Heronamycin A: a new benzothiazine ansamycin from an Australian marine-derived Streptomyces sp.

Chemical analysis of a marine-derived Streptomyces sp. (CMB-M0392) isolated from sediment collected off Heron Island, Queensland, Australia, yielded a new benzothiazine ansamycin, heronamycin A. The absolute stereostructure of heronamycin A was determined by detailed spectroscopic analysis and X-ray crystallography. Heronamycin A exhibited modest antimicrobial activity against Bacillus subtilis strains ATCC 6051 and 6633 (IC₅₀ = 18 and 14 μM, respectively).     

Lactoquinomycin C and D,two new medermycin derivatives from the marine-derived Streptomyces sp. SS17A

Abstract

Lactoquinomycin C (1) and Lactoquinomycin D (2), two new medermycin derivatives together with six known compounds (3–8) were isolated from the rice solid fermentation of the marine-derived Streptomyces sp. SS17A. The intriguing structural features of the Lactoquinomycin D (2) which contains 5,14-epoxidation is relatively rare in medermycin derivatives. Compounds 1 and 2 exhibited no cytotoxicity against PC-3 and HCT-116 cancer cell lines, whereas compound 3 showed stronger cytotoxicity with IC₅₀ values of 0.02 and 0.04?μM, respectively. A structure-activity relationship was observed for the cytotoxicity of the medermycin derivatives with a γ-lactone unit is required for significant cytotoxicity based on compounds 1–3.     

Angucycline antibiotics and its derivatives from marine-derived actinomycete Streptomyces sp. A6H

Vineomycin A₁ (1) and B₂ (2) were isolated from the culture broth of marine actinomycete Streptomyces sp. A6H. Five hydrolysis products were obtained by rational hydrolysis and methanolysis of the fermentation extract. Their structures were characterised as aquayamycin (3), vineomycinone B₂ (4), 9-C-_D-olivosyltetrangulol (5), 7-O-methylgaltamycinone (6) and vineomycinone B₂ methyl ester (7). In addition to these compounds, two ester derivatives, vineolactone A (8) and vineomycinone B₂ benzyl ester (9) of compound 4 were generated semisynthetically. Compound 6 is a new analogue of galtamycinone, while compounds 8 and 9 are new members of vineomycins. Cytotoxic activities and antimicrobial activities were determined for all compounds. The results indicate that only compound 1 showed significant activities with IC₅₀ value of 0.34 μM against H1975 and MIC value of 4 μg/mL against Staphylococcus aureus.     

Synthesis of enantioenriched propargylic alcohols related to polyketide natural products. A comparison of methodologies

[reaction: see text] Applications of methodology for the synthesis of propargylic alcohols related to polyketide natural products were examined. Noyori's asymmetric transfer hydrogenation of alpha-chiral alkynones was found to be highly selective and catalyst controlled. Additions of TMS acetylene to alpha-chiral aldehydes, catalyzed by a Ti(O-i-Pr)(4)-BINOL complex, were diastereoselective but substrate dependent.     

Biomimetic synthesis of pyrone-derived natural products: exploring chemical pathways from a unique polyketide precursor

Our biomimetic hypothesis proposes that families of diverse natural products with complex core structures such as 9,10-deoxytridachione, photodeoxytridachione and ocellapyrone A are derived in nature from a linear and conformationally strained all-( E) tetraene-pyrone precursor. We therefore synthesized such a precursor and investigated its biomimetic transformation under a variety of reaction conditions, both to the above natural products as well as to diverse isomers which we propose to be natural products "yet to be discovered". We also report herein the first synthesis of the natural product iso-9,10-deoxytridachione.     

Total syntheses of (+)-spiculoic acid A and (+)-zyggomphic acid, new marine natural products of polyketide origin

The total syntheses of both natural (+)-spiculoic acid A and (+)-zyggomphic acid, new cytotoxic marine natural products of polyketide origin, have been accomplished for the first time. These syntheses were achieved by the highly stereoselective and high-yielding intramolecular Diels-Alder reaction of a functionalized (E,E,E)-2,7,9-dodecanal derivative to construct the core tetrahydroindan-2-one skeleton. A stereocongener of (+)-spiculoic acid A, i.e., the (2R,5S,6R)-isomer, was also synthesized. The details of these total syntheses are described.     

Conformation-activity relationships in polyketide natural products: a new perspective on the rational design of epothilone analogues

The syntheses of C14-methyl analogues of epothilone B and D are described. Conformational analysis using computational methods, X-ray crystallography, and NMR studies showed that the stereochemistry at C14 has a pronounced effect on the conformation of the epoxide region. Biological assays indicated significant differences in their biological activity. Substitution which stabilized conformer I retained significant biological activity. In contrast, substitution which stabilized conformer II provided analogues with no measurable cytotoxicity. The conformation-activity relationships strongly support the importance of conformer I as the bioactive conformation of the epoxide region of epothilone. The approach presented here offers a new perspective on rational design of modified biologically active polyketides.     

A pair of enantiomeric 5-oxabicyclic[4.3.0]lactam derivatives and one new polyketide from the marine-derived fungus Penicillium griseofulvum

A pair of enantiomeric 4-oxabicyclic[4.3.0]lactam derivatives, (+)- and (?)-penicilactam A (1), and one new polyketide derivative penicitrinone F (2) were isolated from the marine-derived fungus Penicillium griseofulvum GT-10. Their structures and absolute configurations were elucidated through extensive spectroscopic analyses combined with the calculated ECD spectra. Penicitrinone F (2) had moderate inhibitory activity towards Bacillus subtilis with a MIC value of 6.3 μM.     

Streptocarbazoles A and B, two novel indolocarbazoles from the marine-derived actinomycete strain Streptomyces sp. FMA

Streptocarbazoles A (1) and B (2), two novel indolocarbazoles featuring unprecedented cyclic N-glycosidic linkages between 1,3-carbon atoms of the glycosyl moiety and two indole nitrogen atoms of the indolocarbazole core, were isolated from the marine-derived actinomycetes strain Streptomyces sp. FMA. Their structures were established by spectroscopic methods, CD spectra, and ECD quantum mechanical calculations. Compound 1 was cytotoxic on HL-60 and A-549 cell lines and could arrest the cell cycle of Hela cells at the G(2)/M phase.     

Amphotericin biosynthesis in Streptomyces nodosus: deductions from analysis of polyketide synthase and late genes.

BACKGROUND: The polyene macrolide amphotericin B is produced by Streptomyces nodosus ATCC14899. Amphotericin B is a potent antifungal antibiotic and has activity against some viruses, protozoans and prions. Treatment of systemic fungal infections with amphotericin B is complicated by its low water-solubility and side effects which include severe nephrotoxicity. Analogues with improved properties could be generated by manipulating amphotericin biosynthetic genes in S. nodosus. RESULTS: A large polyketide synthase gene cluster was cloned from total cellular DNA of S. nodosus. Nucleotide sequence analysis of 113193 bp of this region revealed six large polyketide synthase genes as well as genes for two cytochrome P450 enzymes, two ABC transporter proteins, and genes involved in biosynthesis and attachment of mycosamine. Phage KC515-mediated gene disruption was used to show that this region is involved in amphotericin production. CONCLUSIONS: The availability of these genes and the development of a method for gene disruption and replacement in S. nodosus should allow production of novel amphotericins. A panel of analogues could lead to identification of derivatives with increased solubility, improved biological activity and reduced toxicity.     

A new polyketide purpurogenic acid: the activated production of polyketides by the diethyl sulphate mutagenesis of marine-derived Penicillium purpurogenum G59

A new polyketide, purpurogenic acid (1), and two known polyketides, (-)-mitorubrin (2) and (-)-mitorubrinol (3), were isolated from a fungal mutant derived from the diethyl sulphate (DES) mutagenesis of marine-derived Penicillium purpurogenum G59. The planar structure of new 1 was elucidated by spectroscopic methods and the absolute configuration was assigned on the basis of [α]_D and CD data. In our preliminary MTT assay, 1 inhibited human cancer K562, HL-60, HeLa and BGC-823 cells with the inhibition rates of 52.7, 78.8, 38.4 and 35.3% at the 100 μg/mL, respectively.     

Purification and structure elucidation of three naturally bioactive molecules from the new terrestrial Streptomyces sp. TN17 strain

Thirty litres of fermentation broth was extracted from the newly isolated Streptomyces sp. strain TN17 and various separation and purification steps led to the isolation of three pure bioactive compounds (1-3). Compound 1: cyclo (L-Leu-L-Arg), a diketopiperazine 'DKP' derivative; 2: di-(2-ethylhexyl) phthalate, a phthalate derivative; and 3: cyclo 1-[2-(cyclopentanecarbonyl-3-phenyl-propionyl]-pyrrolidine-2-carboxylic acid (1-carbamoyl-propyl)-amide, a cyclic tetrapeptide derivative. The chemical structure of these three active compounds was established on the basis of spectroscopic studies (MS and NMR) and by comparison with data from the literature. According to our biological studies, the pure compounds (1-3) possess antibacterial and antifungal activities.     

New natural products in the discorhabdin A- and B-series from New Zealand-sourced Latrunculia spp. sponges

A survey of the secondary metabolite chemistry profiles of New Zealand sponges of the genus Latrunculia has yielded new members of the discorhabdin A- and B-type families. The structure elucidation of (+)-(6R,8S)-1-thiomethyldiscorhabdin G^∗/I (5) and both enantiomers of 16a,17a-dehydrodiscorhabdin W (6) are reported. Absolute configurations were assigned by comparison with a dataset of recently reported electronic circular dichroism spectra of discorhabdin alkaloids. A stereochemical correction of the recently reported natural product (+)-3-dihydrodiscorhabdin A from (3S,5R,6S,8S)-(7) to the C3-epimeric (+)-(3R,5R,6S,8S)-(8) and assignment of absolute configuration is also presented. Semi-synthesis of (+)-(3S,5R,6S,8S)-(7) from (+)-discorhabdin A provided further evidence for this structure revision. Cytotoxicity data is reported for 5-8.     

A new and simple approach to chemical complexity. Application to the synthesis of natural products

A new approach to describe the complexity of chemical structures is proposed. This index is simple and can be easily programmed. It derives from Whitlock's index and, despite its empirical character, provides results paralleling those obtained with the mathematical Bertz index. It has been applied to follow the strategic progress of some natural product syntheses.     

High stereochemical diversity and applications for the synthesis of marine natural products: a library of carbohydrate mimics and polyketide segments

We have developed a powerful concept for the rapid assembly of a series of twenty-four homochiral building blocks from simple racemic trans-2,4-dimethyl-8-oxabicyclo[3.2.1]oct-6-en-3-one. The series comprises eight stereochemical pentades of anomeric [3.3.1]lactone acetals, eight stereochemical tetrades of anomeric carbohydrate mimics, and eight stereotetrades of acyclic polypropionate units. The utility of these enantiopure materials (average 94% ee) in natural product synthesis is demonstrated and shown to complement the popular aldol method.     

The stereochemical assignment of acyclic polyols: a computational study of the NMR data of a library of stereopentad sequences from polyketide natural products

The reliable stereochemical assignment of flexible molecules, such as acyclic polypropionates is an enormously challenging task. This is illustrated by the NMR chemical shifts for a complete set of sixteen diastereomeric stereopentads whose experimental data is reported here for the first time. Although the experimental spectra are very similar to each other, analysis of the similarity between the shifts of different diastereoisomers reveals that some diastereoisomers are much more distinctive than others. In addition, the NMR shifts of the sixteen compounds have also been calculated using DFT GIAO calculations, and the use of our recently developed CP3 parameter for structure assignment is illustrated for these molecules. Even in cases where the experimental spectra are very similar, our CP3 parameter makes possible the correct assignment of pairs of diastereoisomers with high confidence.     

ent-Homoabyssomicins A and B, two new spirotetronate metabolites from Streptomyces sp. Ank 210

ent-Homoabyssomicins A (1) and B (2) are new complex polycyclic spirotetronate metabolites isolated from Streptomyces sp. isolate Ank 210. The structures of 1 and 2 were elucidated by detailed spectroscopic analyses of 1D and 2D NMR data. The absolute configuration of 1 was established by subsequent single-crystal X-ray diffraction studies.     

Isolation and structure elucidation of diazaquinomycin C from a terrestrial Streptomyces sp. and confirmation of the akashin structure

In the screening of terrestrial Streptomycetes for bioactive components, a new antibiotic designated as diazaquinomycin C (2b) was isolated. The new antibiotic was found to be a homologue of diazaquinomycin A (2a) by spectroscopic methods and by comparison of the NMR data with those of 2a. The same strain additionally produced the akashins 1a-1c. The configuration of the N-O acetale bond in these rare glycosylated dichloroindigo derivatives was confirmed to be beta.