Bergman Cycloaromatization Research Articles

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.

DNA Binding and Cleavage Modes of Shishijimicin A.

Although shishijimicin A and its extreme potencies against an array of cancer cell lines have been known for more than a decade, its assumed DNA-cleaving mechanism has not been substantiated as yet. Herein we report studies that reveal binding and scission of double-stranded DNA by shishijimicin A. The results of these studies support the proposed hypothesis that DNA strand scissions are caused by 1,4-benzenoid diradicals formed by Bergman cycloaromatization of the enediyne core of shishijimicin A upon activation by thiols. In addition, double-stranded supercoiled DNA-cleavage experiments with shishijimicin A in competition with known minor groove binders, UV spectroscopic studies, and electrophoretic analysis were utilized to clarify the binding mode of the molecule to DNA. These investigations indicate that shishijimicin A binds to the minor groove of double-stranded DNA and that its β-carboline moiety plays a role in the binding through intercalation. In addition, due to the fact that naked linker regions of DNA in the interphase and metaphase of eukaryotic cells are unprotected by histone proteins during entire cell cycles and because these unprotected regions of DNA are vulnerable to attack by DNA binders, it was concluded that the observed double-strand DNA cleavage and very low sequence selectivity by shishijimicin A may account for its extraordinary cytotoxicity.

Imidazole-Fused Enediynes by Selective C5–C4 Alkynylations of 4,5-Dibromoimidazoles

An efficient synthesis of symmetrical 1,2-disubstituted 4,5-dialkynylimidazoles by Sonogashira alkynylation of the corresponding 4,5-dibromo derivatives was developed. Moreover, through a careful tuning of the palladium ligand, unsymmetrical 1,2-disusbtituted 4,5-dialkynylimidazoles were also prepared through a regioselective C5 alkynylation of 4,5-dibromoimidazoles, followed by a second alkynylation involving the 4-bromo derivatives so obtained. This interesting class of imidazole-fused enediynes is also able to give thermal Bergman cycloaromatization (BC), as proved by DSC experiments.

Synthesis and Biological Activity of Unnatural Enediynes.

The first reports of the natural enediyne anticancer antibiotics date back to the late 1980s; since then, a great deal of interest has been devoted to the chemistry, biology and potential medical applications of this family of compounds. The biological activity of enediynes is linked to the presence of a highly unsaturated hex-1-ene-1,5-diyne system. The thermally induced transformation of this unit into a benzene σ-σ diradical (the Bergman cycloaromatization) is the key step of the antitumor properties of such compounds: 1,4-diaryl radicals are able to abstract H-atoms from the deoxyribose backbone of DNA, thus leading to DNA strand cleavage and ultimately cell death. We undertook a structured search of bibliographic databases for peer-reviewed research literature using focused and high quality papers. Research efforts addressed at understanding and mimicking the various processes involved in the targeting, activation and DNA cleavage associated with these products are described. The potential of a great number of non natural enediynes in the treatment of many infectious diseases, apart their role in anticancer drugs, such as antibacterial activity, protein degradation activity, has been reported Results: Due to the interesting mode of action of this class of compounds, the unique molecular architecture of enediynes has been exploited towards the synthesis of many non natural compounds in order to study and enhance their biological properties. Seventy-six papers were included in this review. It is divided in paragraphs that include: Carbo- oxygen-nitrogen- and sulfur- enediynes, polymers and macrocycles. The synthetic approaches to the different classes of compounds are discussed in detail together with the biological implications of the synthesized compounds Conclusion: The review summarizes the most recent advances in the synthesis and reactivity of non natural enediynes by focusing the attention particularly to the biological properties of the most interesting members of the family of carbo- and hetero- enediynes. The findings of this review confirm the importance of non natural enediynes as potential drugs in the treatment of cancer and many infectious diseases.

Photoactivated Transition-Metal Triggers for Ambient Temperature Enediyne and Dienyne Cyclization: Ruthenium-η6-Naphthalene Complexes

A persistent challenge confronting potential applications of the Bergman cycloaromatization reaction is the development of methods for spatiotemporal control of diradical formation. Photochemical variants (photo-Bergman cycloaromatizations) have thus far met with limited success, failing completely in the case of acyclic enediynes. Here we describe the development of efficient photoactivated transition-metal complexes that allow for spatiotemporal control of enediyne cycloaromatization at ambient temperatures. This strategy relies on air- and moisture-stable ruthenium naphthalene complexes that undergo photochemical dissociation of the naphthalene ligand, thereby generating coordination sites for enediyne binding and cycloaromatization. The same ruthenium naphthalene complexes also trigger dienyne cyclization under photochemical conditions.

Thermal Isomerizations of Diethynyl Cyclobutadienes and Implications for Fullerene Formation.

The mechanism by which carbon condenses to form PAHs or fullerenes is a problem that has garnered considerable theoretical and experimental attention. The ring-coalescence and annealing model for the formation of C(60) involves a [2 + 2] cycloaddition reaction of a cyclopolyyne to form a tetraalkynyl cyclobuta-1,3-diene intermediate, followed by a Bergman cycloaromatization reaction of the enediyne moiety. Intramolecular trapping of the incipient p-benzyne diradical across a diyne moiety of the macrocyclic ring affords an aromatic ring that must undergo further intramolecular reactions via polyradical intermediates to produce a condensed graphitic structure or fullerene. Computational studies of a model system for the intriguing tetraalkynylcyclobuta-1,3-diene intermediate, however, reveal that the corresponding p-benzyne diradical lies in a shallow minimum with a very low barrier to ring opening to cyclooctadienediyne. This pathway has not been previously considered in the mechanism for carbon condensation.

Synthesis and evaluation of cytotoxic activity derived 2,3-diyne-1,4-naphthoquinones

In the present study ten 2,3-diyne-1,4-naphthoquinone derivatives ( 3a-j ) were synthesized by Sonogashira coupling reaction between the 2,3-dibromo-1,4-naphthoquinone ( 2 ) and several functionalized terminal alkynes using a catalytic complex of palladium (II) and CuI. Alkynes are among phenylacetylene, 1-ethyl-4-methoxybenzene, 2-methyl-3-butyn-2-ol, 1-ethynyl-1-cyclohexanol, 4-pentyn-2-ol, 4-pentyn-1-ol, 1-pentyne, 1-hexyne, 1-decyne and 1-octyne. The yields of products obtained ranged 15 to 55%. The enediynes having hydroxyl groups, in their structures such as 2,3-di(3-hydroxy-3-methylbut-1-in-1-yl)-, 2,3-di[(1-hydroxycyclohexyl)ethynyl]- and 2,3-di(5-hydroxypent-1-yl)-1,4-naphthoquinone were subjected to acetylation reaction using acetic anhydride and montmorillonite clay K-10 under sonication, thereby obtaining three new enediyne derivatives ( 3c’ , d’ and f’ ) with yields ranging from 56 to 71%. The compounds were all characterized by 1 H NMR and 13 C NMR spectra, IR and MS-LC. These compounds containing the 1,4-naphthoquinone nucleus and acetylenic substituents in the quinonoid ring form a enediyne system ( Z -3-ene-1,5-diyne) highly reactive, possibly subject to Bergman cycloaromatization, with potential antitumor activity. The enediynes underwent evaluation of the cytotoxic potential against three tumor cell lines, OVCAR-8 (ovarian adenocarcinoma - human), PC-3M (metastatic prostate cancer - human), NCI-H358M (bronchoalveolar lung carcinoma - human), presenting, in general, satisfactory results for inhibition of cell growth. The compound 2,3-di(3-hydroxy-3-methylbut-1-in-yl)-1,4-naphthoquinone ( 3c ) where said among the substances analyzed by presenting a lower IC 50 (˂ 2 µg/mL) for three cell lines tested, which is characterized as a potent cytotoxic agent.

ChemInform Abstract: Synthesis and Investigations of Enetetraynes.

Abstract Several enetetrayne containing compounds have been synthesized and their chemistry explored vis-a-vis the Bergman cycloaromatization. With one exceptio

Conformationally Gated Fragmentations and Rearrangements Promoted by Interception of the Bergman Cyclization through Intramolecular H-Abstraction: A Possible Mechanism of Auto-Resistance to Natural Enediyne Antibiotics?

A variety of fragmentations and rearrangements can follow Bergman cyclization in enediynes equipped with acetal rings mimicking the carbohydrate moiety of natural enediyne antibiotics of the esperamicine and calchiamicine families. In the first step of all these processes, intramolecular H-atom abstraction efficiently intercepts the p-benzyne product of the Bergman cyclization through a six-membered TS and transforms the p-benzyne into a new more stable radical. Depending on the substitution pattern and reaction conditions, this radical follows four alternative paths: (a) abstraction of an external hydrogen atom, (b) O-neophyl rearrangement which transposes O- and C-atoms of the substituent, (c) fragmentation of the O-C bond in the acetal ring, or (d) fragmentation with elimination of the appended acetal moiety as a whole. Experiments with varying concentrations of external H-atom donor (1,4-cyclohexadiene) were performed to gain further insight into the competition between intermolecular H-abstraction and the fragmentations. The Thorpe-Ingold effect in gem-dimethyl substituted enediynes enhances the efficiency of fragmentation to the extent where it cannot be prevented even by a large excess of external H-atom donor. These processes provide insight into a possible mechanism of unusual fragmentation of esperamicin A(1) upon its Bergman cycloaromatization and lay foundation for a new approach for the conformational control of reactivity of these natural antitumor antibiotics. Such an approach, in conjunction with supramolecular constraints, may provide a plausible mechanism for resistance to enediyne antibiotics by the enediyne-producing microorganisms.

Transition-Metal Hydrides as Hydrogen Atom Donors: Stronger Metal−Hydrogen Bonds Can Be Advantageous

The tungsten hydride complex (η5-C5H5)W(CO)3H (1-W) functions as a hydrogen atom donor in the [(η5-C5Me5)Ru(NCMe)3]PF6-mediated Bergman cycloaromatization reaction of (Z)-dodeca-4,8-diyn-6-ene. The strong M−H bond in 1-W does not react with the enediyne substrate but does react with the diradical arising from cyclization, thereby demonstrating the advantages of strong metal−hydrogen bonds in the hydrogen atom transfer reactions of metal hydrides with substrates involving alkenes and alkynes.

Enediyne compounds - new promises in anticancer therapy

Scientists of all kinds have long been intrigued by the nature, action and potential of natural toxins that possess exceptional antibacterial and anticancer activities. These compounds, named enediynes, are among the most effective chemotherapeutic agents known. Often compared with intelligent weapons, due to the unique structure and sophisticated mechanism by which they destroy double-helical DNA, enediyne antibiotics are nowadays the most promising leaders in the anticancer therapy. Apart from their diversity, enediyne compounds share some structural and functional similarities. One fragment of a structure is responsible for the recognition and transport, another part acts as molecular trigger while the third, reactive enediyne unit, undergoes Bergman cycloaromatization and causes DNA breakage. Members of the enediyne family are already in clinical use to treat various cancers, but more general use is limited by their complex structure, which makes them formidable targets for synthetic chemists. There are three main approaches in the design of new enediyne-related compounds: improvement of enediyne >>warheads<<, increasing the selectivity and control of chemical or photo-induced activation. This paper gives an overview of naturally occurring enediynes, their mode of action and efforts undertaken to design artificial enediyne-related DNA cleaving agents.

A synthetic route to enediyne-bridged amino acids

A general strategy for the preparation of enediyne-bridged amino acids has been disclosed. A cross-coupling reaction between amino- and carboxyl-modified amino acids under Sonogashira reaction conditions gave a protected enediyne–peptide conjugate. The model obtained can be used as a template in studies of Bergman cycloaromatization or peptide conformational preferences induced by the presence of the enediyne moiety.

Ortho Effect in the Bergman Cyclization: Electronic and Steric Effects in Hydrogen Abstraction by 1-Substituted Naphthalene 5,8-Diradicals

We present a detailed theoretical study of geometries, electronic structure, and energies of transition states and intermediates completing the full Bergman cycloaromatization pathway of ortho-substituted enediynes with a focus on polar and steric contributions to the kinetics and thermodynamics of hydrogen abstraction. This study provides a rare unambiguous example of remote substitution that affects reactivity of a neutral reactive intermediate through an sigma framework.

Ortho Effect in the Bergman Cyclization: Comparison of Experimental Approaches and Dissection of Cycloaromatization Kinetics

Four different experimental sources of kinetic information were combined to study the effect of ortho substituents on the rate of Bergman cycloaromatization. All methods confirm that the cyclization barrier is highly sensitive to the nature of the ortho substituents. However, the measured activation energies strongly depend on the choice of experimental technique: even the relative trends provided by the different methods agree with each other only in the case of acceptor substituents. Both the onset peaks and the activation energies determined by differential scanning calorimetry (DSC; either in neat enediynes or in their solutions in 10.6 M 1,4-cyclohexadiene (1,4-CHD)) strongly overestimate the reactivity of 1,2-diethynylbenzene, suggesting that DSC cannot be taken as a reliable indicator of enediyne reactivity. This discrepancy is likely to stem from the presence of side reactions with low activation barriers, especially important when the reaction is conducted in neat enediyne. On the other hand, kinetic measurements based on monitoring the concentrations of enediyne reactants and naphthalene products provide reliable general trends that include the parent benzannelated enediyne. These measurements confirm that both ortho-NO2 and ortho-CHO substituents substantially decrease activation energies for the Bergman cyclization, supporting earlier computational predictions. A comparison of theory and experiment suggests that computations at the Moeller-Plesset second-order perturbation theory (MP2)/6-31G level provide an excellent alternative to DFT when an accurate description of the contribution of noncovalent interactions to the activation energy is needed. Activation energies derived from k(eff), the effective rate constant under the pseudo-first-order approximation, depend on the 1,4-CHD concentrations. The true rate constant, k(1), for the cyclization step and the ratio of constants for the retro-Bergman ring opening, k(-1), and the intermolecular H-atom abstraction, k2, were determined from the dependence of cycloaromatization kinetics of ortho- and para-NO2 substituted enediynes on the concentration of 1,4-CHD.

Ortho Effect in the Bergman Cyclization: Interception of p-Benzyne Intermediate by Intramolecular Hydrogen Abstraction

Intramolecular hydrogen atom (H-atom) abstraction from the o-OCH3 group effectively intercepts the p-benzyne intermediate in the Bergman cycloaromatization of 2,3-diethynyl-1-methoxybenzene (1) before this intermediate undergoes either retro-Bergman ring opening or external H-atom abstraction. This process leads to the formation of a new diradical and renders the cyclization step essentially irreversible. Chemical and kinetic consequences of this phenomenon were investigated through the combination of computational and experimental studies.

Photoinduced Bergman Cycloaromatization of Imidazole‐Fused Enediynes.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Application of Photochemical Decarbonylation of Cyclopropenones for the in Situ Generation of Reactive Enediynes. Construction of a Cyclopropenone-Containing Enediyne Precursor by Using a Cyclopropenone Acetal Building Block

[reaction: see text] A cyclopropenone-containing enediyne photoprecursor, 6-tert-butyldimethylsilyloxy-3-(alpha-hydroxybenzyl)bicyclo[8.1.0]undeca-1(10),2-diene-4-yn-11-one (1), was prepared in 10 steps by sequential modification of the cyclopropenone 2,2-dimethyl-1,3-propanediyl acetal (5). The crucial cyclization step was achieved under Nozaki conditions, while the endocylic double bond has been introduced by the allylic rearrangement. UV irradiation of the cyclopropenone 1 results in efficient decarbonylation and the formation of the reactive enediyne 2. The latter undergoes Bergman cycloaromatization with a half-life of 12 h at 40 degrees C and in the presence of 1,4-dihydrobenzene quantitatively produces corresponding tetralin 29.

Photoinduced Bergman cycloaromatization of imidazole-fused enediynes

A series of 4,5-bis-(alkyn-1-yl)imidazoles—‘imidazole-fused’ enediynes—were synthesized and their reactivities in photoinduced Bergman cycloaromatization reactions were determined. The more conformationally rigid analogues gave cycloaromatized products in good yields upon irradiation (450 W low-pressure mercury lamp, ambient temperature). A bicyclic analogue ( 3 ) was shown to cleave supercoiled plasmid DNA.

Bergman Cycloaromatization of Imidazole‐Fused Enediynes: The Remarkable Effect of N‐Aryl Substitution.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Bergman cycloaromatization of imidazole-fused enediynes: the remarkable effect of N-aryl substitution

A series of N-aryl substituted `imidazole-fused' ( Z) 3-ene-1,5-diynes was prepared and kinetic parameters for their Bergman cycloaromatization reactivities were determined. N-Arylation enhanced rates relative to N-alkyl derivatives by up to sevenfold (ANOVA p<0.0001). The greatest enhancement was exhibited by the N-phenyl derivative (sevenfold at 145 °C).