Analysis of Diazofluorene DNA Binding and Damaging Activity: DNA Cleavage by a Synthetic Monomeric Diazofluorene

The lomaiviticins and kinamycins are complex DNA damaging natural products that contain a diazofluorene functional group. Herein, we elucidate the influence of skeleton structure, ring and chain isomerization, D‐ring oxidation state, and naphthoquinone substitution on DNA binding and damaging activity. We show that the electrophilicity of the diazofluorene appears to be a significant determinant of DNA damaging activity. These studies identify the monomeric diazofluorene 11 as a potent DNA cleavage agent in tissue culture. The simpler structure of 11 relative to the natural products establishes it as a useful lead for translational studies.     

Diazo group electrophilicity in kinamycins and lomaiviticin A: potential insights into the molecular mechanism of antibacterial and antitumor activity

Theoretical and chemical studies of the reactivity of isoprekinamycin, the kinamycins, and the lomaiviticins support the proposal that these natural products exhibit enhanced diazonium salt character and may owe their antitumor antibiotic properties to their ability to act as electrophilic azo-coupling agents in vivo.     

Natural products containing a diazo group

Although diazo compounds are probably best known for their involvement as versatile intermediates in modern synthetic organic chemistry, a small number of such compounds also occur naturally. Many of the early examples, such as azaserine, originally isolated in the 1950s, have antitumour properties and consist of modified α-amino acids. More recently, other more complex diazo compounds have been isolated from natural sources, and these include diazobenzoquinones, diazonaphthoquinones, such as the SF2415 and A80915 antibiotics, and the diazofluorene-based kinamycins and lomaiviticins. This report will cover the isolation, biosynthesis, biological activity and synthesis of natural products containing a diazo group.     

Cytotoxic and antioxidant marine prenylated quinones and hydroquinones

Covering: 1972 to 2011. This review covers the literature of prenylated quinone, hydroquinone and naphthoquinone marine natural products with reported cytotoxic and/or antioxidant properties. The structures, biological activity and, where applicable, the syntheses of 159 cytotoxic/antioxidant compounds, isolated from various marine organisms, are presented, while trends in the distribution of these cytotoxic metabolites, across the different marine phyla, are highlighted. Marine prenylated quinones, hydroquinones and naphthoquinones are of mixed polyketide and terpenoid biogenesis and recent biosynthetic studies of selected compounds are discussed.     

(S,S)-2,3-Dihydroxy-2,3-dihydrobenzoic acid: microbial access with engineered cells of Escherichia coli and application as starting material in natural-product synthesis

Cyclohexadiene-trans-5,6-diols such as (S,S)-2,3-dihydroxy-2,3-dihydrobenzoic acid (2,3-trans-CHD) have been shown to be of importance as chiral starting materials for the syntheses of bioactive substances, especially for the syntheses of carbasugars. By using methods of metabolic-pathway engineering, the Escherichia coli genes entB and entC, which encode isochorismatase and isochorismate synthase, were cloned and over-expressed in E. coli strains with a deficiency of entA, which encodes 2,3-dihydroxybenzoate synthase. A 30-fold increase in the corresponding EntB/EntC enzyme activities affects the accumulation of 2,3-trans-CHD in the cultivation medium. Although the strains did not contain deletions in chorismate-utilising pathways towards aromatic amino acids, neither chorismate nor any other metabolic intermediates were found as by-products. Fermentation of these strains in a 30 L pH-controlled stirred tank reactor showed that 2,3-trans-CHD could be obtained in concentrations of up to 4.6 g L(-1). This demonstrates that post-chorismate metabolites are accessible on a preparative scale by using techniques of metabolic-pathway engineering. Isolation and separation from fermentation salts could be performed economically in one step through anion-exchange chromatography or, alternatively, by reactive extraction. Starting from 2,3-trans-CHD as an example, we established short syntheses towards new carbasugar derivatives.     

Microwave Flow Chemistry as a Methodology in Organic Syntheses,Enzymatic Reactions,and Nanoparticle Syntheses

Several studies have used microwaves as a heat source for carrying out various types of reactions employing circulation reaction vessels. The microwave flow chemical synthesis methodology is most appropriate in the use of microwaves in chemical syntheses. It can attenuate the problem of microwave heating (non‐uniform heating and penetration depth) and maximize the benefits (rapid heating and first temperature adjustments). In this brief review, we examine and explain some of the relevant features of microwave heating with applicative examples of the usage of microwave flow chemistry equipment in carrying out organic syntheses, enzymatic reactions, and (not least) nanoparticle syntheses.     

Resolvins,Protectins, and Maresins: DHA-Derived Specialized Pro-Resolving Mediators,Biosynthetic Pathways,Synthetic Approaches,and Their Role in Inflammation

Marine organisms are an important source of natural products with unique and diverse chemical structures that may hold the key for the development of novel drugs. Docosahexaenoic acid (DHA) is an omega-3 fatty acid marine natural product playing a crucial regulatory role in the resolution of inflammation and acting as a precursor for the biosynthesis of the anti-inflammatory specialized pro-resolving mediators (SPMs) resolvins, protectins, and maresins. These metabolites exert many beneficial actions including neuroprotection, anti-hypertension, or anti-tumorigenesis. As dysregulation of SPMs is associated with diseases of prolonged inflammation, the disclosure of their bioactivities may be correlated with anti-inflammatory and pro-resolving capabilities, offering new targets for drug design. The availability of these SPMs from natural resources is very low, but the evaluation of their pharmacological properties requires their access in larger amounts, as achieved by synthetic routes. In this report, the first review of the total organic syntheses carried out for resolvins, protectins, and maresins is presented. Recently, it was proposed that DHA-derived pro-resolving mediators play a key role in the treatment of COVID-19. In this work we also review the current evidence on the structures, biosynthesis, and functional and new-found roles of these novel lipid mediators of disease resolution.     

Pyrroloiminoquinone and related metabolites from marine sponges

This review presents the structure, biological activity, biosynthetic studies and, where applicable, references to syntheses of 81 marine alkaloids containing either tetra-, hexa- or octa-hydrogenated variants of pyrrolo[4,3,2-de]quinoline, pyrrolo[4,3,2-de]pyrrolo[2,3-h]quinoline and pyrido[2,3-h]pyrrolo[4,3,2-de]quinoline core skeletons. The literature describing the isolation of pyrroloiminoquinones, and related metabolites, from marine sponges is littered with taxonomic inconsistencies and recent efforts to clarify the taxonomy of the sponges that produce this group of metabolites are discussed.     

Ruthenium-catalyzed olefin metathesis double-bond isomerization sequence

A novel ruthenium-catalyzed tandem ring-closing metathesis (RCM) double-bond isomerization reaction is described in this paper. The utility of this method for the efficient syntheses of five-, six-, and seven-membered cyclic enol ethers is demonstrated. It relies on the conversion of a metathesis-active ruthenium carbene species to an isomerization-active ruthenium-hydride species in situ. This conversion is achieved by using various additives. Scope and limitations of the different protocols are discussed, and some mechanistic considerations based on (31)P and (1)H NMR spectroscopic studies are presented.     

Utilization of glycosyltransferases to change oligosaccharide structures

Carbohydrates on cell surfaces are important biomolecules in various biological recognition processes. Elucidation of the biological roles of complex oligosaccharides necessitates an efficient methodology to synthesize these compounds and their analogs. Enzymatic synthesis renders itself to be useful in the construction of an oligosaccharide structure owing to its mild reaction condition, high regio- and stereoselectivity. This review article focuses on the recent progress in oligosaccharide syntheses catalyzed by glycosyltransferases, namely sialyltransferase, galactosyltransferase, fucosyltransferase, andN-acetylglucosaminyltransferase. A survey of the latest patent and literature related to this field is also included.     

Beta-phenylethylamines and the isoquinoline alkaloids

This review covers beta-phenylethylamines and isoquinoline alkaloids that are derived from them, including further products of oxidation, condensation with formaldehyde and rearrangement, some of which do not contain an isoquinoline system, together with naphthylisoquinoline alkaloids, which have a different biogenetic origin. The occurrence of the alkaloids, with the structures of new bases, together with their reactions, syntheses and biological activities are reported. The literature from July 2000 to June 2001 is reviewed, with 495 references cited.     

Kinamycin-mediated DNA cleavage under biomimetic conditions

The kinamycins are biologically active secondary metabolites characterized by an uncommon diazobenzo[b]fluorene skeleton. Kinamycin D has been shown to potently cleave DNA under mild biomimetic conditions. Use of the endogenously abundant reductant glutathione at 570 μM, kinamycin D effectively cleaved DNA in a concentration, temperature, and time-dependent fashion. Dithiothreitol also proved effective at low concentration while other reductants failed to induce DNA cleavage. Mechanistic consequences of the DNA cleavage results are described.     

Beta-phenylethylamines and the isoquinoline alkaloids

This review covers beta-phenylethylamines and isoquinoline alkaloids and compounds derived from them, including further products of oxidation, condensation with formaldehyde and rearrangement, some of which do not contain an isoquinoline system, together with naphthylisoquinoline alkaloids, which have a different biogenetic origin. The occurrence of the alkaloids, with the structures of new bases, together with their reactions, syntheses and biological activities are reported. The literature from July 2001 to June 2002 is reviewed, with 581 references cited.     

Recent developments of metallic nanoparticles and their catalytic activity in organic reactions

During the last two decades, with the development of nanotechnology, various nanomaterials have been designed and generated. Among them, hybrid organic–inorganic nanoparticles as a particular immobilizing carrier of the catalyst active sites have shown an important contribution in the current research studies. This is due to the large area and loads of active sites. This prominent review is focused on the novel various exa about the immobilization of nanoparticles with organic compounds as versatile and efficient catalysts in organic syntheses.     

beta-Phenylethylamines and the isoquinoline alkaloids

This review covers beta-phenylethylamines and isoquinoline alkaloids derived from them, including further products of oxidation. condensation with formaldehyde and rearrangement, some of which do not contain an isoquinoline system, together with naphthylisoquinoline alkaloids, which have a different biogenetic origin. The occurrence of the alkaloids, with the structures of new bases, together with their reactions, syntheses and biological activities are reported. The literature from July 2002 to June 2003 is reviewed, with 568 references cited.     

Concise, asymmetric, stereocontrolled total synthesis of stephacidins A, B and notoamide B

Concise asymmetric total syntheses of the fungal metabolites (-)-stephacidin A, (+)-stephacidin B, and (+)-notoamide B are described. Key features of these total syntheses include (1) a facile synthesis of (R)-allyl proline methyl ester, (2) a revised route toward the pyranoindole ring system, (3) a novel cross-metathesis strategy for the introduction of important functional groups, and (4) an SN2' cyclization to form the [2.2.2] bridged bicyclic ring system. Furthermore, our synthesis has taken advantage of microwave heating to shorten reaction times as well as increase yields for the preparation of vital intermediates.     

Bioanalytical methods for determination of tamoxifen and its phase I metabolites: a review

The selective estrogen receptor modulator tamoxifen is used in the treatment of early and advanced breast cancer and in selected cases for breast cancer prevention in high-risk subjects. The cytochrome P450 enzyme system and flavin-containing monooxygenase are responsible for the extensive metabolism of tamoxifen into several phase I metabolites that vary in toxicity and potencies towards estrogen receptor (ER) alpha and ER beta.An extensive overview of publications on the determination of tamoxifen and its phase I metabolites in biological samples is presented. In these publications techniques were used such as capillary electrophoresis, liquid, gas and thin layer chromatography coupled with various detection techniques (mass spectrometry, ultraviolet or fluorescence detection, liquid scintillation counting and nuclear magnetic resonance spectroscopy). A trend is seen towards the use of liquid chromatography coupled to mass spectrometry (LC-MS). State-of-the-art LC-MS equipment allowed for identification of unknown metabolites and quantification of known metabolites reaching lower limit of quantification levels in the sub pg mL⁻¹ range. Although tamoxifen is also metabolized into phase II metabolites, the number of publications reporting on phase II metabolism of tamoxifen is scarce. Therefore the focus of this review is on phase I metabolites of tamoxifen.We conclude that in the past decades tamoxifen metabolism has been studied extensively and numerous metabolites have been identified. Assays have been developed for both the identification and quantification of tamoxifen and its metabolites in an array of biological samples. This review can be used as a resource for method transfer and development of analytical methods used to support pharmacokinetic and pharmacodynamic studies of tamoxifen and its phase I metabolites.     

Selectivity and charge transfer in photoreactions of arenes with olefins: 2, Mode of cycloaddition

An empirical rule is presented which can rationalize the modes of cycloaddition in photoreactions of arenes with olefins. This rule bases on the exciplex mechanism and on the Rehm-Weller equation of electron transfer. The correlations between the selectivities and the free enthalpies of electron transfer (ΔG) were carried out for various systems. They also include the “exceptions” according to Bryce-Smith's ΔIP-rule. Therefore, this rule which is presented here may provide a useful guide for planning syntheses.