- A post-modification strategy for the synthesis of uniform, hydrophilic/hydrophobic patterned a-hydroxy acid oligomers
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Hydrophilic/hydrophobic patterning is a well-established design strategy to guide secondary structure formation of both natural as well as non-natural oligomers and polymers. This contribution explores the feasibility of a new approach for the synthesis of uniform, sequence-defined, hydrophilic/hydrophobic patterned oligo(α-hydroxy acid)s. The proposed strategy is based on post-modification of a reactive oligoester scaffold composed of an alternating sequence of hydrophobic [(2S)-2-hydroxy-4-methylpentanoic acid] and masked hydrophilic [(2S)-2-hydroxypent-4-enoic acid] a-hydroxy acids. The use of (2S)-2-hydroxypent-4-enoic acid instead of a complex side-chain-protected hydrophilic building block obviates the need for additional protective group chemistry during chain extension. In a subsequent post-modification step, the allyl side chains can be quantitatively modified via free-radical addition of different co-functional thiols to afford hydrophilic/hydrophobic patterned oligoesters. The proposed synthetic strategy provides an interesting alternative to rapidly generate libraries of foldamers with identical chain length and monomer sequence but different side-chain functionalities.
- Franz, Nadja,Menin, Laure,Klok, Harm-Anton
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- Total synthesis of cyclohexadepsipeptides exumolides A and B
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Exumolides A and B are two cyclodepsipeptides that was previously isolated from marine fungus. Both peptides were synthesized using a combination of solid- and solution-phase method. The linear precursor was synthesized through solid-phase method on 2-chlorotrityl resin with standard Fmoc strategy. The hydroxy acid, (S)-2-hydroxy-4-methylpentanoic acid (Hmp), was prepared from its precursor L-leucine, and attached on the resin with a double-coupling protocol. The depside bond formation that was carried out at the end of the coupling process, was beneficial, particularly, in the blockage of the diketopiperazine formation during Fmoc deprotection. The cyclic product was obtained through HATU-based cyclisation. Exumolides A and B were successfully synthesized with overall yields of 4.12% and 6.39%, respectively.
- Rahmadani, Agung,Masruhim, Muhammad Amir,Rijai, Laode,Hidayat, Ace Tatang,Supratman, Unang,Maharani, Rani
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- Enantioselective synthesis of α-hydroxy carboxylic acids: Direct conversion of α-oxocarboxylic acids to enantiomerically enriched α-hydroxy carboxylic acids via neighboring group control
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α-Oxocarboxylic acids can be reduced to the corresponding α-hydroxy carboxylic acids employing DIP-CI(TM) as a reducing agent. The α-carboxylic substituent exerts a remarkable neighboring group effect on the reduction. The reaction presumably proceeds in an intramolecular fashion through a 'rigid' bicyclic transition state assembly, which produces enantioselectivities approaching 99%.
- Wang, Zhe,La, Brittany,Fortunak, Joseph M.,Meng, Xian-Jun,Kabalka, George W.
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- ACCURATE DETERMINATION OF THE INTRINSIC RACEMIZATION IN CHIRAL SYNTHESIS VIA ENANTIOMER RESOLUTION OF UNDERIVATIZED VICINAL DIOLS
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The accurate assessment of the intrinsic racemization (down to 0.01percent), inherent to reactions typically applied in chiral synthesis, demands for (i) a precursor of almost 100percent e.e. (e.g., S-1a, e.e. >=99.99percent), and (ii) a reliable method for the determination of e.e. of the product (e.g., the derivatization-free enantiomer resolution of the vicinal diol 3a by GC on Chirasil-Val).
- Koppenhoefer, B.,Trettin, U.,Figura, R.,Lin, B.
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- Synthesis of enantiopure (S)-α-hydroxy carboxanilides from (S)-α-amino acids
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α-Hydroxy carboxanilides 3 a-c were obtained without racemization in a synthetically simple way starting from the corresponding α-amino acids by diazotization and subsequent treatment of the sodium α-hydroxy carboxylates with anilinium chloride in moderate yields. The enantiopurity of 3a-c was easily determined by 1H NMR spectroscopy of the diastereomeric O,O-acetals 5/6a-c derived from exo-lactol 4.
- Girreser,Noe
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- Cyclodepsipeptides, sesquiterpenoids, and other cytotoxic metabolites from the filamentous fungus Trichothecium sp. (MSX 51320)
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Two new cyclodepsipeptides (1 and 2), two new sesquiterpenoids (3 and 4), and the known compounds guangomide A (5), roseotoxin S, and three simple trichothecenes were isolated from the cytotoxic organic extract of a terrestrial filamentous fungus, Trichothecium sp. The structures were determined using NMR spectroscopy and mass spectrometry. Absolute configurations of the cyclodepsipeptides were established by employing chiral HPLC, while the relative configurations of 3 and 4 were determined via NOESY data. The isolation of guangomide A was of particular interest, since it was reported previously from a marine-derived fungus.
- Sy-Cordero, Arlene A.,Graf, Tyler N.,Adcock, Audrey F.,Kroll, David J.,Shen, Qi,Swanson, Steven M.,Wani, Mansukh C.,Pearce, Cedric J.,Oberlies, Nicholas H.
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- A small synthetic molecule forms chloride channels to mediate chloride transport across cell membranes
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Synthetic ion channels that mimic the functions of natural ion channels are of great interest in chemistry, biochemistry, biology, and materials science. In this paper, we present a novel small synthetic molecule that self-assembles to form chloride channels in lipid bilayers. This compound is the smallest molecule known to form potent synthetic chloride ion channels. It can also partition into plasma membranes of living cells and therein increase anion permeability. This compound has the potential to become a novel lead compound for the treatment of human diseases associated with Cl- channel dysfunctions. Copyright
- Li, Xiang,Shen, Bing,Yao, Xiao-Qiang,Yang, Dan
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- Biocontrolled formal inversion or retention of L -α-amino acids to enantiopure (R)- or (S)-hydroxyacids
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Natural L-α-amino acids and L-norleucine were transformed to the corresponding α-hydroxy acids by formal biocatalytic inversion or retention of absolute configuration. The one-pot transformation was achieved by a concurrent oxidation reduction cascade in aqueous media. A representative panel of enantiopure (R)- and (S)-2-hydroxy acids possessing aliphatic, aromatic and heteroaromatic moieties were isolated in high yield (67-85 %) and enantiopure form (>99 % ee) without requiring chromatographic purification.
- Busto, Eduardo,Grischek, Barbara,Kroutil, Wolfgang,Richter, Nina
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p. 11225 - 11228,4
(2014)
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- Mo–Catalyzed One-Pot Synthesis of N-Polyheterocycles from Nitroarenes and Glycols with Recycling of the Waste Reduction Byproduct. Substituent-Tuned Photophysical Properties
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A catalytic domino reduction–imine formation–intramolecular cyclization–oxidation for the general synthesis of a wide variety of biologically relevant N-polyheterocycles, such as quinoxaline- and quinoline-fused derivatives, and phenanthridines, is reported. A simple, easily available, and environmentally friendly dioxomolybdenum(VI) complex has proven to be a highly efficient and versatile catalyst for transforming a broad range of starting nitroarenes involving several redox processes. Not only is this a sustainable, step-economical as well as air- and moisture-tolerant method, but also it is worth highlighting that the waste byproduct generated in the first step of the sequence is recycled and incorporated in the final target molecule, improving the overall synthetic efficiency. Moreover, selected indoloquinoxalines have been photophysically characterized in cyclohexane and toluene with exceptional fluorescence quantum yields above 0.7 for the alkyl derivatives.
- Hernández-Ruiz, Raquel,Rubio-Presa, Rubén,Suárez-Pantiga, Samuel,Pedrosa, María R.,Fernández-Rodríguez, Manuel A.,Tapia, M. José,Sanz, Roberto
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supporting information
p. 13613 - 13623
(2021/08/23)
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- Total Synthesis of the Natural Herbicide MBH-001 and Analogues
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The first total synthesis of the natural herbicide MBH-001 (1) is reported. Structurally it is a 2-methyloxazol-5(2H)-one with a (1-hydroxyethyl) substituent at the 2-position. By relying on cyclic nitrones, a flexible route to MBH-001 and relevant analogues was developed. Key steps include the reaction of a 2-hydroxyimino ester with an aldehyde to form a 5-oxo-2,5-dihydrooxazole 3-oxide. In an aldol-type reaction, the anion of these cyclic nitrones reacted with an aldehyde at the 2-position. A final reduction of the nitrone to the corresponding imine using zinc led to the target compounds. The cyclic nitrones are also accessible by reacting an α-keto acid with an oxime. These two versatile synthetic routes enabled us to prepare the first MBH-001 analogues for structure activity relationship analysis of the herbicidal efficacy. Thus, furthering our aim of developing new herbicides to tackle the ever-growing problem of weed resistance.
- Barber, David M.,D?ller, Uwe,Dietrich, Hansj?rg,Hoffmann, Michael G.,Kocakaya, Tamer,Kuhn, Birgit,Maier, Martin E.,Morkunas, Marius,Schmutzler, Dirk,Schnatterer, Stefan
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p. 2271 - 2290
(2020/04/23)
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- Learning from Peptides to Access Functional Precision Polymer Sequences
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Functional precision polymers based on monodisperse oligo(N-substituted acrylamide)s and oligo(2-substituted-α-hydroxy acid)s have been synthesized. The discrete sequences originate from a direct translation of side-chain functionality sequences of a peptide with well-studied properties. The peptide was previously selected to solubilize the photosensitizer meta-tetra(hydroxyphenyl)chlorin. The resulting peptidomimetic formulation additives preserve the drug solubilization and release characteristics of the parent peptide. In some cases, superior properties are obtained, reaching up to 40 % higher payloads and 27-times faster initial drug release.
- Maron, Eva,Swisher, Jordan H.,Haven, Joris J.,Meyer, Tara Y.,Junkers, Tanja,B?rner, Hans G.
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supporting information
p. 10747 - 10751
(2019/07/09)
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- A novel Anti-Cancer Stem Cells compound optimized from the natural symplostatin 4 scaffold inhibits Wnt/β-catenin signaling pathway
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Cancer stem cells (CSCs) are responsible for carcinogenesis, cancer progression, relapse, metastasis and drug resistance. Therefore, the development of drug molecules targeting CSCs plays a vital role in medicinal researching field. However, there are extremely rare molecules that selectively ablate CSCs. The research and development of drugs targeting CSCs is limited due to a lack of anti-CSCs lead compounds. In this study, an anti-CSCs lead compound 35b was discovered, which was derived from the natural chemical scaffold of Symplostatin 4. This compound exhibited a significantly suppressive effect on tumor growth both in vitro and in vivo. Additionally, 35b could significantly reduce the number of melanoma tumor spheres and decrease the percentage of ALDH+ melanoma cells. Further mechanism study illustrated that compound 35b could eliminate the melanoma CSCs by efficiently blocking Wnt/β-catenin signaling pathway. Collectively, our findings would provide a novel chemical scaffold and alternative idea of molecular design for development of anti-CSCs drugs.
- Liu, Shuangwei,Gao, Xian,Zhang, Lisong,Qin, Shuanglin,Wei, Mingming,Liu, Ning,Zhao, Rui,Li, Benlong,Meng, Ye,Lin, Gang,Lu, Cheng,Liu, Xinhua,Xie, Maodun,Liu, Tongtong,Zhou, Honggang,Qi, Min,Yang, Guang,Yang, Cheng
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- Readily Accessible 1,2-Amino Ether Ligands for Enantioselective Intramolecular Carbolithiation
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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
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p. 4949 - 4957
(2017/05/12)
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- Identification of Cyclic Depsipeptides and Their Dedicated Synthetase from Hapsidospora irregularis
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Seven cyclic depsipeptides were isolated from Hapsidospora irregularis and structurally characterized as the calcium channel blocker leualacin and six new analogues based on the NMR and HRESIMS data. These new compounds were named leualacins B-G. The absolute configurations of the amino acids and 2-hydroxyisocaproic acids were determined by recording the optical rotation values. Biological studies showed that calcium influx elicited by leualacin F in primary human lobar bronchial epithelial cells involves the TRPA1 channel. Through genome sequencing and targeted gene disruption, a noniterative nonribosomal peptide synthetase was found to be involved in the biosynthesis of leualacin. A comparison of the structures of leualacin and its analogues indicated that the A2 and A4 domains of the leualacin synthetase are substrate specific, while A1, A3, and A5 can accept alternative precursors to yield new molecules.
- Zhang, Shuwei,Qiu, Yixing,Kakule, Thomas B.,Lu, Zhenyu,Xu, Fuchao,Lamb, John G.,Reilly, Christopher A.,Zheng, Yong,Sham, Shing Wo Simon,Wang, Wei,Xuan, Lijiang,Schmidt, Eric W.,Zhan, Jixun
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p. 363 - 370
(2017/03/08)
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- α-Aminoxy Oligopeptides: Synthesis, Secondary Structure, and Cytotoxicity of a New Class of Anticancer Foldamers
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α-Aminoxy peptides are peptidomimetic foldamers with high proteolytic and conformational stability. To gain an improved synthetic access to α-aminoxy oligopeptides we used a straightforward combination of solution- and solid-phase-supported methods and obtained oligomers that showed a remarkable anticancer activity against a panel of cancer cell lines. We solved the first X-ray crystal structure of an α-aminoxy peptide with multiple turns around the helical axis. The crystal structure revealed a right-handed 28-helical conformation with precisely two residues per turn and a helical pitch of 5.8 ?. By 2D ROESY experiments, molecular dynamics simulations, and CD spectroscopy we were able to identify the 28-helix as the predominant conformation in organic solvents. In aqueous solution, the α-aminoxy peptides exist in the 28-helical conformation at acidic pH, but exhibit remarkable changes in the secondary structure with increasing pH. The most cytotoxic α-aminoxy peptides have an increased propensity to take up a 28-helical conformation in the presence of a model membrane. This indicates a correlation between the 28-helical conformation and the membranolytic activity observed in mode of action studies, thereby providing novel insights in the folding properties and the biological activity of α-aminoxy peptides.
- Diedrich, Daniela,Moita, Ana J. Rodrigues,Rüther, Anja,Frieg, Benedikt,Reiss, Guido J.,Hoeppner, Astrid,Kurz, Thomas,Gohlke, Holger,Lüdeke, Steffen,Kassack, Matthias U.,Hansen, Finn K.
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p. 17600 - 17611
(2016/11/28)
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- Design and synthesis of a new class of cryptophycins based tubulin inhibitors
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Tubulin binding compounds represent one of the most attractive targets for anticancer drug development. They broadly fall into two categories viz., tubulin polymerization inhibitors, which block microtubule growth and destabilize microtubules like vinca alkaloids and cryptophycins, and the others, which polymerize microtubules into hyperstable forms represented by family of taxanes. In this context, we aimed at design and synthesis of cryptophycins based macrocyclic depsipeptides, which are synthetically more accessible, however have the basic information to target tubulins and establish structure activity relationship (SAR). Thus, a new class of cryptophycins based marocyclic depsipeptides with a truncated epoxide chain were synthesized as potential tubulin inhibitors. The resultant lead analogues 15a and 16a exhibited good anti-cancer activity, induced apoptosis, caused block/delay in cell cycle as well as significantly reduced the expression of α- and β-tubulins. Molecular modelling studies show that 15a and 16a bind in the same domain as that of cryptophycins.
- Kumar, Arvind,Kumar, Manjeet,Sharma, Simmi,Guru, Santosh Kumar,Bhushan, Shashi,Shah, Bhahwal Ali
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supporting information
p. 55 - 63
(2015/02/19)
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- Synthesis and antimycobacterial activity of novel camphane-based agents
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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
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p. 165 - 167
(2014/01/17)
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- Preparation and evaluation at the delta opioid receptor of a series of linear Leu-enkephalin analogues obtained by systematic replacement of the amides
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Leu-enkephalin analogues, in which the amide bonds were sequentially and systematically replaced either by ester or N-methyl amide bonds, were prepared using classical organic chemistry as well as solid phase peptide synthesis (SPPS). The peptidomimetics were characterized using competition binding, ERK1/2 phosphorylation, receptor internalization, and contractility assays to evaluate their pharmacological profile over the delta opioid receptor (DOPr). The lipophilicity (LogD7.4) and plasma stability of the active analogues were also measured. Our results revealed that the last amide bond can be successfully replaced by either an ester or an N-methyl amide bond without significantly decreasing the biological activity of the corresponding analogues when compared to Leu-enkephalin. The peptidomimetics with an N-methyl amide function between residues Phe and Leu were found to be more lipophilic and more stable than Leu-enkephalin. Findings from the present study further revealed that the hydrogen-bond donor properties of the fourth amide of Leu-enkephalin are not important for its biological activity on DOPr. Our results show that the systematic replacement of amide bonds by isosteric functions represents an efficient way to design and synthesize novel peptide analogues with enhanced stability. Our findings further suggest that such a strategy can also be useful to study the biological roles of amide bonds.
- Rochon, Kristina,Proteau-Gagne, Arnaud,Bourassa, Philippe,Nadon, Jean-Francois,Coite, Jerome,Bournival, Veronique,Gobeil, Fernand,Guerin, Brigitte,Dory, Yves L.,Gendron, Louis
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p. 1204 - 1216
(2013/09/23)
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- Continuous multiple liquid-liquid separation: Diazotization of amino acids in flow
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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.
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supporting information; experimental part
p. 4246 - 4249
(2012/10/08)
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- Synthesis of new chiral ionic liquids from α-hydroxycarboxylic acids
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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
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experimental part
p. 294 - 299
(2011/05/17)
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- Highly efficient macrolactonization of ω-hydroxy acids using benzotriazole esters: Synthesis of Sansalvamide A
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A facile and mild macrolactonization reaction of ω-hydroxy acids was developed based on the transesterification of benzotriazole esters. Treatment of ω-hydroxy acids with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) and 1-hydroxy benzotriazole (HOBT) in chloroform provided macrolactones in excellent yields. The reactions were performed under basic, neutral and acidic conditions using N,N-dimethylaminopyridine (DMAP), tetrabutylammonium tetrafluoroborate (TBABF4) and BF3·Et2O, respectively. A calcined hydrotalcite was also used instead of DMAP. Finally, to test the scope of the protocol in the synthesis of biologically relevant macrolactones, the total synthesis of Sansalvamide A was carried out.
- Morales-Serna, Jose Antonio,Sanchez, Ericka,Velazquez, Ricardo,Bernal, Jorge,Garcia-Rios, Erendira,Gavino, Ruben,Negron-Silva, Guillermo,Cardenas, Jorge
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experimental part
p. 4940 - 4948
(2010/11/24)
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- Modular total synthesis of archazolid A and B
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(Chemical Equation Presented) A modular total synthesis of the potent V-ATPase inhibitors archazolid A and B is reported. The convergent preparation was accomplished by late-stage diversification of joint intermediates. Key synthetic steps involve asymmetric boron-mediated aldol reactions, two consecutive Still-Gennari olefinations to set the characteristic (Z,Z)-diene system, a Brown crotyboration, and a diastereo-selective aldol condensation of highly elaborate intermediates. For macrocyclization, both an HWE reaction and a Heck coupling were successfully employed to close the 24-membered macrolactone. During the synthetic campaign, a generally useful protocol for an E-selective Heck reaction of nonactivated alkenes and a method for the direct nucleophilic displacement of the Abiko-Masamune auxiliary with sterically hindered nucleophiles were developed. The expedient and flexible strategy will enable further SAR studies of the archazolids and more detailed evaluations of target-inhibitor interactions. 2009 American Chemical Society.
- Menche, Dirk,Hassfeld, Jorma,Li, Jun,Mayer, Kerstin,Rudolph, Sven
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supporting information; experimental part
p. 7220 - 7229
(2010/02/17)
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- Toward stereocontrolled, chemoenzymatic synthesis of unnatural peptides
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An efficient, chemoenzymatic method for the multicomponent synthesis of unnatural tripeptides is presented. Development of a previously described procedure combines the diversity offered by multicomponent reactions with the selectivity of biocatalysts and allows the convenient introduction of varied amino acid moieties into the tripeptide scaffold, with control of the stereochemistry. Additionally, it allows the introduction of a methyl group to the amide nitrogen, leading to derivatives of N-methylated amino acids.
- Szymanski, Wiktor,Ostaszewski, Ryszard
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p. 3197 - 3203
(2008/09/19)
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- Synthetic Ion Channels
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Provided herein are self-assembling compounds that can form ion channels in lipid bilayers or cell membranes and ion-channel-forming compositions comprising the self-assembling compounds. Also provided are methods of making and using the ion channels formed from a plurality of molecules of the self-assembling compounds. Further, provided are methods of treating or preventing conditions and diseases that are related to the dysfunction of ion channels, including chloride channels.
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Page/Page column 17-18
(2008/12/06)
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- Zinc-catalyzed enantiospecific sp3-sp3 cross-coupling of α-hydroxy ester triflates with grignard reagents
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(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
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supporting information; experimental part
p. 5451 - 5455
(2009/03/12)
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- Total synthesis of cryptophycin analogues via a scaffold approach
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Allylation of in situ generated β,γ-unsaturated aldehydes affords rapid access to vinyl halide analogues of fragment A of the cryptophycins. Three scaffolds are prepared in gram quantities by a ring-closing metathesis approach. Derivatization via a variety of cross-coupling protocols is possible, which affords novel analogues of these potent antimitotic agents.
- McCubbin, J. Adam,Maddess, Matthew L.,Lautens, Mark
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p. 2993 - 2996
(2007/10/03)
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- α-Hydroxy carboxylic acids as ligands for enantioselective diethylzinc additions to aromatic and aliphatic aldehydes
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The first examples of the enantioselective titanium-mediated diethylzinc additions to aromatic and aliphatic aldehydes catalyzed by optically active α-hydroxy acids are presented. The reactions proceed with very good yield and good asymmetric induction. Enantioselectivities up to 90% are obtained depending on ligand and aldehyde used. A stereochemical model for the reaction is proposed.
- Bauer, Tomasz,Gajewiak, Joanna
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p. 9163 - 9170
(2007/10/03)
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- Syntheses of depsipeptide analogues of the insect neuropeptide proctolin.
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Four depsipeptide analogues of the insect neuropeptide proctolin (H-Arg-Tyr-Leu-Pro-Thr-OH) have been prepared, containing a single ester linkage between Arg(1) and Tyr(2), Tyr(2) and Leu(3), and between Pro(4) and Thr(5), respectively. A didepsipentapeptide containing an ester linkage between Tyr(2) and Leu(3) and between Pro(4) and Thr(5), has also been prepared. The depsipeptide 4 is the first example of a backbone-modified proctolin analogue which shows full myotropic activity.
- Scherkenbeck, Juergen,Plant, Andrew,Stieber, Frank,Loesel, Peter,Dyker, Hubert
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p. 1625 - 1628
(2007/10/03)
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- Synthesis and characterization of chiral N-O turns induced by α-aminoxy acids
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Chiral α-aminoxy acids of various side chains were synthesized with high optical purity starting from chiral α-amino acids. The conformations of diamides 13a-e, 15, and 16 were probed by using NMR, FT-IR, and CD spectroscopic methods as well as X-ray crystallography. The right-handed turns with eight-membered-ring intramolecular hydrogen bonds between adjacent residues (called the N-O turns) were found to be preferred for D-aminoxy acid residues, and they were independent of the side chains. The rigid chiral N-O turns should have great potential in molecular design.
- Yang,Li,Ng,Yan,Qu,Wu
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p. 7303 - 7312
(2007/10/03)
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- Synthesis and structure of a small macrocyclic hexapeptide model for antiparallel β-sheet containing two restrained 2-(3'-aminopropynyl)-aniline reverse-turn mimetics
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A new reverse-turn mimetic containing a 2-(3'-aminopropynyl)-phenyl moiety in place of the natural i + 1 and i + 2 turn residues is described in which the key C-C bond was formed from an N-protected propargylamine and 2- iodoaniline using Heck chemistry. Nucleophilic displacement of triflate from activated (2S)-2-hydroxyalkanoate esters by the anilino N-atom, with inversion at C-2, gave homochiral tripeptide mimetics. Two variants of these were coupled and the product was deprotected and then cyclised to give a stable cyclo-hexapeptide analogue that possessed an anti-parallel β-sheet structure as determined by NMR spectroscopy.
- Pitt, Nigel,Gani, David
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p. 3811 - 3814
(2007/10/03)
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- Synthesis and evaluation of backbone/amide-modified analogs of leualacin
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Leualacin (1), a cyclic depsi-pentapeptide, and its backbone/amidemodified analogs 2-4 were synthesized. Amide analogue 3 exhibited stronger vasodilatory effects. It also strongly inhibited collagen- and arachidonic acid (AA)induced platelet aggregations with IC50s of 0.6 μM and 2.0 μM, respectively.
- Hu, Ming-Kuan,Yang, Fu-Chu,Chou, Chi-Cheun,Yen, Mao-Hsiung
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p. 563 - 568
(2007/10/03)
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- PEPTIDE, PEPTIDE ANALOG AND AMINO ACID ANALOG PROTEASE INHIBITORS
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Methods of use of compounds and compounds for the treatment of disorders characterized by the cerebral deposition of amyloid are provided. Among the compounds are those of formulae (I), (II) and (III): STR1 in which R. sub.1 is preferably 2-methyl propene, 2-butene, norleucine; R 2, R 4, and R 8 are each independently methyl or ethyl; R 3 is preferably iso-butyl or phenyl; R 5 is preferably iso-butyl; R 6 is H or methyl; R 7--(Q) n is preferably benzyloxycarbonyl or acetyl; Q is preferably--C(O)--; R B is preferbly iso-butyl; R A =--(T) m--(D) m--R 1, is which T is preferably oxygen or carbon, and D is preferably a mono-unsaturated C 3-4 alkenyl being more preferred; and X is an alcohol, particularly a secondary alcohol.
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- PEPTIDE AND PEPTIDE ANALOG PROTEASE INHIBITORS
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Methods of use of compounds and compounds for the treatment of disorders characterized by the cerebral deposition of amyloid are provided. Among the compounds are those of formulae I and II: STR1 in which R 1 is preferably 2-methyl propene, 2-butene, cyclohexyl or cyclohexylmethyl; R. sub.2, R 4, and R 8 are each independently methyl or ethyl; R 3 is preferably iso-butyl or phenyl; R 5 is preferably iso-butyl; R 6 is H or methyl; R 7--(Q) n is preferably benzyloxycarbonyl or acetyl; Q is preferably--C(O)--; R 8 is preferbly iso-butyl; R A =--(T) m--(D) m--R 1, is which T is preferably oxygen or carbon, and D is preferably a mono-unsaturated C 3-4 alkenyl being more preferred; and X is preferably an α-ketoester or α-ketoamide.
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- The development of hydrazide γ-Turn mimetics
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Monte Carlo calculations show a classical γ-turn in a family of metabolites known as the malformins. This led to the synthesis of epimeric seven-membered ring γ-turn mimetics starting from leucine. NMR temperature coefficient studies were also performed.
- Ferguson, Mark D.,Meara, Joseph P.,Nakanishi, Hiroshi,Lee, Min S.,Kahna, Michael
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p. 6961 - 6964
(2007/10/03)
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- Pheromone synthesis, CLXXVII: Synthesis of the enantiomers of 2-methyl-4-heptanol and 2-methyl-4-octanol, the pheromone components of the West Indian sugarcane borer
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Both the enantiomers of 2-methyl-4-heptanol (1) and 2-methyl-4-octanol (2), the components of the male-produced aggregation pheromone of the West Indian sugarcane borer (Metamasius hemipterus), were synthesized by starting from the enantiomers of leucine. VCH Verlagsgesellschaft mbH, 1996.
- Takenaka, Motonobu,Takikawa, Hirosato,Mori, Kenji
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p. 1963 - 1964
(2007/10/03)
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- Total synthesis of the cyclic depsipeptide leualacin
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The fungal metabolite leualacin (1), a potent calcium channel antagonist, was synthesized in 15 steps from commercially available amino acids in 25% overall yield using standard solution methods. The synthesis is general and thus would accommodate the incorporation of amino acid replacements as well as the inclusion of peptide mimics and isosteres.
- McLaren
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p. 6082 - 6084
(2007/10/03)
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- Enantioselective Preparation of α-Acyloxy Ketones from α-Hydroxy and α-Amino Acids
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Various chiral α-acyloxy ketones have been easily prepared, in high yields with an excellent enantiomeric purity, by acylation of organomanganese reagents with the corresponding α-acyloxy carboxylic acid chlorides prepared from α-hydroxy and α-amino acids.
- Cahiez, Gerard,Metais, Eric
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p. 6449 - 6452
(2007/10/02)
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- A total synthesis of arenastatin A, an extremely potent cytotoxic depsipeptide, from the Okinawan marine sponge dysidea arenaria
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An asymmetric synthesis of a cyclic depsipeptide arenastatin A (1), which was isolated from the marine sponge Dysidea arenaria and exhibited extremely potent cytotoxicity with IC50 5 pg/ml for KB cells, has been accomplished.
- Kobayashi,Kurosu,Wang,Kitagawa
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p. 2394 - 2396
(2007/10/02)
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- Synthesis of (15)N-Labelled Chiral Boc-Amino Acids from Triflates: Enantiomers of Leucine and Phenylalanine
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An efficient synthesis of (15)N-labelled chiral Boc-amino acids by triflate alkylation of di-tert-butyl iminodicarbonate is reported.Both enantiomers of Boc-Leucine and -phenylalanine were synthesized from commercial α-amino acids of opposite configuration via α-hydroxy carboxylic acids provided by diazotization, thus extending the scope of an earlier exploratory study.The high chiral purity of the final products was confirmed by HPLC.These labelled amino acid derivatives are suitable for direct application to the synthesis of labelled peptides.
- Degerbeck, Fredrik,Fransson, Bengt,Grehn, Leif,Ragnarsson, Ulf
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- A New Entry to 1,3-Polyols, 2-Amino 1,3-Polyols, and β-(1-Hydroxyalkyl)isoserines Using Azetidinone Frameworks as Chiral Templates via Iterative Asymmetric Cycloaddition Reactions
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A new entry to polyfunctional compounds based on an iterative asymmetric cycloaddition reaction of ketenes to O-protected α-hydroxy aldehyde derived imines is described for the first time.
- Palomo, Claudio,Aizpurua, Jesus M.,Urchegui, Raquel,Garcia, Jesus M.
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p. 1646 - 1648
(2007/10/02)
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- A Novel Highly Diastereoselective Synthesis of Cyano Esters by Regioselective Ring Opening of Chiral Oxazolidinium Methiodides with Sodium Cyanide
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Sodium cyanide reacts with chiral oxazolidinium methiodides, prepared by quaternization of oxazolidines with methyl iodide, leading regio- and stereoselectively (d.e. 82-94percent) to cyano esters in moderate to good chemical yields (51-95percent).The open compounds are isolated as a pure diastereomer by a single recrystallization of their ammonium methiodides, and converted into enantiomerically pure α-hydroxy acids by heating with a concentrated solution of hydrochloric acid. - Key words: Chiral Oxazolidinium Iodides; alpha-Cyano ethers, Diastereoselective Ring Opening; alpha-Hydroxy Acids; Asymmetric Synthesis.
- Andres, Celia,Delgado, Manuel,Pedrosa, Rafael,Rodriquez, Raquel
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p. 8325 - 8328
(2007/10/02)
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- On the factors controlling the structural specificity and stereospecificity of the L-lactate dehydrogenase from Bacillus stearothermophilus: Effects of Gln102→Arg and Arg171→Trp/Tyr double mutations
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The factors determining the L-stereospecificity of the L-lactate dehydrogenase from Bacillus stearolhermophilus have been probed by introducing Arg171Trp/Tyr and Gln 102Arg mutations. These changes preclude normal 2-keto acid substrate binding via an Arg171-COO- electrostatic interaction and are positioned to induce a reversal of the natural substrate binding mode, thereby leading to D-2-hydroxy acid formation. However, the L-stereospecificities of the mutant enzymes remain unchanged, showing that there are important fail-safe stereospecificity determinants that take over when the key Arg171-COO- binding interaction is removed. The effects of the mutations on structural specificity are approximately additive, resulting in the broad 2-keto acid specificity of the wild-type enzyme being changed to give catalysts highly selective for the dicarboxylic substrate oxalacetate.
- Kallwass, Helmut K.W.,Hogan, James K.,Macfarlane, Emma L.A.,Martichonok, Valeri,Partis, Wendy,Kay, Cyril M.,Gold, Marvin,Bryan Jones
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p. 10704 - 10710
(2007/10/02)
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- A SYNTHON FOR CHIRAL GLYCOLATE ENOLATE (ROC-HCOOR'): A CAMPHOR-BASED OXAZOLINE
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Alkylations of the anion (7a) derived from a camphor-based oxazoline proceed in good yield.Hydrolysis affords the corresponding α-hydroxy acids in high ee.
- Kelly, T. Ross,Arvanitis, Argyrios
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