cas 51576-04-6, (2S,3S)-2-HYDROXY-3-METHYLPENTANOIC ACID

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Structure revision of isocereulide A, an isoform of the food poisoning emetic Bacillus cereus toxin cereulide
The emetic Bacillus cereus toxin cereulide presents an enormous safety hazard in the food industry, inducing emesis and nausea after the consumption of contaminated foods. Additional to cereulide itself, seven structurally related isoforms, namely the isocereulides A-G, have already been elucidated in their chemical structure and could further be identified in B. cereus contaminated food samples. The newly performed isolation of isocereulide A allowed, for the first time, 1D- and 2D-NMR spectroscopy of a biosynthetically produced isocereulide, revealing results that contradict previous assumptions of an L-O-Leu moiety within its chemical structure. By furthermore applying posthydrolytical dipeptide analysis, amino acid and α-hydroxy acid analysis by means of UPLC-ESITOF- MS, as well as MSn sequencing, the structure of previously reported isocereulide A could be corrected. Instead of the L-O-Leu as assumed to date, one L-O-Ile unit could be verified in the cyclic dodecadepsipeptide, revising the structure of isocereulide A to [(D-O-Leu-D-Ala-L-O-Val-L-Val)2(DO- Leu-D-Ala-L-O-Ile-L-Val)].
Ehling-Schulz, Monika,Hofmann, Thomas F.,Kranzler, Markus,Stark, Timo D.,Walser, Veronika
supporting information

(2021/05/31)

ANTIMICROBIAL PEPTIDES AND METHODS OF USE
Cyclic depsipeptide-class molecules, referred to herein as persephacins (including analogs thereof), having similarities to aureobasidin A, are described. The persephacins have antimicrobial activity, such as antifungal activity against a diverse range of clinically -relevant fungal pathogens, antiprotozoan parasite activity, and antibacterial activity, and can be used for example in treatments of difficult-to-treat ocular fungal infections at lower concentrations than natamycin. The active compounds may be combined with a secondary compound in a composition.
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Paragraph 0009; 0139

(2020/02/14)

Synthesis and Structure-Activity Relationship Studies of C2-Modified Analogs of the Antimycobacterial Natural Product Pyridomycin
A series of derivatives of the antimycobacterial natural product pyridomycin have been prepared with the C2 side chain attached to the macrocyclic core structure by a C-C single bond, in place of the synthetically more demanding enol ester double bond found in the natural product. Hydrophobic C2 substituents of sufficient size generally provide for potent anti-Mtb activity of these dihydropyridomycins (minimum inhibitory concentration (MIC) values around 2.5 μM), with several analogs thus approaching the activity of natural pyridomycin. Surprisingly, some of these compounds, in contrast to pyridomycin, are insensitive to overexpression of InhA in Mycobacterium tuberculosis (Mtb). This indicates that their anti-Mtb activity does not critically depend on the inhibition of InhA and that their overall mode of action may differ from that of the original natural product lead.
Kienle, Maryline,Eisenring, Patrick,Stoessel, Barbara,Horlacher, Oliver P.,Hasler, Samuel,Van Colen, Gwéna?lle,Hartkoorn, Ruben C.,Vocat, Anthony,Cole, Stewart T.,Altmann, Karl-Heinz
p. 1105 - 1131
(2020/03/10)

Discovery, Total Synthesis, and SAR of Anaenamides A and B: Anticancer Cyanobacterial Depsipeptides with a Chlorinated Pharmacophore
New modified depsipeptides and geometric isomers, termed anaenamides A (1a) and B (1b), along with the presumptive biosynthetic intermediate, anaenoic acid (2), were discovered from a marine cyanobacterium from Guam. Structures were confirmed by total synthesis. The alkylsalicylic acid fragment and the C-terminal α-chlorinated α,β-unsaturated ester are novelties in cyanobacterial natural products. Cancer cell viability assays indicated that the C-terminal unit serves as the pharmacophore and that the double-bond geometry impacts the cytotoxicity.
Brumley, David A.,Chen, Qi-Yin,Gunasekera, Sarath P.,Luesch, Hendrik,Paul, Valerie J.
supporting information
p. 4235 - 4239
(2020/06/27)

Stereoselective Modification of N-(α-Hydroxyacyl)-glycinesters via Palladium-Catalyzed Allylic Alkylation
N-(α-Hydroxyacyl)-glycinesters can be used as excellent nucleophiles in Pd-catalyzed allylic alkylation. The method allows for the stereoselective introduction of a wide range of side chains, including highly functionalized ones. Both diastereomers can be accessed through variation of the reaction conditions. Furthermore, the use of stannylated carbonates introduces vinylstannane motifs, which are eligible for subsequent C-C coupling reactions.
Horn, Alexander,Kazmaier, Uli
supporting information
p. 4595 - 4599
(2019/06/27)

APRATYRAMIDE THERAPEUTIC AGENTS AND METHODS OF TREATMENT
The invention is directed towards Apratyramide linear depsipeptide compounds, pharmaceutical compositions thereof, and methods of affecting wound healing, and methods of affecting the biological processes involved in wound healing (e.g., inflammation, cell proliferation, tissue granulation, remodeling of scar tissue, etc.).
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(2019/06/11)

Isolation, structure elucidation and biological evaluation of lagunamide D: A new cytotoxic macrocyclic depsipeptide from marine cyanobacteria
Lagunamide D, a new cytotoxic macrocyclic depsipeptide, was discovered from a collection of marine cyanobacteria from Loggerhead Key in the Dry Tortugas, Florida. An intramolecular ester exchange was observed, where the 26-membered macrocycle could contract to a 24-membered compound via acyl migration at the 1,3-diol unit, and the transformation product was named lagunamide D'. The planar structures of both compounds were elucidated using a combination of nuclear magnetic resonance (NMR) spectroscopy and high-resolution mass spectroscopy (HRMS). The absolute configurations were determined on the basis of enantioselective analysis, modified Mosher's analysis, Kishi NMR database, and direct comparison with lagunamide A, a structure closely resembling lagunamide D. Lagunamides A and D displayed low-nanomolar antiproliferative activity against A549 human lung adenocarcinoma cells, while the structural transformation from the 26-membered lagunamide D macrocycle to the 24-membered ring structure for lagunamide D' led to a 9.6-fold decrease in activity. Lagunamide D also displayed potent activity in triggering apoptosis in a dose- and time-dependent manner. Further investigation on the mechanism of action of the lagunamide scaffold is needed to fully explore its therapeutic potential as an anticancer agent.
Luo, Danmeng,Putra, Masteria Y.,Ye, Tao,Paul, Valerie J.,Luesch, Hendrik
(2019/02/19)

Total syntheses of cathepsin D inhibitory izenamides A, B, and C and structural confirmation of izenamide B
The first total syntheses of izenamides A, B, and C, which are depsipeptides inhibitor of cathepsin D, were accomplished. In addition, the stereochemistry of izenamide B was confirmed by our syntheses. The key features of our synthetic route involve the avoidance of critical 2,5-diketopiperazine (DKP) formation and the minimization of epimerization during the coupling of amino acids for the target peptides.
Lim, Changjin
(2019/10/02)

Readily Accessible 1,2-Amino Ether Ligands for Enantioselective Intramolecular Carbolithiation
A new class of chiral 1,2-amino ether ligands, readily accessible from naturally occurring α-amino- or α-hydroxy acids, was found to provide high levels of both conversion and stereocontrol (up to 95:5 er) in intramolecular carbolithiation reactions, outperforming the benchmark ligand (?)-sparteine. The ligand could be used in a substoichiometric amount (0.25 equiv) without significant loss of enantioselectivity.
Guyon, Hélène,Boussonnière, Anne,Castanet, Anne-Sophie
p. 4949 - 4957
(2017/05/12)

Hormonemate Derivatives from Dothiora sp., an Endophytic Fungus
A search for cytotoxic agents from cultures of the endophytic fungus Dothiora sp., isolated from the endemic plant Launaea arborescens, led to the isolation of six new compounds structurally related to hormonemate, with moderate cytotoxic activity against different cancer cell lines. By using a bioassay-guided fractionation approach, hormonemates A-D (1-4), hormonemate (5), and hormonemates E (6) and F (7) were obtained from the acetone extract of this fungus. Their structures were determined using a combination of HRMS, ESI-qTOF-MS/MS, 1D and 2D NMR experiments, and chemical degradation. The cytotoxic activities of these compounds were evaluated by microdilution colorimetric assays against human breast adenocarcinoma (MCF-7), human liver cancer cells (HepG2), and pancreatic cancer cells (MiaPaca_2). Most of the compounds displayed cytotoxic activity against this panel.
Pérez-Bonilla, Mercedes,González-Menéndez, Víctor,Pérez-Victoria, Ignacio,De Pedro, Nuria,Martín, Jesús,Molero-Mesa, Joaquín,Casares-Porcel, Manuel,González-Tejero, María Reyes,Vicente, Francisca,Genilloud, Olga,Tormo, José R.,Reyes, Fernando
p. 845 - 853
(2017/05/05)

Dudawalamides A-D, Antiparasitic Cyclic Depsipeptides from the Marine Cyanobacterium Moorea producens
A family of 2,2-dimethyl-3-hydroxy-7-octynoic acid (Dhoya)-containing cyclic depsipeptides, named dudawalamides A-D (1-4), was isolated from a Papua New Guinean field collection of the cyanobacterium Moorea producens using bioassay-guided and spectroscopic approaches. The planar structures of dudawalamides A-D were determined by a combination of 1D and 2D NMR experiments and MS analysis, whereas the absolute configurations were determined by X-ray crystallography, modified Marfey's analysis, chiral-phase GCMS, and chiral-phase HPLC. Dudawalamides A-D possess a broad spectrum of antiparasitic activity with minimal mammalian cell cytotoxicity. Comparative analysis of the Dhoya-containing class of lipopeptides reveals intriguing structure-activity relationship features of these NRPS-PKS-derived metabolites and their derivatives.
Almaliti, Jehad,Malloy, Karla L.,Glukhov, Evgenia,Spadafora, Carmenza,Gutiérrez, Marcelino,Gerwick, William H.
p. 1827 - 1836
(2017/06/28)

Further insight into the asymmetric vinylogous Mukaiyama aldol reaction (VMAR); Application to the synthesis of the C27-C45 segment of lagunamide A
Two iterative vinylogous Mukaiyama aldol reactions (VMAR) have been applied in order to selectively install three contiguous stereocenters at C37, C38 and C39, of the southern hemisphere of lagunamide A. The VMAR methodology allows straightforward access of enantiomerically pure material of the essential segment via seven steps, and in an overall yield of 34%. The synthesis has an orthogonal protecting group strategy, essential for upcoming synthesis for completion of lagunamide A. We also demonstrate that steric bulk of the chiral oxazolidinone pose certain challenges when employing stereochemically crowded α-substituted aldehydes in various VMAR's. A simple synthesis of the essential (2R,3S)-2-hydroxy-3-methylpentanoic acid fragment via Mitsunobu chemistry was also accomplished and incorporated into the C27-C45 fragment of lagunamide A.
Banasik, Brent A.,Wang, Lee,Kanner, Arielle,Mikael Bergdahl
supporting information
p. 2481 - 2490
(2016/04/26)

Total Synthesis of the GRP78-Downregulatory Macrolide (+)-Prunustatin A, the Immunosuppressant (+)-SW-163A, and a JBIR-04 Diastereoisomer That Confirms JBIR-04 Has Nonidentical Stereochemistry to (+)-Prunustatin A
A unified total synthesis of the GRP78-downregulator (+)-prunustatin A and the immunosuppressant (+)-SW-163A based upon [1 + 1 + 1 + 1]-fragment condensation and macrolactonization between O(4) and C(5) is herein described. Sharpless asymmetric dihydroxylation was used to set the C(2) stereocenter present in both targets. In like fashion, coupling of the (+)-prunustatin A macrolide amine with benzoic acid furnished a JBIR-04 diastereoisomer whose NMR spectra did not match those of JBIR-04, thus confirming that it has different stereochemistry than (+)-prunustatin A.
Manaviazar, Soraya,Nockemann, Peter,Hale, Karl J.
supporting information
p. 2902 - 2905
(2016/07/06)

Jamaicensamide A, a Peptide Containing β-Amino-α-keto and Thiazole-Homologated η-Amino Acid Residues from the Sponge Plakina jamaicensis
A new cyclic peptide, jamaicensamide A, composed of six amino acids, including a thiazole-homologated amino acid, was isolated from the Bahamian sponge Plakina jamaicensis, along with known compounds bitungolide A and franklinolide A. The structure of the title peptide was solved by integrated analysis of MS, 1D and 2D NMR data, oxidation-hydrolyses to α-amino acids, and their stereodetermination by Marfey's method. The close structural resemblance of Western Atlantic-derived jamaicensamide A to known Western Pacific-derived peptides of lithistid sponges in the genus Theonella and Discodermia suggests a common origin: the symbiotic bacterium Entotheonella sp., a so-called "talented producer" responsible for biosynthesis of most Theonella-associated peptides. Similar natural products from sponges of disparate genera evince the likelihood that these invertebrates harbor the same or a very similar symbiont.
Jamison, Matthew T.,Molinski, Tadeusz F.
supporting information
p. 2243 - 2249
(2016/10/04)

Odoamide, a cytotoxic cyclodepsipeptide from the marine cyanobacterium Okeania sp.
The bioassay-guided fractionation of the Okinawan marine cyanobacterium Okeania sp. led to the isolation of the 26-membered cyclodepsipeptide odoamide (1). The gross structure of 1 was determined by 1D and 2D NMR analyses, whereas its absolute stereochemistry was determined using a variety of different methods, including synthesis and chemical degradation followed by chiral HPLC analysis. Notably, odoamide (1) showed potent cytotoxicity against HeLa S3 human cervical cancer cells with an IC50value of 26.3?nM.
Sueyoshi, Kosuke,Kaneda, Masato,Sumimoto, Shinpei,Oishi, Shinya,Fujii, Nobutaka,Suenaga, Kiyotake,Teruya, Toshiaki
p. 5472 - 5478
(2016/08/05)

Solid-phase total synthesis of bogorol A: Stereocontrolled construction of thermodynamically unfavored (E)-2-amino-2-butenamide
Bogorol A [(E)-1], a potent antibiotic against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus spp., possesses a thermodynamically unfavored (E)-2-amino-2-butenamide within its linear dodecapeptide sequence. The highly efficient total synthesis of natural (E)-isomer (E)-1 and its artificial (Z)-isomer (Z)-1 by employing a full solid-phase strategy is reported. The (E)- and (Z)-2-amino-2-butenamide moieties were stereoselectively constructed by applying traceless Staudinger ligation on the resin. Interestingly, (E)- and (Z)-1 showed comparable antimicrobial activity (MIC = 4 μg/mL).
Yamashita, Tomoya,Kuranaga, Takefumi,Inoue, Masayuki
supporting information
p. 2170 - 2173
(2015/05/13)

Structure and absolute configuration of auriculamide, a natural product from the predatory bacterium herpetosiphon aurantiacus
The genome of the filamentous, predatory bacterium Herpetosiphon aurantiacus harbors a plethora of genes that are predicted to be involved in natural product biosynthesis. Until now, however, no secondary metabolites have been described from this microorganism. Analysis of H. aurantiacus culture extracts by 1H NMR spectroscopy now led to the discovery of a chlorinated amide, which we termed auriculamide. The configuration of the three chiral centers in auriculamide was solved by chromatographic comparison with stereospecifically prepared reference compounds following chemical degradation. Furthermore, a putative gene cluster for the biosynthesis of auriculamide was identified by genome mining. Chemical analysis of culture extracts from the predatory bacterium Herpetosiphon aurantiacus led to the discovery of the new natural product auriculamide, the structure of which was elucidated by MS and NMR analyses. The absolute configuration was determined, after hydrolysis, by chromatographic comparison with synthetic standards. A gene cluster for the biosynthesis of auriculamide is proposed.
Schieferdecker, Sebastian,Domin, Nicole,Hoffmeier, Christine,Bryant, Donald A.,Roth, Martin,Nett, Markus
p. 3057 - 3062
(2015/05/13)

Synthesis and antimycobacterial activity of novel camphane-based agents
A series of six new amidoalcohols was designed and synthesized on the base of the camphor scaffold. Natural amino acids were transformed into their α-hydroxy analogues with retention of configuration, and attached to isobornylamine. The compounds were evaluated for their in vitro activity against Mycobacterium tuberculosis H37Rv. Some of the new compounds show 25 times higher activity than the classical anti-TB drug ethambutol. The activity shifts from micromolar to nanomolar inhibitory concentrations depending on the α-hydroxy acid moiety. Two of the most potent compounds exert low level of cytotoxic activity. These camphane-based amido-alcohols present promising potential lead compounds for further elaboration of antimycobacterial agents.
Stavrakov, Georgi,Philipova, Irena,Valcheva, Violeta,Momekov, Georgi
p. 165 - 167
(2014/01/17)

Facile synthesis of α-hydroxy carboxylic acids from the corresponding α-amino acids
An effective and improved procedure is developed for the synthesis of α-hydroxy carboxylic acids by treatment of the corresponding protonated α-amino acid with tert-butyl nitrite in 1,4-dioxane-water. The amino moiety must be protonated and located α to a carboxylic acid function in order to undergo initial diazotization and successive hydroxylation, since neither β-amino acids nor acid derivatives such as esters and amides undergo hydroxylations. The method is successfully applied for the synthesis of 18 proteinogenic amino acids.
Stuhr-Hansen, Nicolai,Padrah, Shahrokh,Str?mgaard, Kristian
supporting information
p. 4149 - 4151
(2015/02/02)

Lipodiscamides A-C, new cytotoxic lipopeptides from discodermia kiiensis
Lipodiscamides A-C, three new lipodepsipeptides, were characterized from the marine sponge Discodermia kiiensis. These structurally rare cyclic lipodepsipeptides were found to possess an unprecedented dilactone macrocycle and, thus, represent a new family of lipopeptides. They are the only lipopeptides bearing 4S-hydroxy-trans-2-enoate, and noncanonical amino acids, l-3-ureidoalanine (Uda), E-dehydronorvaline (Denor), and d-citrulline (Cit). MTT assays against P388 and HeLa cells revealed the moderate cytotoxicity of all three compounds.
Tan, Karen Co,Wakimoto, Toshiyuki,Abe, Ikuro
supporting information
p. 3256 - 3259
(2014/07/08)

Maedamide, a novel chymotrypsin inhibitor from a marine cyanobacterial assemblage of Lyngbya sp.
Maedamide, a novel chymotrypsin-inhibiting depsipeptide, was isolated from a cyanobacterial assemblage that mostly consisted of Lyngbya sp. Its structure was elucidated by spectroscopic analyses and chiral HPLC analyses of hydrolysis products. Maedamide selectively inhibited chymotrypsin but not elastase and trypsin. In addition, Maedamide strongly inhibited the growth of HeLa cells and HL60 cells.
Iwasaki, Arihiro,Ohno, Osamu,Sumimoto, Shinpei,Suda, Shoichiro,Suenaga, Kiyotake
supporting information
p. 4126 - 4128
(2014/07/22)

Solid-phase synthesis of tetrahydropyridazinedione-constrained peptides
The design and solid-phase synthesis of tetrahydropyridazine-3,6-dione (Tpd) peptidomimetics derived from backbone-aminated peptides is reported. The described protocol features the synthesis of chiral α-hydrazino acids suitable for chemoselective incorporation into growing peptide chains. Acid-catalyzed cyclization to form the Tpd ring during cleavage affords the target peptidomimetics in good yield and purity. The scope of Tpd incorporation is demonstrated through the synthesis of constrained peptides featuring nucleophilic/electrophilic side chains and sterically encumbered α-substituted hydrazino acid residues. (Chemical Equation Presented).
Kang, Chang Won,Ranatunga, Sujeewa,Sarnowski, Matthew P.,Del Valle, Juan R.
supporting information
p. 5434 - 5437
(2015/02/19)

Rare Streptomyces N-formyl amino-salicylamides inhibit oncogenic K-Ras
During a search for inhibitors of oncogenic K-Ras, we detected two known and two new examples of the rare neoantimycin structure class from a liquid cultivation of Streptomyces orinoci, and reassigned/assigned structures to all based on detailed spectroscopic analysis and microscale C3 Marfey's and C3 Mosher chemical degradation/derivatization/analysis. SAR investigations inclusive of the biosynthetically related antimycins and respirantin, and synthetic benzoxazolone, documented a unique N-formyl amino-salicylamide pharmacophore as a potent inhibitor of oncogenic K-Ras.
Salim, Angela A.,Cho, Kwang-Jin,Tan, Lingxiao,Quezada, Michelle,Lacey, Ernest,Hancock, John F.,Capon, Robert J.
supporting information
p. 5036 - 5039
(2015/02/19)

Facile synthesis of α-hydroxy carboxylic acids from the corresponding α-amino acids
An effective and improved procedure is developed for the synthesis of α-hydroxy carboxylic acids by treatment of the corresponding protonated α-amino acid with tert-butyl nitrite in 1,4-dioxane-water. The amino moiety must be protonated and located α to a carboxylic acid function in order to undergo initial diazotization and successive hydroxylation, since neither β-amino acids nor acid derivatives such as esters and amides undergo hydroxylations. The method is successfully applied for the synthesis of 18 proteinogenic amino acids.
Stuhr-Hansen, Nicolai,Padrah, Shahrokh,Str?mgaard, Kristian
supporting information
p. 4149 - 4151
(2014/07/22)

Pleosporin A, an antimalarial cyclodepsipeptide from an elephant dung fungus (BCC 7069)
Cyclodepsipeptides SCH 217048 (1), SCH 218157 (2), and a new analog, pleosporin A (3), were isolated from cultures of an unidentified elephant dung fungus of the family Pleosporaceae. The structure of 3 was elucidated on the basis of detailed spectroscopic interpretation. The absolute configurations of 1-3 were determined by chiral column HPLC analysis and Marfey's method. Cyclodepsipeptides 1-3 exhibited antimalarial activity against Plasmodium falciparum K1 with respective IC50 values of 1.6, 6.4, and 1.6 μg/mL, while they did not show cytotoxicity against KB, MCF-7 and NCI-H187 cell-lines or non-cancerous Vero cells at 50 μg/mL.
Isaka, Masahiko,Palasarn, Somporn,Komwijit, Somjit,Somrithipol, Sayanh,Sommai, Sujinda
supporting information
p. 469 - 471
(2014/01/06)

MACROCYCLIC INHIBITORS OF FLAVIVIRIDAE VIRUSES
Provided are compounds of Formula I and pharmaceutically acceptable salts and esters thereof. The compounds, compositions, and methods provided are useful for the treatment of virus infections, particularly hepatitis C infections.
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(2014/01/08)

Novel camphane-based anti-tuberculosis agents with nanomolar activity
A series of new amidoalcohols and amidodiols were designed on the base of the camphor scaffold and evaluated for their in vitro activity against Mycobacterium tuberculosis H37Rv and MDR strain 43. Some of the new compounds show 25 times higher activity than the classical anti-TB drug ethambutol. Small structural changes in the side chain shift the activity from micromolar to nanomolar inhibitory concentrations. Quantitative structure-activity relationship (QSAR) model is derived to guide the further lead optimization. Two hydrogen bond donors and up to three rings in the molecules are optimal for nanomolar activity. The camphane-based amides present novel promising scaffolds for antimycobacterial agents.
Stavrakov, Georgi,Valcheva, Violeta,Philipova, Irena,Doytchinova, Irini
p. 372 - 379
(2013/11/19)

Design, synthesis, and functional evaluation of leukocyte function associated antigen-1 antagonists in early and late stages of cancer development
The integrin leukocyte function associated antigen 1 (LFA-1) binds the intercellular adhesion molecule 1 (ICAM-1) by its αL-chain inserted domain (I-domain). This interaction plays a key role in cancer and other diseases. We report the structure-based design, small-scale synthesis, and biological activity evaluation of a novel family of LFA-1 antagonists. The design led to the synthesis of a family of highly substituted homochiral pyrrolidines with antiproliferative and antimetastatic activity in a murine model of colon carcinoma, as well as potent antiadhesive properties in several cancer cell lines in the low micromolar range. NMR analysis of their binding to the isolated I-domain shows that they bind to the I-domain allosteric site (IDAS), the binding site of other allosteric LFA-1 inhibitors. These results provide evidence of the potential therapeutic value of a new set of LFA-1 inhibitors, whose further development is facilitated by a synthetic strategy that is versatile and fully stereocontrolled.
San Sebastián, Eider,Zimmerman, Tahl,Zubia, Aizpea,Vara, Yosu,Martin, Elyette,Sirockin, Finton,Dejaegere, Annick,Stote, Roland H.,Lopez, Xabier,Pantoja-Uceda, David,Valcárcel, María,Mendoza, Lorea,Vidal-Vanaclocha, Fernando,Cossío, Fernando P.,Blanco, Francisco J.
p. 735 - 747
(2013/03/28)

Total synthesis of the Marine cyclic depsipeptide viequeamide A
The first total synthesis of viequeamide A, a natural cyclic depsipeptide isolated from a marine button cyanobacterium, was achieved with the N-Me-Val-Thr peptide bond as the final macrocyclization site. The synthetic product gave nearly identical spectroscopic data to that reported for the natural product.
Wang, Dongyu,Song, Shanshan,Tian, Ye,Xu, Youjun,Miao, Zehong,Zhang, Ao
supporting information
p. 974 - 978
(2013/07/05)

Metabolic fate of depsides and alkaloid constituents in aqueous extracts from Mercurialis perennis L. during fermentation
Dog's mercury (Mercurialis perennis L.) is an old medicinal plant, nowadays used in complementary medicine. Aqueous fermented extracts of the plant are being mainly applied in remedies to treat external inflammations, but a thorough phytochemical characterization is still lacking. Therefore, the conversion of characteristic compound classes from M. perennis extracts during fermentation and storage was investigated. The microbial transformation of the two main depsides phaselic acid (=(2R)-O-[(E)-caffeoyl]malic acid; 1) and mercurialis acid (=(2R)-[(E)-caffeoyloxy]glutaric acid; 2) was monitored by HPLC-DAD. The degradation followed a second-order kinetic, and the calculated half-life periods of both constituents were 67 and 30 months, respectively. Several depside metabolites were detected by GC/MS in AcOEt extracts as tBuMe2Si (TBDMS) derivatives after derivatization, mainly dihydrocinnamic acids. Moreover, numerous α-hydroxy acids were found, allegedly as degradation products from amino acids or peptides. The microbial alteration of the main alkaloid hermidin was also examined. After three days of fermentation, three novel N-metabolites were formed and thoroughly assigned in CH2Cl2 extracts as a mixture of 3-ethylhermidin, 3-ethylhermidin quinone, and (E/Z)-3-ethylidenehermidin by GC/MS and NMR methods, as well as by means of total synthesis. A mechanism for the formation of these N-metabolites starting from dimeric hermidin oxidation products is proposed. The obtained results reveal the complex pathways plant constituents may undergo during the fermentation of the extracts. Copyright
Lorenz, Peter,Conrad, Juergen,Stintzing, Florian C.
p. 1706 - 1723
(2013/10/21)

Continuous multiple liquid-liquid separation: Diazotization of amino acids in flow
A second-generation laboratory-scale, modular liquid-liquid separation device based on computer-controlled high-pressure pumps and a high-resolution digital camera has been invented. The diazotization of amino acids to produce valuable chiral hydroxyacids is demonstrated in flow for the first time. The use of a triple-separator system in conjuction with the developed diazotization process allows the safe and efficient production and automated isolation of multigram quantities of valuable chiral hydroxyacids.
Hu, Dennis X.,O'Brien, Matthew,Ley, Steven V.
supporting information; experimental part
p. 4246 - 4249
(2012/10/08)

Total synthesis of the proposed structure of cyclic hexadepsipeptide veraguamide A
We have developed a practical method to assemble the proposed structure of natural product veraguamide A (1) by first preparing the three key fragments followed by optimization of the macrocyclization site. Although the synthetic product gave similar optical rotation to that reported for natural product, significant differences in the 1H and 13C NMR spectra were observed, especially the proton and carbon signals in the two N-MeVal moieties.
Wang, Dongyu,Jia, Xian,Zhang, Ao
supporting information; experimental part
p. 7027 - 7030
(2012/09/22)

Total synthesis and stereochemical revision of lagunamide A
A revised configurational assignment for the marine metabolite lagunamide A is proposed and validated by total synthesis.
Dai, Lu,Chen, Bo,Lei, Honghui,Wang, Zhuo,Liu, Yuqing,Xu, Zhengshuang,Ye, Tao
supporting information; experimental part
p. 8697 - 8699
(2012/10/08)

Synthesis, characterization and activity of new phosphonate dipeptides as potential inhibitors of VanX
VanX, a Zn(II)-dependent D-ala-D-ala dipeptidase, is essential for vancomycin resistance in Enterococcus faecium. The enzymatic activity of VanX was previously found to be inhibited competitively by 2-{[(1-aminoethyl) (hydroxy) phosphoryl]oxy} propanoic acid (1B). Here we report the synthesis and characterization of seven phosphonate dipeptide analogs of D-ala-D-ala with various substituent, the activity evaluation indicated that six of these phosphonate analogs inhibit VanX with IC50 of 0.48-8.21 mM. These data revealed a structure-activity relationship which is that the large substituent group on β-carbon resulted in low binding affinity of the phonphonate analog to VanX. This information will be helpful to guide the design and synthesis of the tightly-binding inhibitors for VanX.
Jia, Chao,Yang, Ke-Wu,Liu, Cheng-Cheng,Feng, Lei,Xiao, Jian-Min,Zhou, Li-Sheng,Zhang, Yi-Lin
supporting information; experimental part
p. 482 - 484
(2012/03/11)

Synthesis and biological evaluation of cremastrine and an unnatural analogue
In this Letter, we describe the first total synthesis of cremastrine, a pyrrolizidine alkaloid from Cremastra appendiculata, with anticholinergic activity as well as an unnatural analogue. The streamlined synthesis proceeds in nine steps, seven steps longest linear sequence, in 25.2% overall yield, and features novel methodology to construct the pyrrolizidine core. Biological evaluation of cremastrine and the unnatural analogue indicated that both are pan-mAChR functional antagonists.
Hahn, Kristopher N.,Fadeyi, Olugbeminiyi O.,Cho, Hyekyung P.,Lindsley, Craig W.
scheme or table
p. 3577 - 3580
(2012/09/21)

Synthesis of new chiral ionic liquids from α-hydroxycarboxylic acids
New functionalized optically active N-methylimidazolium ionic liquids with an asymmetric center at the β-position to the imdazole ring were synthesized as bromide salts from optically active α-hydroxycarboxylic acids. The bromide anions were exchanged by carboxylate anions with Amberlite IRA 400 ionic exchange resin.
Poterala, Marcin,Plenkiewicz, Jan
experimental part
p. 294 - 299
(2011/05/17)

Cytotoxic veraguamides, alkynyl bromide-containing cyclic depsipeptides from the marine cyanobacterium cf. Oscillatoria margaritifera
A family of cancer cell cytotoxic cyclodepsipeptides, veraguamides A-C (1-3) and H-L (4-8), were isolated from a collection of cf. Oscillatoria margaritifera obtained from the Coiba National Park, Panama, as part of the Panama International Cooperative Biodiversity Group program. The planar structure of veraguamide A (1) was deduced by 2D NMR spectroscopy and mass spectrometry, whereas the structures of 2-8 were mainly determined by a combination of 1H NMR and MS2/MS3 techniques. These new compounds are analogous to the mollusk-derived kulomo'opunalide natural products, with two of the veraguamides (C and H) containing the same terminal alkyne moiety. However, four veraguamides, A, B, K, and L, also feature an alkynyl bromide, a functionality that has been previously observed in only one other marine natural product, jamaicamide A. Veraguamide A showed potent cytotoxicity to the H-460 human lung cancer cell line (LD50 = 141 nM). (Chemical Equation Presented).
Mevers, Emily,Liu, Wei-Ting,Engene, Niclas,Mohimani, Hosein,Byrum, Tara,Pevzner, Pavel A.,Dorrestein, Pieter C.,Spadafora, Carmenza,Gerwick, William H.
experimental part
p. 928 - 936
(2011/07/29)

Cyclic depsipeptides, grassypeptolides D and e and Ibu- epidemethoxylyngbyastatin 3, from a Red Sea Leptolyngbya cyanobacterium
Two new grassypeptolides and a lyngbyastatin analogue, together with the known dolastatin 12, have been isolated from field collections and laboratory cultures of the marine cyanobacterium Leptolyngbya sp. collected from the SS Thistlegorm shipwreck in the Red Sea. The overall stereostructures of grassypeptolides D (1) and E (2) and Ibu-epidemethoxylyngbyastatin 3 (3) were determined by a combination of 1D and 2D NMR experiments, MS analysis, Marfey's methodology, and HPLC-MS. Compounds 1 and 2 contain 2-methyl-3-aminobutyric acid and 2-aminobutyric acid, while biosynthetically distinct 3 contains 3-amino-2-methylhexanoic acid and the β-keto amino acid 4-amino-2,2-dimethyl-3-oxopentanoic acid (Ibu). Grassypeptolides D (1) and E (2) showed significant cytotoxicity to HeLa (IC50 = 335 and 192 nM, respectively) and mouse neuro-2a blastoma cells (IC50 = 599 and 407 nM, respectively), in contrast to Ibu-epidemethoxylyngbyastatin 3 (neuro-2a cells, IC50 > 10 μM) and dolastatin 12 (neuro-2a cells, IC 50 > 1 μM).
Thornburg, Christopher C.,Thimmaiah, Muralidhara,Shaala, Lamiaa A.,Hau, Andrew M.,Malmo, Jay M.,Ishmael, Jane E.,Youssef, Diaa T. A.,McPhail, Kerry L.
experimental part
p. 1677 - 1685
(2011/11/04)

Lagunamide C, a cytotoxic cyclodepsipeptide from the marine cyanobacterium Lyngbya majuscula
Lagunamide C (1) is a cytotoxic cyclodepsipeptide isolated from the marine cyanobacterium, Lyngbya majuscula, from the western lagoon of Pulau Hantu Besar, Singapore. The complete structural characterization of the molecule was achieved by extensive NMR spectroscopic analysis as well as chemical manipulations. Several methods, including the advanced Marfey's method, a modified method based on derivatization with Mosher's reagents and analysis using LC-MS, and the use of 3JH-H coupling constant values, were utilized for the determination of its absolute configuration. Compound 1 is related to the aurilide-class of molecules and it differs mainly in the macrocyclic structure by having a 27 membered ring system due to additional methylene carbon in the polyketide moiety. Lagunamide C displayed potent cytotoxic activity against a panel of cancer cell lines, such as P388, A549, PC3, HCT8, and SK-OV3 cell lines, with IC50 values ranging from 2.1 nM to 24.4 nM. Compound 1 also displayed significant antimalarial activity with IC50 value of 0.29 μM when tested against Plasmodium falciparum. In addition, lagunamide C exhibited weak anti-swarming activity when tested at 100 ppm against the Gram-negative bacterial strain, Pseudomonas aeruginosa PA01.
Tripathi, Ashootosh,Puddick, Jonathan,Prinsep, Michele R.,Rottmann, Matthias,Chan, Kok Ping,Chen, David Yu-Kai,Tan, Lik Tong
experimental part
p. 2369 - 2375
(2012/02/03)

Porpoisamides A and B, two novel epimeric cyclic depsipeptides from a Florida Keys collection of Lyngbya sp.
NMR-guided fractionation of a non-polar extract of a Florida Keys collection of Lyngbya sp. resulted in the isolation of two novel epimeric cyclic depsipeptides, porpoisamides A (1) and B (2). The planar structures of these compounds were determined using NMR spectroscopic techniques. The absolute configurations of amino and hydroxy acid subunits were assigned by enantioselective HPLC analysis. These compounds showed weak cytotoxicity towards HCT-116 colorectal carcinoma and U2OS osteosarcoma cells. The porpoisamides are a unique pair of cyclic depsipeptides that are epimeric at C-2 of the β-amino acid, 3-amino-2-methyloctanoic acid.
Meickle, Theresa,Gunasekera, Sarath P.,Liu, Yanxia,Luesch, Hendrik,Paul, Valerie J.
experimental part
p. 6576 - 6580
(2011/12/15)

Pitipeptolides C-F, antimycobacterial cyclodepsipeptides from the marine cyanobacterium Lyngbya majuscula from Guam
Pitipeptolides A (1) and B (2) are cyclic depsipeptides isolated from the marine cyanobacterium Lyngbya majuscula from Piti Bomb Holes, Guam. Additional analogues have now been isolated by revisiting larger collections of the same cyanobacterium. The four identified analogues, pitipeptolides C-F (3-6), are the tetrahydro analogue (3), an analogue with a lower degree of methylation (4) as well as two homologues (5 and 6) of pitipeptolide A. Their structures were elucidated using 2D NMR experiments, chiral HPLC analysis and comparison with pitipeptolide A. The identified analogues showed weaker cytotoxic activities compared to the two major parent compounds, pitipeptolides A (1) and B (2), against HT-29 colon adenocarcinoma and MCF7 breast cancer cells. On the other hand, pitipeptolide F (6) was the most potent pitipeptolide in a disc diffusion assay against Mycobacterium tuberculosis. The latter finding suggests that the structure of pitipeptolides could be optimized for selective antibacterial activity.
Montaser, Rana,Paul, Valerie J.,Luesch, Hendrik
experimental part
p. 2068 - 2074
(2012/01/13)

The hoiamides, structurally intriguing neurotoxic Lipopeptides from Papua New Guinea marine cyanobacteria
Two related peptide metabolites, one a cyclic depsipeptide, hoiamide B (2), and the other a linear lipopeptide, hoiamide C (3), were isolated from two different collections of marine cyanobacteria obtained in Papua New Guinea. Their structures were elucidated by combining various techniques in spectroscopy, chromatography, and synthetic chemistry. Both metabolites belong to the unique hoiamide structural class, characterized by possessing an acetate extended and S-adenosyl methionine modified isoleucine unit, a central triheterocyclic system comprised of two α-methylated thiazolines and one thiazole, and a highly oxygenated and methylated C-15 polyketide unit. In neocortical neurons, the cyclic depsipeptide 2 stimulated sodium influx and suppressed spontaneous Ca2+ oscillations with EC50 values of 3.9 μM and 79.8 nM, respectively, while 3 had no significant effects in these assays.
Choi, Hyukjae,Pereira, Alban R.,Cao, Zhengyu,Shuman, Cynthia F.,Engene, Niclas,Byrum, Tara,Matainaho, Teatulohi,Murray, Thomas F.,Mangoni, Alfonso,Gerwick, William H.
experimental part
p. 1411 - 1421
(2010/11/04)

Lagunamides A and B: Cytotoxic and antimalarial cyclodepsipeptides from the marine cyanobacterium Lyngbya majuscula
Lagunamides A (1) and B (2) are new cyclic depsipeptides isolated from the marine cyanobacterium Lyngbya majuscula obtained from Pulau Hantu Besar, Singapore. The planar structural characterization of these molecules was achieved by extensive spectroscopic analysis, including 2D NMR experiments. In addition to Marfey's method and 3JH-H coupling constant values, a modified method based on Mosher's reagents and analysis using LC-MS was deployed for the determination of the absolute configuration. Lagunamides A and B displayed significant antimalarial properties, with IC50 values of 0.19 and 0.91 μM, respectively, when tested against Plasmodium falciparum. Lagunamides A and B also possessed potent cytotoxic activity against P388 murine leukemia cell lines, with IC50 values of 6.4 and 20.5 nM, respectively. Furthermore, these cyanobacterial compounds exhibited moderate antiswarming activities when tested against Pseudomonas aeruginosa PA01.
Tripathi, Ashootosh,Puddick, Jonathan,Prinsep, Michele R.,Rottmann, Matthias,Tan, Lik Tong
supporting information; experimental part
p. 1810 - 1814
(2011/02/28)

PROTEASE INHIBITORS, COMPOSITIONS AND METHODS OF USE
This invention relates to grassystatins A, B and C, and their isolated or purified forms. The compounds of the invention are useful as aspartic protease, gamma secretase, or metalloprotease inhibitors. Methods of using the compounds and compositions thereof are also disclosed.
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Page/Page column 34-35

(2011/01/12)

Desmethoxymajusculamide C, a cyanobacterial depsipeptide with potent cytotoxicity in both cyclic and ring-opened forms
Cytotoxicity-guided fractionation of the organic extract from a Fijian Lyngbya majuscula led to the discovery of desmethoxymajusculamide C (DMMC) as the active metabolite. Spectroscopic analysis including 1D and 2D NMR, MS/MS, and chemical degradation and derivatization protocols were used to assign the planar structure and stereoconfiguration of this new cyclic depsipeptide. DMMC demonstrated potent and selective anti-solid tumor activity with an IC 50 = 20 nM against the HCT-116 human colon carcinoma cell line via disruption of cellular microfilament networks. A linear form of DMMC was generated by base hydrolysis, and the amino acid sequence was confirmed by mass spectrometry. Linearized DMMC was also evaluated in the biological assays and found to maintain potent actin depolymerization characteristics while displaying solid tumor selectivity equivalent to DMMC in the disk diffusion assay. A clonogenic assay assessing cytotoxicity to HCT-116 cells as a function of exposure duration showed that greater than 24 h of constant drug treatment was required to yield significant cell killing. Therapeutic studies with HCT-116 bearing SCID mice demonstrated efficacy at the highest dose used (%T/C = 60% at 0.62 mg/kg daily for 5 days)
Simmons, T. Luke,Nogle, Lisa M.,Media, Joseph,Valeriote, Frederick A.,Mooberry, Susan L.,Gerwick, William H.
experimental part
p. 1011 - 1016
(2011/03/23)

Antineoplastic agents. 571. total synthesis of bacillistatin 2
The first total synthesis of bacillistain 2 (2) has been achieved in 24 steps and 22.9% overall yield, providing a quite efficient route with maximal convergence. Notable features of this approach include two successful applications of the Mitsunobu reaction during respective assemblies of key intermediates 22 and 27, successful employment of 2-methyl- 6-nitrobenzoic anhydride (MNBA) in the formation by lactonization of a macrocyclic (36-membered) ring, and very flexible access to structural modifications of the bacillistatin-type cyclodepsipeptides.
Pettit, George R.,Hu, Shougang,Knight, John C.,Chapuis, Jean-Charles
experimental part
p. 372 - 379
(2009/12/06)

Grassystatins A-C from marine cyanobacteria, potent cathepsin E inhibitors that reduce antigen presentation
In our efforts to exploremarine cyanobacteria as a source of novel bioactive compounds, we discovered a statine unit-containing linear decadepsipeptide, grassystatin A (1), which we screened against a diverse set of 59 proteases. We describe the structure
Kwan, Jason C.,Eksioglu, Erika A.,Liu, Chen,Paul, Valerie J.,Luesch, Hendrik
experimental part
p. 5732 - 5747
(2010/03/24)

Zinc-catalyzed enantiospecific sp3-sp3 cross-coupling of α-hydroxy ester triflates with grignard reagents
(Chemical Equation Presented) Zinc chloride does the trick and efficiently catalyzes the enantiospecific cross-coupling of α-hydroxy ester triflates with Grignard reagents under mild conditions. Enantiopure α-hydroxy esters are directly available from the chiral pool or by diazotization of α-amino acids. Substantial variations in both reacting partners are tolerated making this methodology an attractive alternative to enolate alkylation featuring a reversal of polarity.
Studte, Christopher,Breit, Bernhard
supporting information; experimental part
p. 5451 - 5455
(2009/03/12)

Viridamides A and B, lipodepsipeptides with antiprotozoal activity from the marine cyanobacterium Oscillatoria nigro-viridis
Parallel chemical and phylogenetic investigation of a marine cyanobacterium from Panama led to the isolation of two new PKS-NRPS-derived compounds, viridamides A and B. Their structures were determined by NMR and mass spectroscopic methods, and the absolute configurations assigned by Marfey's method and chiral HPLC analysis. In addition to six standard, N-methylated amino and hydroxy acids, these metabolites contained the structurally novel 5-methoxydec-9-ynoic acid moiety and an unusual proline methyl ester terminus. Morphologically, this cyanobacterium was identified as Oscillatoria nigro-viridis, and its 16S rDNA sequence is reported here for the first time. Phylogenetic analysis of these sequence data has identified O. nigro-viridis strain OSC3L to be closely related to two other marine cyanobacterial genera, Trichodesmium and Blennothrix. Viridamide A showed antitrypanosomal activity with an IC50 of 1.1 μM and antileishmanial activity with an IC50 of 1.5 μM.
Simmons, T. Luke,Engene, Niclas,Urena, Luis David,Romero, Luz I.,Ortega-Barria, Eduardo,Gerwick, Lena,Gerwick, William H.
experimental part
p. 1544 - 1550
(2009/09/06)

Mirror image supramolecular helical tapes formed by the enantiomeric-depsipeptide derivatives of the amyloidogenic peptide amylin(20-29)
Factors that determine the chirality of supramolecular helical tapes formed by a backbone-modified amylin(20-29) depsipeptide and inverso-depsipeptide, were studied by Fourier transform infrared spectroscopy, circular dichroism and transmission electron microscopy. Although β-sheet propensity was absent in both peptides, it was found that the l-depsipeptide formed left-handed and the enantiomeric d-depsipeptide right-handed helical tapes. Moreover, the backbone-modified depsipeptides, showed a certain degree of cross-recognition between both enantiomers, which might have implications in designing amyloid formation inhibitors.
Elgersma, Ronald C.,Mulder, Gwenn E.,Posthuma, George,Rijkers, Dirk T.S.,Liskamp, Rob M.J.
p. 987 - 991
(2008/09/17)