Lanyamycin, a macrolide antibiotic from Sorangium cellulosum, strain Soce 481 (Myxobacteria)

• Lucky S. Mulwa,
• Rolf Jansen,
• Dimas F. Praditya,
• Kathrin I. Mohr,
• Patrick W. Okanya,
• Joachim Wink,
• Eike Steinmann and
• Marc Stadler

Beilstein J. Org. Chem. 2018, 14, 1554–1562, doi:10.3762/bjoc.14.132

• Bochum, Germany 10.3762/bjoc.14.132 Abstract Lanyamycin (1/2), a secondary metabolite occurring as two epimers, was isolated from the myxobacterium Sorangium cellulosum, strain Soce 481. The structures of both epimers were elucidated from HRESIMS and 1D and 2D NMR data and the relative configuration of

• optimized and scaled up. The main active principle was identified as soraphen A, which is already known from Sorangium cellulosum [9]. However, on close analysis of peak–activity correlation, we detected another biologically active metabolite inhibiting growth of Micrococcus luteus correlating to a

Synthesis of trifluoromethylated 2H-azirines through Togni reagent-mediated trifluoromethylation followed by PhIO-mediated azirination

• Jiyun Sun,
• Xiaohua Zhen,
• Huaibin Ge,
• Guangtao Zhang,
• Xuechan An and
• Yunfei Du

Beilstein J. Org. Chem. 2018, 14, 1452–1458, doi:10.3762/bjoc.14.123

• ][13] (Aubagio®, the active metabolite of leflunomide for the treatment of multiple sclerosis), and pleconaril (Figure 1, C) [14][15][16] (an antiviral drug), all possess this privileged substituent. Although many useful synthetic methods [17][18][19][20][21] have been established for introducing the

Two new 2-alkylquinolones, inhibitory to the fish skin ulcer pathogen Tenacibaculum maritimum, produced by a rhizobacterium of the genus Burkholderia sp.

• Dandan Li,
• Naoya Oku,
• Atsumi Hasada,
• Masafumi Shimizu and
• Yasuhiro Igarashi

Beilstein J. Org. Chem. 2018, 14, 1446–1451, doi:10.3762/bjoc.14.122

• subsequently transferred into IMM-HS medium, which was designed for metabolite production based on the composition of IMM [11] and HS media [12]. The fermented culture was extracted with 1-BuOH and the extract was fractionated by solvent-partitioning to yield n-hexane-, 90% aqueous MeOH-, and 60% aqueous MeOH

On the design principles of peptide–drug conjugates for targeted drug delivery to the malignant tumor site

• Eirinaios I. Vrettos,
• Gábor Mező and
• Andreas G. Tzakos

Beilstein J. Org. Chem. 2018, 14, 930–954, doi:10.3762/bjoc.14.80

• deactivation through deamination in its inactive metabolite dFdU, the acquired multidrug resistance (MDR) and its high hydrophilicity deterring its prolonged drug release from various vehicles [88], which therefore reduces the effective concentration of gemcitabine. It enters cells through nucleoside

Development of novel cyclic NGR peptide–daunomycin conjugates with dual targeting property

• Andrea Angelo Pierluigi Tripodi,
• Szilárd Tóth,
• Kata Nóra Enyedi,
• Gitta Schlosser,
• Gergely Szakács and
• Gábor Mező

Beilstein J. Org. Chem. 2018, 14, 911–918, doi:10.3762/bjoc.14.78

• synthesized by SPPS on a Rink-Amide MBHA Resin, using Fmoc/t-Bu strategy. The anticancer drug daunomycin was conjugated to the Aoa-GFLGK spacer via oxime linkage [17]. This spacer is degraded by lysosomal enzymes ensuring the release of the Dau=Aoa-Gly-OH as the smallest bioactive metabolite in lysosomes [19

• the active metabolite Dau=Aoa-Gly-OH by lysosomal degradation. In contrast, free Dau enters the cells in an unspecific manner which might explain the lower antitumor effect of conjugates in comparison with the free drug. In this experiment we measured the cytostatic effect (6 h treatment and further

• the smallest active Dau containing metabolite Dau=Aoa-Gly-OH. No significant difference in degradation speed of the conjugates was observed. Therefore, the replacement of Lys has no influence on the biological activity through the lysosomal degradation. Cellular uptake Daunomycin is fluorescent

Synthesis and in vitro biochemical evaluation of oxime bond-linked daunorubicin–GnRH-III conjugates developed for targeted drug delivery

• Sabine Schuster,
• Beáta Biri-Kovács,
• Bálint Szeder,
• Viktor Farkas,
• László Buday,
• Zsuzsanna Szabó,
• Gábor Halmos and
• Gábor Mező

Beilstein J. Org. Chem. 2018, 14, 756–771, doi:10.3762/bjoc.14.64

• liver lysosomal homogenate have been performed. All derivatives showed high binding affinities to GnRH receptors and displayed in vitro cytostatic effects on HT-29 and MCF-7 cancer cells with IC50 values in a low micromolar range. Moreover, we found that the release of the active drug metabolite and the

• smallest Dau metabolite obtained by lysosomal degradation is H-Lys(Dau=Aoa)-OH, which is able to bind to DNA resulting in a cytotoxic effect. A variety of oxime bond containing GnRH-III drug conjugates have been designed in our research group and their in vitro cytotoxic effects on hormone dependent human

• ]. During this time, no decomposition of the conjugates was observed, demonstrating that no free drug or small drug containing metabolite was produced in medium during the treatment that might have influence on the in vitro biological assays. Besides stability under physiological conditions, the release of

Volatiles from the xylarialean fungus Hypoxylon invadens

• Jeroen S. Dickschat,
• Tao Wang and
• Marc Stadler

Beilstein J. Org. Chem. 2018, 14, 734–746, doi:10.3762/bjoc.14.62

• (18), one of the major constituents in the H. invadens headspace extracts, has been reported before from various ascomycetes, especially from the genus Daldinia and other endophytic fungi [16][17][18][19][20][21][22][23][24][25]. It did, however, not constitute a major metabolite during the screening

• in fungi [34]. Conclusion The genus Hypoxylon has already been examined extensively for secondary metabolite production, and some of its species like H. pulicicidum and H. rickii are extremely creative with respect to the production of non-volatile compounds [35][36][37]. The current study is the

Electrochemical Corey–Winter reaction. Reduction of thiocarbonates in aqueous methanol media and application to the synthesis of a naturally occurring α-pyrone

• Ernesto Emmanuel López-López,
• José Alvano Pérez-Bautista,
• Fernando Sartillo-Piscil and
• Bernardo A. Frontana-Uribe

Beilstein J. Org. Chem. 2018, 14, 547–552, doi:10.3762/bjoc.14.41

• 1–3 was reported by our research group [7]. These molecules proved to be enantiomers of metabolites isolated from Trichoderma spp and Penicillium isolates. Unfortunately, our efforts for obtaining the natural metabolite trans-6-(pent-1-enyl)-α-pyrone (5) (isolable from Trichoderma viride [8]) via a

• /AcONa buffer 0.5 M as electrolytic media. We term this transformation as the “Electrochemical Corey–Winter (ECW) reaction”. This new environmentally friendly process was used to synthetize a metabolite isolated from Trichoderma viride in high yield. Alkenes and α,β-unsaturated ester functionalities are

Volatiles from the tropical ascomycete Daldinia clavata (Hypoxylaceae, Xylariales)

• Tao Wang,
• Kathrin I. Mohr,
• Marc Stadler and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2018, 14, 135–147, doi:10.3762/bjoc.14.9

• different compound classes including fatty acid derivatives and polyketides, aromatic compounds, terpenes, sulfur and nitrogen compounds, and halogenated compounds is produced by ascomycete fungi [1]. Possibly the most widespread volatile secondary metabolite from fungi is (R)-oct-1-en-3-ol (1, Scheme 1), a

• new compounds. Some of these metabolites were tested for biological effects and found to display only weak activities in biological systems, providing evidence for their safety. In addition, none of the volatiles detected here represents a metabolite that is biosynthetically linked to a known class of

Herpetopanone, a diterpene from Herpetosiphon aurantiacus discovered by isotope labeling

• Xinli Pan,
• Nicole Domin,
• Sebastian Schieferdecker,
• Hirokazu Kage,
• Martin Roth and
• Markus Nett

Beilstein J. Org. Chem. 2017, 13, 2458–2465, doi:10.3762/bjoc.13.242

• subject to enzymatic modifications in their native producers. The exclusive testing of a terpene cyclase might hence unveil a biosynthetic intermediate rather than the final product of a secondary metabolite pathway [5][6]. To avoid this problem, we here describe a method for the identification of

• JP 36. Distribution of isotopic labels from [1-13C]-glucose via the MEP (route a) and MEV pathway (route b). Potentially labeled carbon atoms are highlighted with red dots. High-resolution mass spectra of a metabolite from H. aurantiacus obtained after feeding of unlabeled (A) and [1-13C]-labeled D

Sulfation and amidinohydrolysis in the biosynthesis of giant linear polyenes

• Hui Hong,
• Markiyan Samborskyy,
• Katsiaryna Usachova,
• Katharina Schnatz and
• Peter F. Leadlay

Beilstein J. Org. Chem. 2017, 13, 2408–2415, doi:10.3762/bjoc.13.238

• . Sulfonation has been suggested as a novel approach to block the development of antibiotic resistance [33][34] while the discovery of the sulfated metabolite FR901379 was a critical breakthrough in the successful clinical development of micafungin to combat systemic fungal infections [12]. HPLC–UV–MS analysis

Synthesis of ergostane-type brassinosteroids with modifications in ring A

• Vladimir N. Zhabinskii,
• Darya A. Osiyuk,
• Yuri V. Ermolovich,
• Natalia M. Chaschina,
• Tatsiana S. Dalidovich,
• Miroslav Strnad and
• Vladimir A. Khripach

Beilstein J. Org. Chem. 2017, 13, 2326–2331, doi:10.3762/bjoc.13.229

• -ketones of type 12 The only natural compound of type 12 (Scheme 1) known to date is 3-dehydro-24-epicastasterone (38) which was identified as a metabolite of 24-epicastasterone (1) in cell suspension cultures of Lycopersicon esculentum [32]. All attempts to prepare 38 through the intermediate 27 gave poor

18-Hydroxydolabella-3,7-diene synthase – a diterpene synthase from Chitinophaga pinensis

• Jeroen S. Dickschat,
• Jan Rinkel,
• Patrick Rabe,
• Arman Beyraghdar Kashkooli and
• Harro J. Bouwmeester

Beilstein J. Org. Chem. 2017, 13, 1770–1780, doi:10.3762/bjoc.13.171

• alcohol that can easily be isolated by extraction and column chromatography, which underpins the potential of plants, besides the recently reviewed microbial hosts for the sustainable production of diterpenes [36], as expression systems for secondary metabolite genes. The function of the investigated

The chemistry and biology of mycolactones

• Matthias Gehringer and
• Karl-Heinz Altmann

Beilstein J. Org. Chem. 2017, 13, 1596–1660, doi:10.3762/bjoc.13.159

• (mycolactones C (2), D (3), E (6) and its minor oxo-metabolite (7), F (8) and dia-F (9), S1 (4) and S2 (5)) (Figure 2) were discovered in extracts from different M. ulcerans strains and closely related mycobacteria. Given their close genetic relationship [44], it has been suggested that all currently known

• was the correct one [57]. Besides mycolactone E (6), a minor metabolite (7) with a keto group replacing the hydroxy function at the C13’-position was found in M. ulcerans ecovar liflandii lipid extracts [50][56]. Again, the structure was finally established by Kishi and co-workers using a combination

Characterization of non-heme iron aliphatic halogenase WelO5* from Hapalosiphon welwitschii IC-52-3: Identification of a minimal protein sequence motif that confers enzymatic chlorination specificity in the biosynthesis of welwitindolelinones

• Qin Zhu and
• Xinyu Liu

Beilstein J. Org. Chem. 2017, 13, 1168–1173, doi:10.3762/bjoc.13.115

• application. Results and Discussion H. welwitschii IC-52-3 and UTEX B1830 are two known welwitindolinone producers that were reported to produce identical sets of hapalindole-type alkaloids [20], albeit the detailed metabolite analysis from the latter was never published. During our recent effort to define

From chemical metabolism to life: the origin of the genetic coding process

• Antoine Danchin

Beilstein J. Org. Chem. 2017, 13, 1119–1135, doi:10.3762/bjoc.13.111

• , an amino acid absent from the very first steps of prebiotic metabolism), while purine biosynthesis combines glycine and aspartate, together with phosphorylated derivatives of ribose. These pathways open up a major chemical challenge. Ribose is a very unstable metabolite. Any scenario that advances

Synthesis and enzymatic ketonization of the 5-(halo)-2-hydroxymuconates and 5-(halo)-2-hydroxy-2,4-pentadienoates

• Tyler M. M. Stack,
• William H. Johnson Jr. and
• Christian P. Whitman

Beilstein J. Org. Chem. 2017, 13, 1022–1031, doi:10.3762/bjoc.13.101

• described. General methods Mass spectral data were obtained on an LCQ electrospray ion-trap mass spectrometer (Thermo, San Jose, CA) in the ICMB Protein and Metabolite core facility. The samples were prepared as described previously [21]. Kinetic data were obtained at 24 °C on an Agilent 8453 diode-array

• using 5a–d.a Kinetic parameters for Lc 4-OT using 5a–da. Supporting Information Supporting Information File 166: Analytical data. Acknowledgements The protein mass spectrometry analysis was conducted in the Institute for Cellular and Molecular Biology Protein and Metabolite Analysis Facility at the

Use of costic acid, a natural extract from Dittrichia viscosa, for the control of Varroa destructor, a parasite of the European honey bee

• Kalliopi Sofou,
• Demosthenis Isaakidis,
• Apostolos Spyros,
• Anita Büttner,
• Athanassios Giannis and
• Haralambos E. Katerinopoulos

Beilstein J. Org. Chem. 2017, 13, 952–959, doi:10.3762/bjoc.13.96

• . It has been previously isolated from D. viscosa and its structure was confirmed via NMR analysis [36][37][38]. Moreover, D. viscosa is not the only species containing costic acid as a metabolite. It has been reported in the literature as a component in other plants such as Nectandra cissiflora, Nees

Opportunities and challenges for the sustainable production of structurally complex diterpenoids in recombinant microbial systems

• Katarina Kemper,
• Max Hirte,
• Markus Reinbold,
• Monika Fuchs and
• Thomas Brück

Beilstein J. Org. Chem. 2017, 13, 845–854, doi:10.3762/bjoc.13.85

• in-process-accumulation of the inhibitory metabolite indole [28]. A suitable method for most fermentations is an overlay with apolar alkanes such as dodecane [28][79][95] although subsequent product extraction from this phase may be challenging and oxygenation capacity is reduced. Engineering efflux

Secondary metabolome and its defensive role in the aeolidoidean Phyllodesmium longicirrum, (Gastropoda, Heterobranchia, Nudibranchia)

• Alexander Bogdanov,
• Cora Hertzer,
• Stefan Kehraus,
• Samuel Nietzer,
• Sven Rohde,
• Peter J. Schupp,
• Heike Wägele and
• Gabriele M. König

Beilstein J. Org. Chem. 2017, 13, 502–519, doi:10.3762/bjoc.13.50

• retention times around 14 min in the chromatograms of VLC 5 and 6 contained a metabolite showing an m/z of 319.23 (M + H) and 341.21 (M + Na), which indicated the presence of bisepoxide 12, having a molecular weight of 318.45 Da. A mass charge ratio of 475.39 (M + H − H2O) and 493.39 (M + H), found for the

• cembranoid pavidolide A isolated from the soft coral Sinularia pavida [30] and a metabolite from Sarcophyton glaucum – methyl sarcoate reported by Ishitsuka et al. [29] (see Figure 7). Obvious differences, however were the smaller number of keto groups in compound 5 (only one at C-2 instead of two at C-2 and

• –46.7, c 0.9 in chloroform) for the cembranoid bisepoxide isolated from the soft coral Sarcophyton sp., pointing towards the same structure for this secondary metabolite. However, no 2D NMR data or stereochemistry of this molecule was reported up to now. Here we include the results of 2D NMR (COSY, HMBC

Synthesis of 1-indanones with a broad range of biological activity

• Marika Turek,
• Dorota Szczęsna,
• Marek Koprowski and
• Piotr Bałczewski

Beilstein J. Org. Chem. 2017, 13, 451–494, doi:10.3762/bjoc.13.48

• . Nakiterpiosin (117) is a marine sponge metabolite which demonstrates a potent cytotoxicity against the P388 leukemic cell line. The photo-variant of the Nazarov cyclization has been applied as one of the steps in the total synthesis of nakiterpiosin (117, Scheme 37) [63]. Starting from substrate 115, 1-indanone

Structure–efficiency relationships of cyclodextrin scavengers in the hydrolytic degradation of organophosphorus compounds

• Sophie Letort,
• Michaël Bosco,
• Benedetta Cornelio,
• Frédérique Brégier,
• Sébastien Daulon,
• Géraldine Gouhier and
• François Estour

Beilstein J. Org. Chem. 2017, 13, 417–427, doi:10.3762/bjoc.13.45

• pesticide inclusion into the cyclodextrin cavity undeniably influence the degradation process. Indeed, it was shown that the lowest hydrolysis rates correspond to the highest dissociation constants from TRIMEB [36][37]. As methyl paraoxon represents the main and first metabolite of methyl parathion [38

Polyketide stereocontrol: a study in chemical biology

• Kira J. Weissman

Beilstein J. Org. Chem. 2017, 13, 348–371, doi:10.3762/bjoc.13.39

• ] and hydroxy-/methoxymalonyl-ACP [42] are generated via multi-step pathways from a primary metabolite, with the intermediates tethered to a discrete ACP domain. The building blocks are then transferred onto the AT domains of the PKS, and from there to the downstream integral ACP to participate in chain

Enduracididine, a rare amino acid component of peptide antibiotics: Natural products and synthesis

• Darcy J. Atkinson,
• Briar J. Naysmith,
• Daniel P. Furkert and
• Margaret A. Brimble

Beilstein J. Org. Chem. 2016, 12, 2325–2342, doi:10.3762/bjoc.12.226

• mechanism is operative [31]. Indole metabolite In 1996, during a screening program for biologically active metabolites from marine ascidians, Riguera et al. identified a small group of amino acid containing compounds in a cytotoxic extract of the ascidian Leptoclinides dubius [32]. Among these compounds was

• the unique enduracididine-containing bromoindole metabolite 11 (Figure 4). This was the first time the enduracididine motif had been isolated from a marine source. The exact compound responsible for the observed cytotoxicity was not determined. Mannopeptimycins Mannopeptimycins α–ε (12–16, Figure 5

Rearrangements of organic peroxides and related processes

• Ivan A. Yaremenko,
• Vera A. Vil’,
• Dmitry V. Demchuk and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2016, 12, 1647–1748, doi:10.3762/bjoc.12.162

• both fragments of the polypropionate metabolite dolabriferol from a common precursor. The endoperoxide 304 was converted into ketone 305 with the help of the pseudo-enantiomeric quinine-derived catalyst (deMeQ-Ac) in toluene with moderate 47% yield. The peroxide 306 was transformed into ketone 307 with