN197 exhibits a cytotoxic effect below 0.5 µM, on MDA-MB-231, HeLa, and HT-29 cells. At low doses, WN197 inhibits topoisomerase I. At higher doses, it inhibits topoisomerase IIα and IIß, and displays DNA intercalation properties. DNA damage is detected by the presence of γH2AX. The activation of the DNA Damage Response (DDR) occurs through the phosphorylation of ATM/ATR, Chk1/2 kinases, and the increase of p21, a p53 target. WN197 induces a G2 phase arrest characterized by the unphosphorylated form of histone H3, the accumulation of phosphorylated Cdk1, and an association of Cdc25C with 14.3.3. Cancer cells die by autophagy with Beclin-1 accumulation, LC3-II formation, p62 degradation, and RAPTOR phosphorylation in the mTOR complex. Finally, WN197 by inhibiting topoisomerase I at low concentration with high efficiency is a promising agent for the development of future DNA damaging chemotherapies.

Capture of Gaseous Iodine in Isoreticular Zirconium-Based UiO-n Metal-Organic Frameworks: Influence of Amino Functionalization, DFT Calculations, Raman and EPR Spectroscopic Investigation.

A series of Zr-based UiO-n MOF materials (n=66, 67, 68) have been studied for iodine capture. Gaseous iodine adsorption was collected kinetically from a home-made set-up allowing the continuous measurement of iodine content trapped within UiO-n compounds, with organic functionalities (-H, -CH3 , -Cl, -Br, -(OH)2 , -NO2 , -NH2 , (-NH2 )2 , -CH2 NH2 ) by in-situ UV-Vis spectroscopy. This study emphasizes the role of the amino groups attached to the aromatic rings of the ligands connecting the {Zr6 O4 (OH)4 } brick. In particular, the preferential interaction of iodine with lone-pair groups, such as amino functions, has been experimentally observed and is also based on DFT calculations. Indeed, higher iodine contents were systematically measured for amino-functionalized UiO-66 or UiO-67, compared to the pristine material (up to 1211 mg/g for UiO-67-(NH2 )2 ). However, DFT calculations revealed the highest computed interaction energies for alkylamine groups (-CH2 NH2 ) in UiO-67 (-128.5 kJ/mol for the octahedral cavity), and pointed out the influence of this specific functionality compared with that of an aromatic amine. The encapsulation of iodine within the pore system of UiO-n materials and their amino-derivatives has been analyzed by UV-Vis and Raman spectroscopy. We showed that a systematic conversion of molecular iodine (I2 ) species into anionic I- ones, stabilized as I- ⋅⋅⋅I2 or I3 - complexes within the MOF cavities, occurs when I2 @UiO-n samples are left in ambient light.

Visible-Light-Driven CarboxyLic Amine Protocol (CLAP) for the Synthesis of 2-Substituted Piperazines under Batch and Flow Conditions.

Piperazines are privileged scaffolds in medicinal chemistry. Disclosed herein is a visible-light-promoted decarboxylative annulation protocol between a glycine-based diamine and various aldehydes to access 2-aryl, 2-heteroaryl, as well as 2-alkyl piperazines. The iridium-based complex [Ir(ppy)2(dtbpy)]PF6 and carbazolyl dicyanobenzene 4CzIPN were found to be the photocatalysts of choice to efficiently perform the transformation under mild conditions, whether in batch or in continuous mode.

Effects of Ferrocenyl 4-(Imino)-1,4-Dihydro-quinolines on Xenopus laevis Prophase I - Arrested Oocytes: Survival and Hormonal-Induced M-Phase Entry.

Xenopus oocytes were used as cellular and molecular sentinels to assess the effects of a new class of organometallic compounds called ferrocenyl dihydroquinolines that have been developed as potential anti-cancer agents. One ferrocenyl dihydroquinoline compound exerted deleterious effects on oocyte survival after 48 h of incubation at 100 µM. Two ferrocenyl dihydroquinoline compounds had an inhibitory effect on the resumption of progesterone induced oocyte meiosis, compared to controls without ferrocenyl groups. In these inhibited oocytes, no MPF (Cdk1/cyclin B) activity was detected by western blot analysis as shown by the lack of phosphorylation of histone H3. The dephosphorylation of the inhibitory Y15 residue of Cdk1 occurred but cyclin B was degraded. Moreover, two apoptotic death markers, the active caspase 3 and the phosphorylated histone H2, were detected. Only 7-chloro-1-ferrocenylmethyl-4-(phenylylimino)-1,4-dihydroquinoline (8) did not show any toxicity and allowed the assembly of a histologically normal metaphase II meiotic spindle while inhibiting the proliferation of cancer cell lines with a low IC50, suggesting that this compound appears suitable as an antimitotic agent.

Reductive Amination/Cyclization of Methyl Levulinate with Aspartic Acid: Towards Renewable Polyesters with a Pendant Lactam Unit.

Environmental regulation and depletion of fossil resources are boosting the search for new polymeric materials produced from biomass. Here, the synthesis of a new diester bearing a pendant lactam unit from methyl levulinate and aspartic acid is reported. The palladium-catalyzed reductive amination/cyclization sequence was carefully optimized to afford the diacid with high yield (>95 %). In a second step, the compound was esterified to give the corresponding diester. The latter monomer was copolymerized with α-ω linear diols, yielding polyesters with molecular weights up to 20.5 kg mol-1 .

Synthesis and biological activity of ferrocenyl indeno[1,2-c]isoquinolines as topoisomerase II inhibitors.

Three series of indeno[1,2-c]isoquinolines bearing a ferrocenyl entity were synthesized and evaluated for DNA interaction, topoisomerase I and II inhibition, and cytotoxicity against breast human cancer cell lines. In the first and second series, the ferrocenyl scaffold was inserted as a linker between the two nitrogen atoms. In the last series, it was introduced at the end of the carbon chain. The present study showed that the ferrocenyl entity enhanced the topoisomerase II inhibition. Most compounds showed a potent growth inhibitory effect on MDA-MB-231 cell line with the IC50 in µM range.

Synthesis and in vitro antiplasmodial activity of ferrocenyl aminoquinoline derivatives.

The aim of this study was to synthesize a series of ferrocenyl 4-aminoquinolines and to evaluate their activities against Plasmodium falciparum F32 (chloroquine-sensitive) and FCB1 and K1 (chloroquino-resistant). Some of the ferrocenyl compounds exhibited in vitro antiplasmodial activity in the nM range. In particular, (1R,4R)-N1-(7-chloroquinolin-4-yl)-N4-(ferrocenylmethyl)-N4-methylcyclohexane-1,4-diamine 17 presented the lowest IC50 value (26 nM) against CQ-resistant strains.

Enantioselective organocatalytic partial transfer hydrogenation of lactone-fused quinolines.

The first enantioselective synthesis of 4-aza-podophyllotoxin derivatives by partial transfer hydrogenation of lactone-fused quinolines was achieved using a chiral Brønsted acid catalyst. This reaction was extended to a large scope of substrates with good yields and enantioselectivities.

Capture of iodine in highly stable metal-organic frameworks: a systematic study.

A series of aluminum-based metal-organic frameworks were investigated for sorption of iodine (I2) in cyclohexane. The best sorption uptake was obtained with solids decorated by electro-donor groups attached either to the organic ligand (-NH2) or the inorganic sub-network (-OH).

The next chapter in MOF pillaring strategies: trigonal heterofunctional ligands to access targeted high-connected three dimensional nets, isoreticular platforms.

A new pillaring strategy, based on a ligand-to-axial approach that combines the two previous common techniques, axial-to-axial and ligand-to-ligand, and permits design, access, and construction of higher dimensional MOFs, is introduced and validated. Trigonal heterofunctional ligands, in this case isophthalic acid cores functionalized at the 5-position with N-donor (e.g., pyridyl- or triazolyl-type) moieties, are designed and utilized to pillar pretargeted two-dimensional layers (supermolecular building layers, SBLs). These SBLs, based on edge transitive Kagomé and square lattices, are cross-linked into predicted three-dimensional MOFs with tunable large cavities, resulting in isoreticular platforms.

Synthesis and antimycobacterial activity of a series of ferrocenyl derivatives.

In this work we reported the synthesis and evaluation of Mycobacterium tuberculosis activities in vitro of a series of twenty five ferrocenyl derivatives: ferrocenyl amides derived from nicotinamide and pyrazinamide, ferrocenyl pyridinyl, quinolyl and acridinylhydrazones. In particular ferrocenyl acylhydrazones 7 and 8 and ferrocenylquinoxaline amide 57 showed interesting antimycobacterial activities.

N-trialkylsilyl bistrifluoromethanesulfonimides (R3SiNTf2) are powerful catalysts for the highly efficient alpha-amido alkylation reactions of silicon-based nucleophiles.

[reaction: see text] In situ formed N-trialkylsilyl bistrifluoromethanesulfonimides (R3SiNTf2) species have been shown to efficiently catalyze the nucleophilic substitution reactions of chiral 5-oxypyrrolidin-2-ones by silicon-based nucleophiles. The reaction rates were significantly accelerated in comparison to the cases where the usual triflate catalysts are used. Adducts were obtained in high yields and usual stereoselectivities within short reaction times, and the process was compatible with a semipreparative scale.

Toward improving the chemistry of N-acyliminium ions: nucleophilic substitution reactions of pyrrolidinone derivatives with trialkylsilyl nucleophiles catalyzed by triisopropylsilyltrifluoromethane sulfonate (TIPSOTf).

[reaction: see text] Nucleophilic substitution reactions of racemic and chiral 5-acetoxy-, 5-ethoxy-, and 5-methoxypyrrolidin-2-ones by silicon-based nucleophiles were efficiently catalyzed by TIPSOTf. This process was found to be general and accommodates a broad range of substrate-nucleophile combinations.