Anthraquinone Antibiotics Research Articles

Enantioselective Synthesis of Sealutomicin C.

The sealutomicins are a family of anthraquinone antibiotics featuring an enediyne (sealutomicin A) or Bergman-cyclized aromatic ring (sealutomicins B-D). Herein we report the development of an enantioselective organocatalytic method for the synthesis of dihydroquinolines and the use of the developed method in the total synthesis of sealutomicin C which features a transannular cyclization of an aryllithium onto a γ-lactone as a second key step.

Synthesis and Antineoplastic Efficacy of Anthraquinone and Saturated Fatty Acid Conjugates

AbstractThe clinical use of anthraquinone antibiotics such as doxorubicin in cancer chemotherapy is limited due to their toxic cardiomyopathy effects. The conjugation of anthraquinones with fatty acids is known to enhance bioactivity by increasing lipophilicity and facilitating cell membrane permeation. Short‐chain saturated fatty acids such as capric, caprylic, caproic acids, and lauric acids are known for their inherent anticancer properties on human colorectal cancer cells. In this study, 2‐hydroxyanthraquinone and saturated fatty acid esters were synthesized and evaluated against human colon cancer cell line HT‐29 and Colo‐205, breast cancer cell lines MDA‐MB‐231 and MCF‐7, and leukemia cell line K‐562 for their in vitro anticancer properties using a sulforhodamine B (SRB) assay. The anthraquinone‐saturated fatty acid conjugates produced excellent activity against human colon and breast cancer cell lines. The octanoic acid and hexanoic acid derivatives of 2‐hydroxy anthraquinone showed excellent anticancer activity with GI50 values of 0.2 nM and 1.0 nM against human colon cancer cell line Colo‐205 and the human breast cancer cell line MCF‐7, respectively, and emerged as the most active compounds. Furthermore, the in vitro cytotoxicity study against peripheral blood mononuclear cells showed that these derivatives are non‐toxic in nature.

Isolation and anticancer activity evaluation of rare Bisaryl anthraquinone antibiotics from novel Streptomyces sp. strain of NW Himalayan region

Biosynthesis of bisaryl preanthraquinone antibiotics by various microorganisms differs in monomeric subunits as well as their dimerization positions leading to different configurations. The present study relates to the production of rare bisaryl anthraquinone antibiotics by a new Streptomyces strain isolated from Shivalik region of NW Himalayas. In vitro anticancer and anti-migratory effects of Setomimycin (9,9′ bisanthraquinone antibiotic) was seen with a significant reduction in the expression of both MEK as well as ERK pathways in a dose dependent manner at 6.5 μM & 8 μM concentration in HCT-116 and 5.5 μM & 7 μM concentration in MCF-7 cells. In vivo studies in aggressive orthotopic mouse mammary carcinoma model (4T1) demonstrated about 76% reduction of primary tumor weight and 90.5% reduction in the tumor volume within two weeks. In vivo pharmacokinetics study of setomimycin revealed that it can be rapidly absorbed with an adequate plasma exposure and half-life which can be linked to its in vivo efficacy.

Possibility to Biotransform Anthracyclines by Peroxidases Produced by Bjerkandera adusta CCBAS 930 with Reduction of Geno- and Cytotoxicity and Pro-Oxidative Activity.

The aim of this study was to evaluate the bioremoval mechanism of anthracycline antibiotics by the white-rot fungus B. adusta CCBAS 930. The activity of oxidoreductases and levels of phenolic compounds and free radicals were determined during the biotransformation of anthraquinone antibiotics: daunomycin (DNR) and doxorubicin (DOX) by B. adusta strain CCBAS 930. Moreover, phytotoxicity (Lepidium sativum L.), ecotoxicity (Vibrio fischeri), genotoxicity and cytotoxicity of anthraquinone dyes were evaluated before and after biological treatment. More than 80% and 90% of DNR and DOX were removed by biodegradation (decolorization). Initial solutions of DNR and DOX were characterized by eco-, phyto-, geno- and cytotoxicity. Despite efficient decolorization, secondary metabolites, toxic to bacteria, formed during biotransformation of anthracycline antibiotics in B. adusta CCBAS 930 cultures. DNR and DOX metabolites did not increase reactive oxygen species (ROS) production in human fibroblasts and resazurin reduction. DNR metabolites did not change caspase-3 activity.

Identification and Mobilization of a Cryptic Antibiotic Biosynthesis Gene Locus from a Human-Pathogenic Nocardia Isolate.

The genus Nocardia contains >50 human pathogenic species that cause a range of illnesses from skin and soft tissue infections to lung and brain infections. However, despite their membership in the most prominent family of secondary metabolite producers (the Actinomycetes), the ability of Nocardia species, especially those that cause human infections, to produce secondary metabolites has not been as well studied. Using genome mining, we have investigated cryptic secondary metabolite biosynthesis gene clusters from Nocardia species and identified a conserved locus within human pathogenic strains of Nocardia brasiliensis and Nocardia vulneris. Direct capture and heterologous expression in a Streptomyces host activated the biosynthetic locus, revealing it to be the source of the brasiliquinones, benz[a]anthraquinone antibiotics whose biosynthetic pathway has remained hidden for over two decades, until now. Our findings highlight these hitherto neglected human pathogenic Nocardia as a source of diverse and important natural products.

Mitoxantrone – an anthraquinone antibiotic with antitumor activity applied for the treatment of multiple sclerosis

Mitoxantrone is an antineoplastic agent approved for clinical use in the secondary progressive phase of multiple sclerosis (MS). Several scientific reports indicate that mitoxantrone acts through the induction of short-term cell lysis at high concentrations and long-term induction of programmed cell death at lower concentrations of antigen-presenting cells. In this paper, we present the potential cytotoxic effects of mitoxantrone on the cells of the immune system, whose activity is associated with their degenerative effects on axonal myelin sheaths. The article also evaluates the results from the hospital treatment of patients diagnosed with MS. The presented data indicate that, apart from the cytostatic properties, mitoxantrone also exhibits side effects of its clinical application. This drug has high cardiotoxicity, and is associated with decreased left ventricular ejection fraction and increased risk of congestive heart failure. Therefore researchers are currently looking for new substances that can reduce the toxic effects of mitoxantrone in healthy tissues, resulting in the generation of reactive oxygen species during its metabolism.

Total Synthesis of the Proposed Structure of the Anthrapyran Metabolite δ‐Indomycinone

The first total synthesis of the proposed structure of delta-indomycinone has been accomplished. The key steps involve the Diels-Alder reaction of a bromonaphthoquinone (6) and 1-methoxy-3-methyl-1-trimethylsiloxy-1,3-butadiene (7) to access the anthraquinone skeleton, representing a common building block of other naturally occurring anthraquinone antibiotics, regioselective bromination of anthraquinone (14) and a highly diastereoselective alkylation of enantiomerically pure dioxolanone 8. The reported synthetic approach has the advantage of high yields, excellent selectivity and a remarkable general applicability for the total synthesis of other anthrapyran natural products. The spectroscopic data obtained for the synthetic compounds 2 and 36 are not in agreement with those reported for the natural product, and therefore revision of the assigned structure is required.

Quinones and Malaria

The intensive usage and the efficacy of quinoline and artemisinin antimalarials have led scientists to focus mainly on these two families of compounds resulting in the other classes of antimalarial drugs being ignored. Recently atovaquone, a hydroxy-naphtoquinone derivative, was reported as an effective antimalarial drug against the multidrugresistant parasite with a novel drug mechanism. This discovery, which emerged from earlier studies, opened a new approach for the design of new quinone antimalarials. Other well known anthraquinone antibiotics such as tetracycline and doxycycline have been in use in malaria prophylaxis for more than three decades. This review aims to explore the background to the discovery of existing quinone antimalarials, and the advance in the chemistry and biochemistry of synthetic and naturally occurring quinones with antimalarial activity. Reactions and metabolism of antimalarial quinones in animals and men are considered, focusing on compounds that are or have been used to treat human malaria, with an emphasis on the relationship between metabolism and biological effects. Keywords: Quinones, malaria, metabolism and biological effects

Cytotoxic compounds from the marine actinobacterium Streptomyces corchorusii AUBN1/71

We isolated a bioactive streptomycete from marine sediment samples collected at Bay of Bengal, India, during our systematic study of marine actinobacteria. The taxonomic studies indicated that the isolate is related to Strepomyces corchorusii. However, it differed in certain aspects, and, hence, was designated as S. corchorusii AUBN(1)/7. A solvent extraction followed by a chromatographic purification helped obtain from the isolate two cytotoxic compounds, which were identified as resistomycin, a quinone-related antibiotic, and tetracenomycin D, an anthraquinone antibiotic, on the basis of spectral data of pure compounds. They demonstrated in vitro a potent cytotoxic activity against cell lines HMO2 (gastric adenocarcinoma) and HepG2 (hepatic carcinoma) and also exhibited weak antibacterial activities against Gram-positive and Gram-negative bacteria. The English version of the paper: Russian Journal of Bioorganic Chemistry, 2006, vol. 32, no. 3; see also http://www.maik.ru.

Exploring the biosynthetic potential of bimodular aromatic polyketide synthases

Polycyclic aromatic polyketides such as actinorhodin and tetracenomycin are synthesized from acetate equivalents by type II polyketide synthases (PKS). Their carbon chain backbones are derived from malonyl-CoA building blocks through the action of a minimal PKS module consisting of a ketosynthase, a chain length factor, an acyl carrier protein (ACP) and a malonyl-CoA/ACP transacylase. In contrast to these acetogenic polyketides, the backbones of a few aromatic polyketide natural products, such as the R1128 antibiotics, are primed by non-acetate building blocks. These polyketides are synthesized by bimodular PKSs comprising of a dedicated initiation module, which includes a ketosynthase, acyl transferase and ACP, as well as a minimal PKS module. Recently we showed that regioselectively modified polyketides could be synthesized through the genetic recombination of initiation modules and minimal PKS modules from different polyketide biosynthetic pathways (Tang et al. PLoS Biol. 2004, 2, 227–238). For example, the actinorhodin and tetracenomycin minimal PKSs could accept and elongate unnatural primer units from the R1128 initiation module. In this report we provide further examples of using heterologous bimodular PKSs for the engineered biosynthesis of new aromatic polyketides. In addition to providing insights into the biosynthetic mechanisms of aromatic PKSs, our findings also highlight considerable potential for crosstalk between amino acid catabolism and aromatic polyketide biosynthesis. For example, exogenously supplied unnatural amino acids are efficiently incorporated into bioactive anthraquinone antibiotics.

Engineered biosynthesis of regioselectively modified aromatic polyketides using bimodular polyketide synthases.

Bacterial aromatic polyketides such as tetracycline and doxorubicin are a medicinally important class of natural products produced as secondary metabolites by actinomyces bacteria. Their backbones are derived from malonyl-CoA units by polyketide synthases (PKSs). The nascent polyketide chain is synthesized by the minimal PKS, a module consisting of four dissociated enzymes. Although the biosynthesis of most aromatic polyketide backbones is initiated through decarboxylation of a malonyl building block (which results in an acetate group), some polyketides, such as the estrogen receptor antagonist R1128, are derived from nonacetate primers. Understanding the mechanism of nonacetate priming can lead to biosynthesis of novel polyketides that have improved pharmacological properties. Recent biochemical analysis has shown that nonacetate priming is the result of stepwise activity of two dissociated PKS modules with orthogonal molecular recognition features. In these PKSs, an initiation module that synthesizes a starter unit is present in addition to the minimal PKS module. Here we describe a general method for the engineered biosynthesis of regioselectively modified aromatic polyketides. When coexpressed with the R1128 initiation module, the actinorhodin minimal PKS produced novel hexaketides with propionyl and isobutyryl primer units. Analogous octaketides could be synthesized by combining the tetracenomycin minimal PKS with the R1128 initiation module. Tailoring enzymes such as ketoreductases and cyclases were able to process the unnatural polyketides efficiently. Based upon these findings, hybrid PKSs were engineered to synthesize new anthraquinone antibiotics with predictable functional group modifications. Our results demonstrate that (i) bimodular aromatic PKSs present a general mechanism for priming aromatic polyketide backbones with nonacetate precursors; (ii) the minimal PKS controls polyketide chain length by counting the number of atoms incorporated into the backbone rather than the number of elongation cycles; and (iii) in contrast, auxiliary PKS enzymes such as ketoreductases, aromatases, and cyclases recognize specific functional groups in the backbone rather than overall chain length. Among the anthracyclines engineered in this study were compounds with (i) more superior activity than R1128 against the breast cancer cell line MCF-7 and (ii) inhibitory activity against glucose-6-phosphate translocase, an attractive target for the treatment of Type II diabetes.

YM-181741, a novel benz[a]anthraquinone antibiotic with anti-Helicobacter pylori activity from Streptomyces sp.

A novel benz[a]anthraquinone, YM-181741, was isolated from the culture broth of actinomycete strain Q57219. The strain was identified as Streptomyces sp. by morphological and chemotaxonomic characterization. YM-181741 was purified from the culture supernatant by serial column chromatography. The structure of YM-181741 was determined by spectroscopic analysis including one- and two-dimensional NMR experiments. YM-181741 showed selective anti-Helicobacterpylori activity with a MIC value of 0.2 microg/ml.

Luisols A and B, new aromatic tetraols produced by an estuarine marine bacterium of the genus Streptomyces (Actinomycetales).

Luisols A (1) and B (2), two new aromatic tetraols, have been isolated from the cultivation broth of an estuarine marine actinomycete of the genus Streptomyces (strain #CNH-370). The structures of luisols A and B were assigned by combined spectroscopic methods, including extensive 2D NMR experiments. Luisol A appears related to the anthraquinone antibiotics of the granaticin class, while the structure of luisol B contains the rare epoxynaphtho[2,3c]furan, a structural feature found in only one natural product, the fungal metabolite anthrinone.

Some aspects of the purification of anthraquinone antibiotics by preparative reversed-phase liquid chromatography

Elloramycin was chosen as a representative anthraquinone antibiotic to determine the separation efficiency of preparative reversed-phase liquid chromatography with regard to dependency on sample solubility, sample solvent strength, sample concentration and particle size of the stationary phase. In the case of elloramycin, which shows moderate lipophilic properties, it was demonstrated that an optimal strength of the sample solvent avoided front elution and peak fronting, that a diluted sample led to a better separation, and that a small particle size like 10 μm resulted in a strong increase in the purity of the separated compound in contrast to low-cost 15–25-μm particles.

Brasiliquinones A, B and C, New Benz(a)anthraquinone Antibiotics from Nocardia brasiliensis. I. Producing Strain, Isolation and Biological Activities of the Antibiotics.

New benz[alpha]anthraquinone antibiotics (brasiliquinones A, B and C) with an ethyl group at C-3 were isolated. The producer was identified as Nocardia brasiliensis. The antibiotics were active against Gram-positive bacteria including Mycobacterium sp., but not active against Gram-negative bacteria or fungi. They were also active against multiple drug-resistant P388/ADR tumor cells.

New benz[a]anthraquinone secondary metabolites from Streptomyces phaeochromogenes

Four new benz[a]anthraquinone metabolites related to PD 116198, a known benz[a]anthraquinone antibiotic, were isolated from Streptomyces phaeochromogenes WP 3688 and characterized. Two showed strong structural similarities with PD 116198, while two others were less similar and possessed novel oxidized skeletons. The relative stereochemistry of these metabolites was obtained by analysis of difference NOE and NOESY spectra

Action-mode of Antimicrobial Altersolanol A inPseudomonas aeruginosa

The antimicrobial mechanism of altersolanol A was studied by using Pseudomonas aeruginosa IFO 3080. This reduced anthraquinone antibiotic inhibited the incorporation of radioactive precursors into macromolecules (DNA, RNA, and Protein) in whole cells nonspecifically. It increased respiration of P. aeruginosa cells, though it had no effect on proton condution. Oxidation of NADH in the membrane fraction isolated from P. aeruginosa was enhanced by altersolanol A. Furthermore, altersolanol A stimulated the oxidation of NADH by the enzyme preparation of cytochrome c reductase in the absence of cytochrome c. Altersolanol A seemed to interfere with the respiratory chain in the bacterial membrane as an electron acceptor.

Dioxamycin, a new benz(a)anthraquinone antibiotic.

A new antibiotic, dioxamycin (1) was isolated from the culture broth of the strain MH406-SF1, which was closely related to Streptomyces xantholiticus. This antibiotic was purified by countercurrent chromatography, column chromatography and preparative HPLC. The molecular formula of 1 was determined to be C38H40O15 by HRFAB-MS. The structure was determined by spectral analysis of 2D NMR; 1H-1H COSY, 13C-1H COSY, long range 13C-1H COSY (HMBC) and NOESY. The antibiotic is active in vitro against Gram-positive bacteria and some tumor cells. Dioxamycin is a benz[a]anthraquinone antibiotic related to capoamycin.

Identification of the site of adriamycin-activation in the heart cell

Based on the assumption, the selective cardiotoxicity of anthraquinone antibiotics is due to peculiarities concerning their metabolism in the heart, we have investigated the exogenous NADH oxidoreductase, a heart-specific enzyme recently described (H. Nohl, Eur. J. Biochem. 169, 585 1987) for its possible role in the development of cardiotoxic effects. Cytosolic anthraquinones have direct access since the enzyme was shown to be associated with the cytosolic face of the inner mitochondrial membrane. Redox properties, kinetic data and the poor substrate selectivity suggest the exogenous NADH-oxidoreductase to be involved in the activation of cellular anthraquinones. According to this concept, a direct single electron-shuttle from exogenous NADH to the anthraquinone adriamycin was demonstrated by the detection of adriamycin-semiquinone-related ESR signals. Activation of adriamycin to its semiquinone state at the expense of NADH was also observed with the solubilized NADH-oxidoreductase of heart mitochondria. Microsomal activation of adriamycin was found to result from contaminating exogenous NADH-oxidoreductase of heart mitochondria attached to microsomal membrane fractions. Based on these findings, it was concluded that adriamycin activation in heart cells is due to the existence of the heart specific exogenous NADH-oxidoreductase. Considering the physiological function of this enzyme, activation of cellular adriamycin also appears to be regulated by metabolic changes of cytosolic NADH/NAD ratios.

Fujianmycins A and B, new benz(a)anthraquinone antibiotics from a Streptomyces species.

Fujianmycins A and B, new benz(a)anthraquinone antibiotics from a Streptomyces species.