Enediyne Compounds Research Articles

Synthesis, Reaction Mechanism, DNA Cleavage, and Antitumor Properties of Pyridazinedione‐Fused Enediynes

AbstractNatural enediyne antibiotics undergo thermally induced cycloaromatization under physiological conditions to generate highly reactive diradicals that effectively abstract hydrogen atoms from biomacromolecules like DNA, leading to DNA cleavage and inducing programmed cell death in tumor cells, exhibiting potent cytotoxicity and broad‐spectrum antitumor properties. In order to further explore promising synthetic analogues of natural enediynes, a 3,6‐pyridazinedione moiety was fused at the ene‐position, and 10 new enediyne compounds with different atoms at the propargylic positions were synthesized. Differential scanning calorimetry (DSC) and electron paramagnetic resonance results indicated that these enediynes exhibited a rather low onset temperature and the capability to generate radical species at physiological temperatures. Density functional theory (DFT) calculations demonstrated that the pyridazinedione moiety facilitates cascade rearrangement processes, thereby endowing the key cycloaromatization with a low energy barrier. The enediynes with propargylic oxygen exhibit strong DNA cleavage capabilities, and all pyridazinedione‐fused enediynes showed IC50 values in the range of several tens of micromolars against HeLa cells.

Jejucarbosides B-E, Chlorinated Cycloaromatized Enediynes, from a Marine Streptomyces sp.

Four new chlorinated cycloaromatized enediyne compounds, jejucarbosides B-E (1-4), were discovered together with previously-identified jejucarboside A from a marine actinomycete strain. Compounds 1-4 were identified as new chlorinated cyclopenta[a]indene glycosides based on 1D and 2D nuclear magnetic resonance, high-resolution mass spectrometry, and circular dichroism (CD) spectra. Jejucarbosides B and E bear a carbonate functional group whereas jejucarbosides C and D are variants possessing 1,2-diol by losing the carbonate functionality. It is proposed that the production of 1-4 occurs via Bergman cycloaromatization capturing Cl- and H+ in the alternative positions of a p-benzyne intermediate derived from a 9-membered enediyne core. Jejucarboside E (4) displayed significant cytotoxicity against human cancer cell lines including SNU-638, SK-HEP-1, A549, HCT116, and MDA-MB-231, with IC50 values of 0.31, 0.40, 0.25, 0.29, and 0.48 μM, respectively, while jejucarbosides B-D (1-3) showed moderate or no cytotoxic effects.

Preparation of Maleimide‐Based Enediynes with Propargyl Ester for Efficient Tumor Cell Suppression

AbstractAcyclic enediynes are much easier to be synthesized comparing to natural or synthetic cyclic enediynes. However, the conditions for their thermal reactions to produce free radicals through Bergman cyclization (BC) are typically demanding, limiting their applications as antitumor agents. On the other hand, the acyclic compounds with enyne‐allene structures prone to proceed through Myers‐Saito cyclization (MCS) under much milder conditions. Therefore, it is vital to design acyclic enediynes which can permit propargyl‐allenyl rearrangement and then undergo MSC at low temperature for antitumor applications. In this work, we synthesized a series of maleimide‐based enediyne compounds with propargyl ester functionalities. The facile propargyl‐allenyl tautomerization assisted by the maleimide group enabled the formation of enyne‐allene structures and the subsequent occurrence of MSC. The generation of free radicals, which further raised the reactive oxygen species level in physiological environments, was confirmed by electron paramagnetic resonance analysis. The highly reactive radicals showed excellent DNA‐cleaving ability as confirmed with DNA gel electrophoresis. In addition, this kind of acyclic enediynes effectively inhibited the proliferation of HeLa cells with half inhibition concentration down to submicromolar level, comparable or even superior to many clinically used antitumor agents, showing promising application aspect.

Enhancement of Cytotoxicity of Enediyne Compounds by Hyperthermia: Effects of Various Metal Complexes on Tumor Cells.

Enediyne natural products are a class of compounds that were recognized for their potential as chemotherapeutic agents many years ago, but found to be highly cytotoxic due to their propensity for low thermal activation. Bergman cyclization of the enediyne moiety produces a diradical intermediate, and may subsequently induce DNA damage and account for the extreme cytotoxicity. While difficulties in controlling the thermal cyclization reaction have limited the clinical use of cyclic enediynes, we have previously shown that enediyne activity, and thus toxicity at physiological temperatures can be modulated by metallation of acyclic enediynes. Furthermore, the cytotoxicity of "metalloenediynes" can be potentiated by hyperthermia. In this study, we characterized a suite of novel metallated enediyne motifs that usually induced little or no cytotoxicity when two different human cancer cell lines were treated with the compounds at 37°C, but showed a significant enhancement of cytotoxicity after cells were exposed to moderate hyperthermia during drug treatment. Cultured U-1 melanoma or MDA-231 breast cancer cells were treated with various concentrations of Cu, Fe and Zn complexes of the enediyne (Z)-N,N'-bis[1-pyridyl-2-yl-meth-(E)-ylidene]octa-4-ene-2,6-diyne-1,8-diamine (PyED) and clonogenic survival was assessed to determine the effects of the drugs at 37°C and 42.5°C. Toxicity at 37°C varied for each compound, but hyperthermia potentiated the cytotoxicity of each compound in both cell lines. Cytotoxicity was concentration-, time- and temperature-dependent. Heating cells during drug treatment resulted in enhanced apoptosis, but the role of cell cycle perturbation in the response of the cells to the drugs was less clear. Lastly, we showed that hyperthermia enhanced the number of DNA double-strand breaks (DSBs) induced by the compounds, and inhibited their repair after drug treatment. Thus, thermal enhancement of cytotoxicity may be due, at least in part, to the propensity of the enediyne moiety to induce DSBs, and/or a reduction in DSB repair efficiency. We propose that "tuning" of metalloenediyne toxicity through better-controlled reactivity could have potential clinical utility, since we envision that such compounds could be administered systemically as relatively non-toxic agents, but cytotoxicity could be enhanced in, and confined to a tumor volume when subjected to localized heating.

Self‐Delivery Nanoparticles of Amphiphilic Acyclic Enediynes for Efficient Tumor Cell Suppression

Summary of main observation and conclusionFour acyclic maleimide‐based enediyne compounds with different hydrophilicity were synthesized through Sonogashira reaction to reveal a self‐delivery antitumor drug platform. As proved by ESR analysis, the enediyne compounds undergo Bergman‐like cyclization and generate diradical intermediates at physiological temperature, which are able to induce DNA‐cleavage through the abstraction of H atoms from the sugar‐phosphate backbones. When the critical aggregation concentration is reached in water, the amphiphilic enediyne compounds self‐assemble into nanoparticles and possess the self‐delivery ability to be facilely admitted by tumor cells, resulting in greatly improved cytotoxicity (IC50 down to 10 μmol·L–1) and much higher tumor cell apoptosis rate (up to 86.6%) in comparison with either the hydrophilic or the lipophilic enediyne compound. The enhanced endocytosis of the amphiphilic enediyne compounds was further confirmed through confocal laser scanning microscopy analysis. The unveiled relationship between the hydrophilicity of enediyne drugs and their therapeutic efficacy will provide a guideline for the design of new self‐delivery drugs employed in medicinal applications.

Concurrent Radical Addition and [3+2] Cycloaddition between Nitrones and Maleimide‐Based Acyclic Enediynes

AbstractEnediyne compounds undergo Bergman cyclization while being activated with thermal or UV‐light triggers, and generate benzyne diradical intermediates, endowing their great potential as antitumor agents. The radical nature of the Bergman cyclization is generally confirmed through radical trapping experiments. While using phenyl tert‐butyl nitrone (PBN) as a radical trapping agent to study the Bergman cyclization of maleimide‐based enediyne compounds, we uncovered concurrent radical addition and [3+2] cycloaddition reactions between nitrones and enediyne compounds. The radical addition between the diradical intermediates and PBN was revealed through EPR analysis, while the [3+2] cycloaddition products were separated out and their structures were confirmed by NMR, HRMS and single crystal XRD analysis. Computational investigations showed that the energy barrier of the [3+2] cycloaddition was much lower than that of the Bergman reaction, corroborating the dominance of [3+2] cycloaddition between nitrone and enediyne compounds.

An acyclic enediyne anticancer compound attributed to a Bergman cyclization at physiological temperature

Enediyne cytotoxic drugs have attracted much attention because of their unique structure and potent anticancer activity. However, acyclic enediynes are long considered as inactive at physiological temperature due to their long C1-C6 distance. By adjusting the steric bulkiness of the functional groups at the alkynyl termini and the electron-withdrawing effect at the ene moiety, herein, a simple acyclic enediyne was designed and synthesized to achieve the onset of thermal Bergman cyclization at physiological temperature in polar solvents. The spontaneous generation of diradical intermediates was confirmed through EPR analysis and further supported by spin trapping experiment, radical indicator experiment, and high resolution MS analysis. The reactive diradicals generated in aqueous media induced single and double stranded cleavage of DNA, and showed high cytotoxicity to Hela cells. The IC50 value of the enediyne compound is comparable to many clinical used anti-tumor agents.

Cycloaromatization of Enediyne Compounds under the Action of Bromide Ions: Diradical/Zwitterionic/Anionic Pathways

AbstractCycloaromatization reactions of enediynes are renowned for their widespread applications and interesting reactivity characteristics. In the presence of a lithium halide and a weak acid, the cycloaromatization of cyclodeca‐1,5‐diyn‐3‐ene can be redirected away from the usual formation of a phenyl diradical towards a zwitterionic pathway. We extended this zwitterionic reaction system to other enediyne compounds and found that it offered good applicability to all‐carbon systems. However, in the case of maleimide‐based enediynes, only diradical (phenyl‐substituted) or anionic (butyl‐substituted) cyclization pathways were observed. Notably, the nucleophilic cyclization of maleimide‐based enediynes that was initiated by bromide ions exhibited a previously unreported C2−C7 cyclization pattern.

Unexpected [2+2] Photocycloaddition between Enediyne Compounds in Solid State

AbstractEnediyne compounds generally undergo a Bergman cyclization reaction under photo‐irradiation conditions. In this study, we observed an unexpected [2+2] photo‐cycloaddition between enediyne compounds under photo‐irradiation conditions. The structure of the cycloaddition product was confirmed through NMR, HR‐MS and single crystal XRD analyses. The cycloaddition was only preferred when the reaction was conducted in the solid state or under highly concentrated conditions in the solution state. In contrast, the use of dilute conditions favored the Bergman cyclization. The concentration dependence of the enediyne substrate was further confirmed by EPR and MALDI‐TOF analyses of the products. Computational investigations showed that the initial step would involve the formation of a [4+4] dimer structure, which would be converted to the [2+2] product in the second step. Interestingly, the [2+2] reaction was found to be reversible back to the enediyne monomer, where it could undergo a photo‐Bergman cyclization under diluted conditions, thereby providing a new method for the formation of “masked” enediynes for further applications.

A Novel Approach toward Polyfulvene: Cationic Polymerization of Enediynes

Enediyne compounds have found limited applications in polymer science and material chemistry due to the poor regioselectivity and/or the step-growth nature in their radical polymerizations. However, the cationic cyclization of enediynes exhibits a high regioselective 5-exo-dig mechanism, providing a new strategy for the synthesis of polyfulvene derivatives. The expected polymers were successfully produced by cationic polymerization of enediynes induced by CF3SO3H, and a well-defined conjugated structure was confirmed by NMR, IR, and UV–vis spectroscopy. GPC analysis shows a relatively narrow molecular weight distribution, and the molecular weight reaches up to 62.9 kDa. On the other hand, the structural features of the obtained polymers and the mechanism of the cationic polymerization were investigated through kinetic study and MALDI-TOF MS analysis, which revealed a second-order consumption of enediyne monomer and the polymerization being probably terminated through intramolecular abstraction of proton f...

ChemInform Abstract: Aerobic Dimerization of Enediyne Compounds: Construction of Naphthalene Frameworks.

AbstractA novel bimolecular oxygenative annulation of enediyne compounds leading to naphthalene frameworks is introduced.

Aerobic Dimerization of Enediyne Compounds: Construction of Naphthalene Frameworks.

The first bimolecular oxygenative annulation of enediyne compounds leading to naphthalene frameworks has been developed by using Pd(OAc)2 as the catalyst in the presence of NaI under O2 (1 atm). This reaction provided efficient access to a class of symmetric core-annulated naphthalenes by the homoannulation of enediyne-imides. Intriguingly, the crossover annulation of enediyne-imides and other functionalized enediynes could also be achieved by the same catalytic system, resulting in the formation of several unsymmetrical naphthalene derivatives. Preliminary mechanistic investigation using (18) O isotopic labelling and radical scavengers indicated that radical oxygen incorporation cascades might be involved in this conversion.

ChemInform Abstract: Palladium/Copper‐Catalyzed Aerobic Intermolecular Cyclization of Enediyne Compounds and Alkynes: Interrupting Cycloaromatization for (4 + 2) Cross‐Benzannulation.

AbstractThe process leads to formation of benzene rings and regioselective incorporation of 2 oxygen atoms at positions 2 and 6 from molecular oxygen and H2O, resp., to produce diketone systems.

Palladium/copper-catalyzed aerobic intermolecular cyclization of enediyne compounds and alkynes: interrupting cycloaromatization for (4 + 2) cross-benzannulation.

A tandem coupling-ketooxygenation reaction of readily accessible enediyne-carboxylic compounds with inner alkynes has been developed that utilizes the PdCl2/CuBr2 catalytic system under an O2 atmosphere and assembles a class of isoindolinones and o-acylbenzoic acids. The two oxygen atoms are regioselectively incorporated into enediyne units at the 1- and 6-positions from atmospheric molecular oxygen and H2O, respectively, during the present process. This study uncovered a formal [4C + 2C] benzannulation-diketonization of enediynes and alkynes via a coupling and decoupling strategy.

Biosynthesis of natural products containing β-amino acids.

Covering: up to January, 2014. We focus here on β-amino acids as components of complex natural products because the presence of β-amino acids produces structural diversity in natural products and provides characteristic architectures beyond those of ordinary α-L-amino acids, thus generating significant and unique biological functions in nature. In this review, we first survey the known bioactive β-amino acid-containing natural products including nonribosomal peptides, macrolactam polyketides, and nucleoside-β-amino acid hybrids. Next, the biosynthetic enzymes that form β-amino acids from α-amino acids and the de novo synthesis of β-amino acids are summarized. Then, the mechanisms of β-amino acid incorporation into natural products are reviewed. Because it is anticipated that the rational swapping of the β-amino acid moieties with various side chains and stereochemistries by biosynthetic engineering should lead to the creation of novel architectures and bioactive compounds, the accumulation of knowledge regarding β-amino acid-containing natural product biosynthetic machinery could have a significant impact in this field. In addition, genome mining of characteristic β-amino acid biosynthetic genes and unique β-amino acid incorporation machinery could lead to the discovery of new β-amino acid-containing natural products.

Generation and Characterization of a Distonic Biradical Anion Formed from an Enediynone Prodrug in the Gas Phase

A negatively charged biradical intermediate was successfully generated in the gas phase via cyclization of the deprotonated bicyclo[8.3.0]trideca-12-ene-2,7-diyn-1-one precursor. The inherent negative charge of this biradical allows its characterization via collision-activated dissociation and reactions with a variety of neutral substrates in an FT-ICR mass spectrometer. Although the biradical is unreactive toward reagents that usually react rapidly with positively charged biradicals, such as dimethyl disulfide, it reacts with the halogen-containing substrates carbon tetrachloride, carbon tetrabromide, and bromotrichloromethane via bromine or chlorine atom abstraction, which supports its biradical structure. The results presented in this study indicate that cyclizations commonly used in solution to form biradical intermediates from enediyne compounds may also occur in the gas phase.

Synthesis, Properties and Redox Behavior of Ene–Diyne Scaffolds Bearing 1‐ and 2‐Azulenyl Groups at the Periphery

AbstractEne–diyne systems possessing 1‐ and 2‐azulenyl groups at the periphery were prepared by palladium‐catalyzed cross‐coupling reaction of 1‐ and 2‐ethynylazulenes with 9‐dibromomethylene‐9H‐fluorene and 9,10‐bis(dibromomethylene)‐9,10‐dihydroanthracene or 2‐iodoazulene with 9,10‐bis(diethynylmethylene)‐9,10‐dihydroanthracene under Sonogashira–Hagihara conditions. The redox behavior of the ene–diyne compounds was examined by cyclic voltammetry (CV) and differential pulse voltammetry (DPV). Moreover, a significant color change of the ene–diyne derivatives was observed with visible spectroscopy under electrochemical reduction conditions.

Embedding Co3O4 nanoparticles in SBA-15 supported carbon nanomembrane for advanced supercapacitor materials

A three dimensional porous carbon nanomembrane (CNM), silica-supported CNM (SS-CNM), is developed by formation of a self-assembled monolayer of an enediyne compound on the surface of mesoporous silica (SBA-15) followed by Bergman cyclization and carbonization. The SS-CNM is applied as a conductive support for the electroactive material Co3O4 to fabricate advanced supercapacitors. A large fraction of Co3O4 clusters (66% of total weight) are impregnated in the SS-CNM host to form regularly packed nanorods with diameters of 7 nm. The specific capacitance of the supercapacitor electrode material reaches 1086 F g−1 (1645 F g−1 based on Co3O4) with aqueous electrolyte. This extraordinary high performance of the electrode material is attributed to the unique pore structure of the SS-CNM support that enhances the use of active material and shortens the transport path of ions and electrons.

Synthesis and [2+2] Cycloaddition with Tetracyanoethylene of Ene–Diyne Scaffolds Bearing Ferrocenes at the Periphery

AbstractThe ene–diyne systems 1 and 2, possessing ferrocenyl groups at the periphery, were prepared by a simple one‐pot Sonogashira–Hagihara coupling reaction of ethynylferrocene with 9‐dibromomethylene‐9H‐fluorene (4) and 9,10‐bis(dibromomethylene)‐9,10‐dihydroanthracene (5). Ene–diyne 1 reacted with tetracyanoethylene (TCNE) in a formal [2+2] cycloaddition reaction, followed by ring opening of the initially formed [2+2] cycloadduct, cyclobutene, to afford the corresponding 1,1,4,4‐tetracyanobutadiene (TCBD) derivative 6 in good yield. The redox behavior of the ene–diyne compounds 1 and 2, and the TCBD derivative 6 was examined by cyclic voltammetry (CV) and differential pulse voltammetry (DPV), which revealed their electrochemical oxidation properties with multi‐electron transfer depending on the number of ferrocene units in the molecule, in addition to the two‐electron reduction of the TCBD moiety in the case of TCBD derivative 6. Moreover, a significant color change was observed by visible spectroscopy under electrochemical oxidation conditions and under reduction conditions in the case of TCBD derivative 6.

ChemInform Abstract: The Benzyne Story

AbstractReview: about 100 refs.