Ketone Moiety Research Articles

Synthesis of Novel ent-Kaurane-Type Diterpenoid Derivatives Effective for Highly Aggressive Tumor Cells.

We have designed and synthesized 6 ent-Kaurane-type diterpenoid derivatives containing α,β-unsaturated ketone moieties. In vitro, activity was evaluated against three human tumor cell lines and a rat myogenic cell line (HepG2, NSCLC-H292, SNU-1040, L6) by MTT assay. All the tested compounds exhibited comparable or higher activity than DDP and eriocalyxin B. Compounds 16, 17 and 18 are promising anti-tumor leads due to their cytotoxic potencies and higher selectivity, with SI values of 161.06, 47.80 and 128.20, respectively.

Biosynthetically Inspired Transformation of Iboga to Monomeric Post-iboga Alkaloids

Summary Organisms have evolved to produce various natural products from a common precursor as a means of maximizing the number of secondary metabolites, thus acquiring selectional advantages. By adopting nature's divergent biosynthetic strategy, we transformed (+)-catharanthine to various iboga and post-iboga alkaloids, including (−)-conodusine A, (+)-conodusines B and C, (−)-voatinggine, (−)-tabertinggine, and (+)-dippinine B. Well-orchestrated oxidations and reorganizations of catharanthine derivatives enabled chemical access to these natural products.

Stable 2D Bisthienoacenes: Synthesis, Crystal Packing, and Photophysical Properties.

Two novel 2D bisthienoacenes with annulated thiophene units at different positions were developed. Both 1,2- and 1,4-addition of the α,β-unsaturated ketone moieties lead to the major formation of four-fold alkylsilylethynyl substituted 2D heteroacenes (namely BTT-4TIPS and BTP-4TIPS). The photophysical, electrochemical properties, crystal packing structures, and charge carrier transport performances were investigated in detail.

Osteoconductive Enhancement of Polyether Ether Ketone: A Mild Covalent Surface Modification Approach.

Polyether ether ketone (PEEK, 1) is an important material for the fabrication of implants employed in spinal fusion surgery. Although its radiolucency and favorable elastic modulus have made PEEK an attractive choice for interbody fusion devices, its poor osseointegrative properties prevent the formation of a strong union between implant and surrounding bone structures and remain a major liability. Recent advancements in PEEK surface technology have resulted in improved osseointegration; however, the identification of an ideal implant material has proven challenging. In this manuscript, we describe our preliminary investigation into the realm of PEEK-based fusion devices that has culminated in the discovery of a mild, solution-based process for the preparation of covalently surface modified PEEK biomaterials that display enhanced osteoconductive properties. Surface modification occurred under mild reaction conditions via the acid-mediated addition of various commercially available hydrophilic oxyamine and hydrazine nucleophiles to the diaryl ketone moiety of PEEK. The resulting modified surfaces have been confirmed by contact angle measurements and X-ray photoelectron spectroscopy (XPS). Subsequent in vitro studies demonstrated the enhanced capability of several modified PEEK variants to promote osteogenic differentiation and mineralized calcium deposition relative to unmodified PEEK surfaces.

Synthesis of Benzannulated Medium-ring Lactams via a Tandem Oxidative Dearomatization-Ring Expansion Reaction.

Medium-ring natural products exhibit diverse biological activities but such scaffolds are underrepresented in probe and drug discovery efforts due to the limitations of classical macrocyclization reactions. We report herein a tandem oxidative dearomatization-ring-expanding rearomatization (ODRE) reaction that generates benzannulated medium-ring lactams directly from simple bicyclic substrates. The reaction accommodates diverse aryl substrates (haloarenes, aryl ethers, aryl amides, heterocycles) and strategic incorporation of a bridgehead alcohol generates a versatile ketone moiety in the products amenable to downstream modifications. Cheminformatic analysis indicates that these medium rings access regions of chemical space that overlap with related natural products and are distinct from synthetic drugs, setting the stage for their use in discovery screening against novel biological targets.

A Dual-Modal Molecular Probe for Near-Infrared Fluorescence and Photoacoustic Imaging of Peroxynitrite.

Peroxynitrite (ONOO-), a reactive and short-lived biological oxidant, is closely related with many pathological conditions such as cancer. However, real-time in vivo imaging of ONOO- in tumors remains to be challenging. Herein, we develop a near-infrared fluorescence (NIRF) and photoacoustic dual-modal molecular probe (CySO3CF3) composed of a water-soluble hemicyanine dye caged with a trifluoromethyl ketone moiety for in vivo imaging of ONOO-. The trifluoromethyl ketone moiety can undergo a series of ONOO--induced cascade oxidation-elimination reactions, leading to sensitive and specific fluorescence and photoacoustic turn-on responses toward ONOO-; whereas, a zwitterionic structure of the hemicyanine component ensures good water-solubility. Thus, CySO3CF3 not only specifically detects ONOO- in solution and cells with the limit of detection down to 53 nM but also allows for NIRF and photoacoustic dual-modal imaging of ONOO- in the tumors of living mice.

Enzymatic Desymmetrization of 19‐nor‐Vitamin D3 A‐Ring Synthon Precursor: Synthesis, Structure Elucidation, and Biological Activity of 1α,25‐Dihydroxy‐3‐epi‐19‐nor‐vitamin D3 and 1β,25‐Dihydroxy‐19‐nor‐vitamin D3

AbstractIn a search for novel vitamin D derivatives of potential therapeutic value, structurally simple but synthetically challenging A‐ring epimers of the 19‐nor‐Calcitriol [19‐nor‐1α,25‐(OH)2‐D3] at C1 and C3 were efficiently synthesized. Both analogues (1‐epi‐ and 3‐epi‐19‐nor‐Calcitriol) were obtained through a convergent synthesis starting from cis,cis‐1,3,5‐cyclohexanetriol and the protected 25‐hydroxy Grundmann′s ketone. After Julia‐Kocienski coupling of the corresponding C,D‐ring/side chain sulfone fragment with the A‐ring ketone moiety, both vitamin D analogues were isolated. The critical point was how to determine the structural configuration of both diastereoisomers since similar 1H NMR spectra were observed. For that, a biocatalytic approach was crucial in the synthesis of orthogonally protected derivatives. NMR spectroscopy allows the unambiguous identification of these compounds and as a result the structural elucidation of the desired vitamin D diastereomeric analogues. Affinity studies demonstrated that these 1,25‐19‐nor analogues have a very low affinity for the vitamin D receptor compared with 1α,25‐dihydroxyvitamin D3 or 1α,25‐dihydroxy‐19‐nor‐vitamin D3. In addition, these analogues have a lower binding affinity for the human vitamin D binding protein than the natural hormone. In vitro cell culture studies revealed that synthesized analogues were less active than 1α,25‐dihydroxyvitamin D3 in inhibiting cell proliferation.magnified image

Synthesis and anti-proliferative activity of allogibberic acid derivatives containing 1,2,3-triazole pharmacophore

Sixty novel allogibberic acid derivatives containing 1,2,3-triazole pharmacophore were designed and synthesized. The key chemical processes include aromatization of the A ring in gibberellins, formation of allogibberic azides and its copper mediated Huisgen 1,3-dipolar cycloaddition with alkynes. A number of hybrids containing α,β-unsaturated ketone moiety exhibited excellent in vitro cytotoxic activities. Some of the hybrids were more selective to MCF-7 and SW480 cell lines with IC50 values at least 8-fold more cytotoxic than cisplatin (DDP). The most potent compounds C43 and C45 are more cytotoxic than cisplatin (DDP) against all tested five tumor cell lines, with IC50 values of 0.25–1.72 µM. Mechanism of action studies indicated that allogibberic-triazole derivative C45 could induce the S phase cell cycle arrest and apoptosis in SMMC-7721 cell lines.

An efficient fluorescent probe for rapid sensing of different concentration ranges of cysteine with two-stage ratiometric signals

A diketopyrrolopyrrole-based fluorescent probe (DPP-AC) for rapid sensing of different concentration ranges of cysteine (Cys) has been designed and synthesized, where acrylate group and α,β-unsaturated ketone moiety on DPP-AC are employed as the high and low sensitivity sites, respectively. On the basis of proposed strategy, probe DPP-AC showed ratiometric fluorescent change from 605 nm to 578 nm in presence of low concentration of Cys because of the conjugate addition-cyclization-elimination sequence reaction of acrylate group of DPP-AC with Cys. The addition of excess Cys caused second stage of ratiometric fluorescent change from 578 nm to 560 nm, which due to the Michael addition reaction between α,β-unsaturated ketone of DPP-AC and Cys. Moreover, different concentration ranges of cysteine detection can be completed in 6 min at room temperature. The limit of detection (LOD) was found to be 0.18 μM and 2.9 μM in less and excess Cys ranges, respectively. Furthermore, probe DPP-AC possessed highly selective property to differentiate Cys over glutathione and homocysteine. DPP-AC was also successfully used in cell imaging.

Selective On/Off-Nitroxides as Radical Probes to Investigate Non-radical Enzymatic Activity by Electron Paramagnetic Resonance.

A nitroxide carrying a peptide specific to the binding pocket of the serine proteases chymotrypsin and cathepsin G is prepared. This peptide is attached as an enol ester to the nitroxide. Upon enzymatic hydrolysis of the peptide, the enol ester moiety is transformed into a ketone moiety. This transformation affords a difference of 5 G in phosphorus hyperfine coupling constant between the electronic paramagnetic resonance (EPR) signals of each nitroxide. This property is used to monitor the enzymatic activity of chymotrypsin and cathepsin G by EPR. Michaelis constants were determined and match those reported for conventional optical probes.

Sequential Modification of ADMET Polyketone via Oxime Chemistry and Electrophilic Alkoxyetherification

Post-polymerization modification is a facile and efficient method for the generation of diverse functional polymers. Herein, polymer-based molecular arrays were obtained by using sequential modification. First, periodic polyketone P0 was synthesized via acyclic diene metathesis (ADMET) polymerization of α,ω-diene M0. Oxime chemistry was employed in the functionalization of the ketone moieties of P0 using three commercially available alkoxyamine hydrochlorides. Finally, electrophilic alkoxyetherification, a four-component reaction, was employed in the modification of alkene groups on polymer main chains using N-bromosuccinimide (NBS), tetrahydrofuran, and fluorinated carboxylic acid. Complete conversion of reactive sites was observed in both steps, and the two modification reactions exhibited excellent compatibility. The thermal properties of the polymers as thermal stability, and glass transition and melting behaviours were investigated by thermal gravimetric analysis (TGA) and differential scanning calorimetry (DSC).

Occurrence, biological activity and metabolism of 6-shogaol.

As one of the main bioactive compounds of dried ginger, 6-shogaol has been widely used to alleviate many ailments. It is also a major pungent flavor component, and its precursor prior to dehydration is 6-gingerol, which is reported to be responsible for the pungent flavor and biological activity of fresh ginger. Structurally, gingerols including 6-gingerol have a β-hydroxyl ketone moiety and is liable to dehydrate to generate an α,β-unsaturated ketone under heat and/or acidic conditions. The conjugation of the α,β-unsaturated ketone skeleton in the chemical structure of 6-shogaol explicates its higher potency and efficacy than 6-gingerol in terms of antioxidant, anti-inflammatory, anticancer, antiemetic and other bioactivities. Research on the health benefits of 6-shogaol has been conducted and results have been reported recently; however, scientific data are scattered due to a lack of systematic collection. In addition, action mechanisms of the preventive and/or therapeutic actions of 6-shogaol remain obscurely non-collective. Herein, we review the preparations, biological activity and mechanisms, and metabolism of 6-shogaol as well as the properties of 6-shogaol metabolites.

Periodic Trends in the Binding of a Phosphine-Tethered Ketone Ligand to Fe, Co, Ni, and Cu.

π-Coordinating ligands are commonly found in intermediate structures in homogeneous catalysis, and are gaining interest as supporting ligands for the development of cooperative catalysts. Herein, we systematically investigate the binding of the ketone group, a strongly accepting π ligand, to mid-to-late metals of the first transition series. To this end, the coordination of 2,2'-bis(diphenylphosphino)benzophenone (Ph dpbp), which features a ketone moiety flanked by two strongly binding P-donor groups, to Fe, Co, Ni, and Cu was explored. The ketone moiety does not bind to the metal in MII complexes, whereas MI complexes (Fe, Co, Ni) adopt an η2 (C,O) coordination. A structural and computational investigation of periodic trends in this series was performed. These data suggest that the coordination of the ketone to MI can mostly be described by the resonance extremes of the Dewar-Chatt-Duncanson model, that is, the π complex and the metallaoxacycle extreme, with a possible minor contribution from a ketyl radical resonance structure in the case of the iron complex.

Substituent-Directed Regioselective Azidation: Copper-Catalyzed C-H Azidation and Iodine-Catalyzed Dearomatizative Azidation of Indole.

Azidation of indoles using iodine and copper bromide as catalysts under ambient reaction conditions is presented. The regioselectivity is directed by the substituent at the C3-position of indole. A radical stabilizing group such as an ester or ketone moiety at the C3-position of indole leads to azidation at the C2-position, whereas a less radical stabilizing group such as an alkyl or amide group at the C3-position of indole furnishes the 3-azidooxindole product. This protocol is mild and efficient to obtain several 2-azidoindole derivatives and 3-azidooxindole derivatives in moderate to good yields. The reaction conditions hold well for gram-scale synthesis.

Enantioselective Total Synthesis of 3β-Hydroxy-7β-kemp-8(9)-en-6-one, a Diterpene Isolated from Higher Termites.

The first total synthesis of the title diterpene was accomplished starting from the Wieland-Miescher ketone. A diastereoselective sulfa-Michael addition enabled the generation of the delicate β,γ-unsaturated ketone moiety, while the tetracyclic kempane skeleton was readily constructed through domino metathesis.

Novel α, β-Unsaturated Sophoridinic Derivatives: Design, Synthesis, Molecular Docking and Anti-Cancer Activities.

Using sophoridine 1 and chalcone 3 as the lead compounds, a series of novel α, β-unsaturated sophoridinic derivatives were designed, synthesized, and evaluated for their in vitro cytotoxicity. Structure-activity relationship (SAR) analysis indicated that introduction of α, β-unsaturated ketone moiety and heterocyclic group might significantly enhance anticancer activity. Among the compounds, 2f and 2m exhibited potential effects against HepG-2 and CNE-2 human cancer cell lines. Furthermore, molecular docking studies were performed to understand possible docking sites of the molecules on the target proteins and the mode of binding. This work provides a theoretical basis for structural optimizations and exploring anticancer pathways of this kind of compound.

Star-shaped Polymers through Simple Wavelength-Selective Free-Radical Photopolymerization.

Star-shaped polymers represent highly desired materials in nanotechnology and life sciences, including biomedical applications (e.g., diagnostic imaging, tissue engineering, and targeted drug delivery). Herein, we report a straightforward synthesis of wavelength-selective multifunctional photoinitiators (PIs) that contain a bisacylphosphane oxide (BAPO) group and an α-hydroxy ketone moiety within one molecule. By using three different wavelengths, these photoactive groups can be selectively addressed and activated, thereby allowing the synthesis of ABC-type miktoarm star polymers through a simple, highly selective, and robust free-radical polymerization method. The photochemistry of these new initiators and the feasibility of this concept were investigated in unprecedented detail by using various spectroscopic techniques.

Synthesis and cytotoxicity against KB and NCI-H187 cell lines of sporogen AO-1 analogues

20 Analogues of sporogen AO-1 were synthesized by chemical modification at α,β-unsaturated carbonyl, 3-hydroxyl and vinylic methyl groups of sporogen AO-1 precursor, and were evaluated for their cytotoxic activities against human oral epidermoid carcinoma (KB) and human small cell lung (NCI-H187) cancer cell lines. Structure-activity relationship study indicated the importance of α,β-unsaturated carbonyl moiety for both cancer cell lines. Vinylic methyl and R-configuration of 3-hydroxyl group were crucial for cytotoxicity toward KB cells. In contrast, conversion of vinylic methyl and 3-hydroxyl groups to ketone moieties afforded triketone 19 which displayed comparable cytotoxicity against NCI-H187 cells lines to sporogen AO-1, and was more potent than ellipticine, a standard drug. Interestingly, compound 19 was weakly cytotoxic toward Vero cells, whereas sporogen AO-1 showed strong cytotoxicity.

Isobenzofuranone- and Chromone-Based Blue Delayed Fluorescence Emitters with Low Efficiency Roll-Off in Organic Light-Emitting Diodes

Significant efforts have been devoted to the development of novel efficient blue-emitting molecules for organic light-emitting diode (OLED) applications. Blue organic emitters exhibiting thermally activated delayed fluorescence (TADF) have the potential to achieve ∼100% internal electroluminescence quantum efficiency in OLEDs. In this paper, we report a promising molecular design strategy for obtaining appropriate high singlet and triplet excited energies, short exciton lifetimes, and high quantum efficiencies in blue TADF emitters. We introduce isobenzofuranone and chromone containing a cyclic ketone or lactone moiety as effective acceptor building units to construct donor–acceptor TADF emitters. Owing to their small singlet–triplet energy splitting, properly contracted π-conjugation, and weakened intramolecular charge-transfer character, these new emitters display strong blue TADF emissions with high photoluminescence quantum yields (53–92%) and notably short TADF emission lifetimes (2.8–4.3 μs) in thin...

Binding of the Microbial Cyclic Tetrapeptide Trapoxin A to the Class I Histone Deacetylase HDAC8.

Trapoxin A is a microbial cyclic tetrapeptide that is an essentially irreversible inhibitor of class I histone deacetylases (HDACs). The inhibitory warhead is the α,β-epoxyketone side-chain of (2S,9S)-2-amino-8-oxo-9,10-epoxydecanoic acid (l-Aoe), which mimics the side-chain of the HDAC substrate acetyl-l-lysine. We now report the crystal structure of the HDAC8-trapoxin A complex at 1.24 Å resolution, revealing that the ketone moiety of l-Aoe undergoes nucleophilic attack to form a zinc-bound tetrahedral gem-diolate that mimics the tetrahedral intermediate and its flanking transition states in catalysis. Mass spectrometry, activity measurements, and isothermal titration calorimetry confirm that trapoxin A binds tightly (Kd = 3 ± 1 nM) and does not covalently modify the enzyme, so the epoxide moiety of l-Aoe remains intact. Comparison of the HDAC8-trapoxin A complex with the HDAC6-HC toxin complex provides new insight regarding the inhibitory potency of l-Aoe-containing natural products against class I and class II HDACs.