Reactivity vs. selectivity of quinone methides: synthesis of pharmaceutically important molecules, toxicity and biological applications.

Quinone methides (QMs) are considered to be highly reactive intermediates because of their aromatization both in chemical and biological systems. Being highly accessible, quinone methides (QMs) have been widely exploited and their concurrent use has been manifested for the synthesis of tertiary and quaternary carbon centers of bioactives, drugs and drug-like molecules. In this feature article, the synthetic routes, structure-reactivity relationships and synthetic applications of quinone methides are discussed. Formation of the intermediates during bioactivation of different chemical entities and possible chemical manifestations leading to their toxicity in biological systems are also covered.

Photochemical Reactivity of Naphthol-Naphthalimide Conjugates and Their Biological Activity.

Quinone methide precursors 1a-e, with different alkyl linkers between the naphthol and the naphthalimide chromophore, were synthesized. Their photophysical properties and photochemical reactivity were investigated and connected with biological activity. Upon excitation of the naphthol, Förster resonance energy transfer (FRET) to the naphthalimide takes place and the quantum yields of fluorescence are low (ΦF ≈ 10-2). Due to FRET, photodehydration of naphthols to QMs takes place inefficiently (ΦR ≈ 10-5). However, the formation of QMs can also be initiated upon excitation of naphthalimide, the lower energy chromophore, in a process that involves photoinduced electron transfer (PET) from the naphthol to the naphthalimide. Fluorescence titrations revealed that 1a and 1e form complexes with ct-DNA with moderate association constants Ka ≈ 105-106 M-1, as well as with bovine serum albumin (BSA) Ka ≈ 105 M-1 (1:1 complex). The irradiation of the complex 1e@BSA resulted in the alkylation of the protein, probably via QM. The antiproliferative activity of 1a-e against two human cancer cell lines (H460 and MCF 7) was investigated with the cells kept in the dark or irradiated at 350 nm, whereupon cytotoxicity increased, particularly for 1e (>100 times). Although the enhancement of this activity upon UV irradiation has no imminent therapeutic application, the results presented have importance in the rational design of new generations of anticancer phototherapeutics that absorb visible light.

A versatile toolbox for investigating biological processes based on quinone methide chemistry: From self-immolative linkers to self-immobilizing agents.

Quinone methide (QM) species have been included in the design of various functional molecules. In this review, we present a comprehensive overview of bioanalytical tools based on QM chemistry. In the first part, we focus on self-immolative linkers that have been incorporated into functional molecules such as prodrugs and fluorescent probes. In the latter half, we outline how the highly electrophilic property of QMs, enabling them to react rapidly with neighboring nucleophiles, has been applied to develop inhibitors or labeling probes for enzymes, as well as self-immobilizing fluorogenic probes with high spatial resolution. This review systematically summarizes the versatile QM toolbox available for investigating biological processes.

Synthesis, In Vitro and In Silico Studies of Indolequinone Derivatives against Clinically Relevant Bacterial Pathogens.

BACKGROUND: According to the World Health Organization, antimicrobial resistance is one of the most important public health threats of the 21st century. Therefore, there is an urgent need for the development of antimicrobial agents with new mechanism of action, especially those capable of evading known resistance mechanisms. OBJECTIVE: We described the synthesis, in vitro antimicrobial evaluation, and in silico analysis of a series of 1H-indole-4,7-dione derivatives. METHODS: The new series of 1H-indole-4,7-diones was prepared with good yield by using a copper(II)- mediated reaction between bromoquinone and ß-enamino ketones bearing alkyl or phenyl groups attached to the nitrogen atom. The antimicrobial potential of indole derivatives was assessed. Molecular docking studies were also performed using AutoDock 4.2 for Windows. Characterization of all compounds was confirmed by one- and two-dimensional NMR techniques 1H and 13C NMR spectra [1H, 13C - APT, 1H x 1H - COSY, HSQC and HMBC], IR and mass spectrometry analysis. RESULTS: Several indolequinone compounds showed effective antimicrobial profile against Grampositive (MIC = 16 µg.mL-1) and Gram-negative bacteria (MIC = 8 µg.mL-1) similar to antimicrobials current on the market. The 3-acetyl-1-(2,5-dimethylphenyl)-1H-indole-4,7-dione derivative exhibited an important effect against different biofilm stages formed by a serious hospital life-threatening resistant strain of Methicillin-Resistant Staphylococcus aureus (MRSA). A hemocompatibility profile analysis based on in vitro hemolysis assays revealed the low toxicity effects of this new series. Indeed, in silico studies showed a good pharmacokinetics and toxicological profiles for all indolequinone derivatives, reinforcing their feasibility to display a promising oral bioavailability. An elucidation of the promising indolequinone derivatives binding mode was achieved, showing interactions with important sites to biological activity of S. aureus DNA gyrase. These results highlighted 3-acetyl-1-(2-hydroxyethyl)-1Hindole- 4,7-dione derivative as broad-spectrum antimicrobial prototype to be further explored for treating bacterial infections. CONCLUSION: The highly substituted indolequinones were obtained in moderate to good yields. The pharmacological study indicated that these compounds should be exploited in the search for a leading substance in a project aimed at obtaining new antimicrobials effective against Gram-negative bacteria.

ortho-Quinone Methide Cyclizations Inspired by the Busseihydroquinone Family of Natural Products.

A series of cascade reactions of o-quinone methides have been developed based on the proposed biosynthesis of busseihydroquinone and parvinaphthol meroterpenoid natural products. The polycyclic framework of the most complex family members, busseihydroquinone E and parvinaphthol C, was assembled by an intramolecular [4 + 2] cycloaddition of an electron-rich chromene substrate. The resultant cyclic enol ether underwent rearrangements under acidic or oxidative conditions, which led to a new total synthesis of rhodonoid D.

Optimization of pyrrolo[3,4-f]indole-5,7-dione and indole-5,6-dicarbonitrile derivatives as inhibitors of monoamine oxidase.

In recent studies, we have investigated the monoamine oxidase (MAO) inhibition properties of pyrrolo[3,4-f]indole-5,7-dione and indole-5,6-dicarbonitrile derivatives. Since numerous high potency MAO inhibitors are present among these chemical classes, the present study synthesizes 44 additional derivatives in an attempt to further derive structure-activity relationships (SARs) and to establish optimal substitution patterns for MAO inhibition. The results show that, with the exception of one compound, all indole-5,6-dicarbonitrile derivatives (10) exhibit submicromolar IC50 values for the inhibition of MAO, with the most potent MAO-A inhibitor exhibiting an IC50 value of 0.006 µM while the most potent MAO-B inhibitor exhibits an IC50 value of 0.058 µM. Interestingly, an N-oxide derivative (4c) also proved to be a potent and nonspecific MAO inhibitor. With the exception of one compound, all of the pyrrolo[3,4-f]indole-5,7-diones (28) also exhibit submicromolar IC50 values for the inhibition of an MAO isoform. The most potent inhibitor exhibit an IC50 value of 0.011 µM for MAO-A. This study proposes that high potency MAO inhibitors such as those investigated here, may act as lead compounds for the development of treatments for neurodegenerative and neuropsychiatric disorders such as Parkinson's disease and depression.

Visible-Light-Triggered Cyanoalkylation of para-Quinone Methides and Its Application to the Synthesis of GPR40 Agonists.

Cyanoalkylated diarylmethanes with biological and pharmacological potentials were synthesized from para-quinone methides and cyanoalkylating reagents through a photocatalytic process. This protocol is operationally simple and mild and has high efficiency, which gave the corresponding products in moderate to good yields. The synthetic utility of this work has been illustrated in the efficient synthesis of GPR40 agonists, which play an important role in FA-induced glucose-sensitive insulin secretion.

One-Step Multigram-Scale Biomimetic Synthesis of Psiguadial†B.

A gram-scale synthesis of psiguadial B, a purported inhibitor of human hepatoma cell growth, has been achieved in one step by a biomimetic three-component coupling of caryophyllene, benzaldehyde, and diformylphloroglucinol. This cascade reaction is catalyzed by N,N'-dimethylethylenediamine, and proceeds at ambient temperature to generate four stereocenters, two rings, one C-O bond, and three C-C bonds. Combined computational and experimental investigations suggest the biosynthesis of the natural product is non-enzyme mediated, and is the result of a Michael addition between caryophyllene and a reactive ortho-quinone methide, followed by two sequential intramolecular cationic cyclization events.

Oleanane-, ursane-, and quinone methide friedelane-type triterpenoid derivatives: Recent advances in cancer treatment.

Natural pentacyclic triterpenoids (PTs) have been often reported to exhibit a wide range of biological activities. Among them, the anticancer and anti-inflammatory activities are the most studied. Over the last two decades, the number of publications reporting the anticancer effects of PTs has risen exponentially, reflecting the increasing interest in these natural products for the development of new antineoplastic drugs. Among of the most investigated PTs regarding their anticancer properties are oleanane-, ursane and friedelane-types, including oleanolic, glycyrrhetinic, ursolic and asiatic acids, and celastrol, among others. The extensive research in this field shows that the anticancer effects of PTs are mediated by several mechanisms, as they modulate a diverse range of molecular targets and signaling pathways, involved in cancer cell proliferation and survival. Considering the anticancer potential of this class of compounds, a number of semisynthetic derivatives has been synthetized aiming to improve their therapeutic activity and pharmacokinetic properties, and decrease their toxicity. Some of these new semisynthetic derivatives have shown improved anticancer activity in various cancer cell lines and animal models compared with the parent compound. Moreover, some of these compounds have been assessed in clinical trials, proving to be safe for human use. This review updates the most recent findings on the semisynthetic derivatives of oleanane-, ursane- and quinone methide friedelane-type PTs with anticancer activity. A brief introduction concerning the PTs and their anticancer activity is given, and the main semisynthetic modifications that have been performed between 2012 and early 2017 are reviewed and discussed.

Enantioselective [4 + 1] cycloaddition of ortho-quinone methides and bromomalonates under phase-transfer catalysis.

An enantioselective [4 + 1] cycloaddition reaction of ortho-quinone methides and bromomalonates using a quinine and BINOL derived phase-transfer catalyst is described. With high yields and enantioselectivities, the method provided a variety of optically active dihydrobenzofurans, which represent a valuable structural motif present in numerous naturally occurring and biologically active molecules.

Harnessing a p-Quinone Methide Intermediate in the Biomimetic Total Synthesis of the Highly Active Antibiotic 20-Deoxy-Elansolid B1.

The polyketide, 20-deoxy elansolid B1, was prepared by a convergent strategy that relied on a putative biomimetic intramolecular Diels-Alder cycloaddition (IMDA) via a vinylic p-quinone methide intermediate to furnish the key tetrahydroindane unit. The (Z,E,Z)-configured triene unit was constructed by Pd-catalyzed Suzuki-Miyaura and Stille cross-coupling reactions without isomerization of any of the olefinic double bonds. Formation of a p-methide quinone intermediate under basic conditions and subsequent Michael addition by water to this intermediate proceeded with high facial selectivity which terminated this total synthesis. Remarkably, the new elansolid derivative 2 c shows very good inhibitory effect against Bacillus subtilis and Staphylococcus aureus (including MRSA) similarly to the best elansolid derivatives reported so far. Consequently, the hydroxyl group at C20 is not essential for antibacterial activity.

Aminochrome induces dopaminergic neuronal dysfunction: a new animal model for Parkinson's disease.

L-Dopa continues to be the gold drug in Parkinson's disease (PD) treatment from 1967. The failure to translate successful results from preclinical to clinical studies can be explained by the use of preclinical models which do not reflect what happens in the disease since these induce a rapid and extensive degeneration; for example, MPTP induces a severe Parkinsonism in only 3 days in humans contrasting with the slow degeneration and progression of PD. This study presents a new anatomy and develops preclinical model based on aminochrome which induces a slow and progressive dysfunction of dopaminergic neurons. The unilateral injection of aminochrome into rat striatum resulted in (1) contralateral rotation when the animals are stimulated with apomorphine; (2) absence of significant loss of tyrosine hydroxylase-positive neuronal elements both in substantia nigra and striatum; (3) cell shrinkage; (4) significant reduction of dopamine release; (5) significant increase in GABA release; (6) significant decrease in the number of monoaminergic presynaptic vesicles; (7) significant increase of dopamine concentration inside of monoaminergic vesicles; (8) significant increase of damaged mitochondria; (9) significant decrease of ATP level in the striatum (10) significant decrease in basal and maximal mitochondrial respiration. These results suggest that aminochrome induces dysfunction of dopaminergic neurons where the contralateral behavior can be explained by aminochrome-induced ATP decrease required both for anterograde transport of synaptic vesicles and dopamine release. Aminochrome could be implemented as a new model neurotoxin to study Parkinson's disease.

Synthesis, analysis and biological evaluation of novel indolquinonecryptolepine analogues as potential anti-tumour agents.

A small library of cryptolepine analogues were synthesised incorporating halogens and/or nitrogen containing side chains to optimise their interaction with the sugar-phosphate backbone of DNA to give improved binding, interfering with topoisomerase II hence enhancing cytotoxicity. Cell viability, DNA binding and Topoisomerase II inhibition is discussed for these compounds. Fluorescence microscopy was used to investigate the uptake of the synthesised cryptolepines into the nucleus. We report the synthesis and anti-cancer biological evaluation of nine novel cryptolepine analogues, which have greater cytotoxicity than the parent compound and are important lead compounds in the development of novel potent and selective indoloquinone anti-neoplastic agents.

o-Quinone Methides via Oxone-Mediated Benzofuran Oxidative Dearomatization and Their Intramolecular Cycloaddition with Carbonyl Groups: An Expeditious Construction of the Central Tetracyclic Core of Integrastatins, Epicoccolide A, and Epicocconigrone A.

The intramolecular cycloaddition of o-quinone methides (o-QMs) with a carbonyl group has been envisaged and executed successfully in the context of constructing the complex and rare [6,6,6,6]-tetracyclic core found in the integrastatins, epicoccolide A, and epicocconigrone A. These transient o-QMs were generated easily from the oxidative dearomatization of the corresponding C2-(aryl)benzofuran by employing Oxone in acetone-water at rt. The subsequent cycloaddition with the carbonyl (or conjugated olefin) present on the C2-aryl group was spontaneous.

Enantioselective Multicomponent Condensation Reactions of Phenols, Aldehydes, and Boronates Catalyzed by Chiral Biphenols.

Chiral diols and biphenols catalyze the multicomponent condensation reaction of phenols, aldehydes, and alkenyl or aryl boronates. The condensation products are formed in good yields and enantioselectivities. The reaction proceeds via an initial Friedel-Crafts alkylation of the aldehyde and phenol to yield an ortho-quinone methide that undergoes an enantioselective boronate addition. A cyclization pathway was discovered while exploring the scope of the reaction that provides access to chiral 2,4-diaryl chroman products, the core of which is a structural motif found in natural products.

Catalytic Asymmetric 1,6-Conjugate Addition of para-Quinone Methides: Formation of All-Carbon Quaternary Stereocenters.

Described herein is a general and mild catalytic asymmetric 1,6-conjugate addition of para-quinone methides (p-QMs), a class of challenging reactions with previous limited success. Benefiting from chiral Brønsted acid catalysis, which allows in situ formation of p-QMs, our reaction expands the scope to general p-QMs with various substitution patterns. It also enables efficient intermolecular formation of all-carbon quaternary stereocenters with high enantioselectivity.

Formal asymmetric catalytic thiolation with a bifunctional catalyst at a water-oil interface: synthesis of benzyl thiols.

The enantioselective conjugated addition of tritylthiol to in situ generated ortho-quinone methides (o-QMs) is catalyzed by an acid-base bifunctional squaramide organocatalyst. The transformation proceeds with high yield (up to 99 %) and stereoselectivity (up to 97:3 e.r.) using water as solvent under mild conditions. The catalyst system provides a new strategy for the synthesis of optically active benzyl mercaptans. Control experiments suggested that o-QMs are generated by the tertiary amine moiety of the squaramide organocatalyst and that the water-oil biphase is crucial for achieving high reactivity and stereoselectivity.

A procedure for transforming indoles into indolequinones.

A procedure that converts a series of structurally diverse, readily available indole derivatives to their corresponding indolequinones is described. The three-step route commences with an iridium catalyzed C-H borylation to give a 7-borylindole that upon oxidation-hydrolysis affords the 7-hydroxyindole. Subsequent oxidation provides the indolequinone.

The domestication of ortho-quinone methides.

CONSPECTUS: An ortho-quinone methide (o-QM) is a highly reactive chemical motif harnessed by nature for a variety of purposes. Given its extraordinary reactivity and biological importance, it is surprising how few applications within organic synthesis exist. We speculate that their widespread use has been slowed by the complications that surround the preparation of their precursors, the harsh generation methods, and the omission of this stratagem from computer databases due to its ephemeral nature. About a decade ago, we discovered a mild anionic triggering procedure to generate transitory o-QMs at low temperature from readily available salicylaldehydes, particularly OBoc derivatives. This novel reaction cascade included both the o-QM formation and the subsequent consumption reaction. The overall transformation was initiated by the addition of the organometallic reagent, usually a Grignard reagent, which resulted in the formation of a benzyloxy alkoxide. Boc migration from the neighboring phenol produced a magnesium phenoxide that we supposed underwent ß-elimination of the transferred Boc residue to form an o-QM for immediate further reactions. Moreover, the cascade proved controllable through careful manipulation of metallic and temperature levers so that it could be paused, stopped, or restarted at various intermediates and stages. This new level of domestication enabled us to deploy o-QMs for the first time in a range of applications including diastereocontrolled reactions. This sequence ultimately could be performed in either multipot or single pot processes. The subsequent reaction of the fleeting o-QM intermediates included the 1,4-conjugate additions that led to unbranched or branched ortho-alkyl substituted phenols and Diels-Alder reactions that provided 4-unsubstituted or 4-substituted benzopyrans and chroman ketals. The latter cycloadducts were obtained for the first time with outstanding diastereocontrol. In addition, the steric effects of the newly created stereocenters in subsequent reactions of chroman ketals and acetals were studied and proved predictable. Through the use of a chiral auxiliary, Diels-Alder products were deployed in numerous enantioselective reactions including several complex natural products syntheses. In this Account, we summarize our efforts, which we hope have contributed to the synthetic renaissance for this venerable species.

A walk along DNA using bipedal migration of a dynamic and covalent crosslinker.

DNA has previously served as an excellent scaffold for molecular transport based on its non-covalent base pairing to assemble both stationary and mobile elements. Use of DNA can now be extended to transport systems based on reversible covalent chemistry. Autonomous and bipedal-like migration of crosslinking within helical DNA is made possible by tandem exchange of a quinone methide intermediate. In this report, net transport is illustrated to proceed over 10 base pairs. This process is driven towards its equilibrium distribution of crosslinks and consumes neither the walker nor the track irreversibly. Successful migration requires an electron-rich quinone methide to promote its regeneration and a continuous array of nucleophilic sites along its DNA track. Accordingly, net migration can be dramatically influenced by the presence of noncanonical structures within duplex DNA as demonstrated with a backbone nick and extrahelical bulge.