- Synthesis and Biological Evaluation of CF3Se-Substituted α-Amino Acid Derivatives
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Several CF3Se-substituted α-amino acid derivatives, such as (R)-2-amino-3-((trifluoromethyl)selanyl)propanoates (5 a/6 a), (S)-2-amino-4-((trifluoromethyl)selanyl)butanoates (5 b/6 b), (2R,3R)-2-amino-3-((trifluoromethyl)selanyl)butanoates (5 c/6 c), (R)-2-((S)-2-amino-3-phenylpropanamido)-3-((trifluoromethyl)selanyl)propanoates (11 a/12 a), and (R)-2-(2-aminoacetamido)-3-((trifluoromethyl)selanyl)propanoates (11 b/12 b), were readily synthesized from natural amino acids and [Me4N][SeCF3]. The primary in vitro cytotoxicity assays revealed that compounds 6 a, 11 a and 12 a were more effective cell growth inhibitors than the other tested CF3Se-substituted derivatives towards MCF-7, HCT116, and SK-OV-3 cells, with their IC50 values being less than 10 μM for MCF-7 and HCT116 cells. This study indicated the potentials of CF3Se moiety as a pharmaceutically relevant group in the design and synthesis of novel biologically active molecules.
- Han, Zhou-Zhou,Dong, Tao,Ming, Xiao-Xia,Kuang, Fu,Zhang, Cheng-Pan
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supporting information
p. 3177 - 3180
(2021/07/28)
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- Promiscuous Enzymes Cooperate at the Substrate Level en Route to Lactazole A
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Enzymes involved in the biosynthesis of ribosomally synthesized and post-translationally modified peptides (RiPPs) often have relaxed specificity profiles and are able to modify diverse substrates. When several such enzymes act together during precursor peptide maturation, a multitude of products can form, yet usually the biosynthesis converges on a single natural product. For the most part, the mechanisms controlling the integrity of RiPP assembly remain elusive. Here, we investigate the biosynthesis of lactazole A, a model thiopeptide produced by five promiscuous enzymes from a ribosomal precursor peptide. Using our in vitro thiopeptide production (FIT-Laz) system, we determine the order of biosynthetic events at the individual modification level and supplement this study with substrate scope analysis for participating enzymes. Our results reveal an unusual but well-defined assembly process where cyclodehydration, dehydroalanine formation, and azoline dehydrogenation events are intertwined due to minimal substrate recognition requirements characteristic of every lactazole enzyme. Additionally, each enzyme plays a role in directing LazBF-mediated dehydroalanine formation, which emerges as the central theme of the assembly process. Cyclodehydratase LazDE discriminates a single serine residue for azoline formation, leaving the remaining five as potential dehydratase substrates. Pyridine synthase LazC exerts kinetic control over LazBF to prevent the formation of overdehydrated thiopeptides, whereas the coupling of dehydrogenation to dehydroalanine installation impedes generation of underdehydrated products. Altogether, our results indicate that substrate-level cooperation between the biosynthetic enzymes maintains the integrity of lactazole assembly. This work advances our understanding of RiPP biosynthesis processes and facilitates thiopeptide bioengineering.
- Vinogradov, Alexander A.,Shimomura, Morito,Kano, Naokazu,Goto, Yuki,Onaka, Hiroyasu,Suga, Hiroaki
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supporting information
p. 13886 - 13897
(2020/09/21)
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- Singlet Oxygen Photooxidation of Peptidic Oxazoles and Thiazoles
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Oxazoles and thiazoles are commonly found moieties in nonribosomal peptides (NRPs) and ribosomally synthesized post-translationally modified peptides (RiPPs), which are important biomolecules present in the environment and in natural waters. From previous studies, they seem susceptible to oxidation by singlet oxygen (1O2); therefore, we designed and synthesized model oxazole- and thiazole-peptides and measured their1O2 bimolecular reaction rate constants, showing slow photooxidation under environmental conditions. We reasoned their stability through the electron-withdrawing effect of the carboxamide substituent. Reaction products were elucidated and support a reaction mechanism involving cycloaddition followed by a series of rearrangements. The first1O2 bimolecular reaction rate constant for a RiPP, the thiazole-containing peptide Aerucyclamide A, was measured and found in good agreement with the model peptide's rate constant, highlighting the potential of using model peptides to study the transformations of other environmentally relevant NRPs and RiPPs.
- Manfrin, Alessandro,Borduas-Dedekind, Nadine,Lau, Kate,McNeill, Kristopher
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p. 2439 - 2447
(2019/02/26)
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- 3-Azaspiro[5,5]undecan-2,4-dioxo-3-yl diphenyl phosphate (ASUD-diphenyl phosphate), a new reagent for the synthesis of the N-protected amino acid-ASUD ester
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A new reagent, 3-azaspiro[5,5]undecan-2,4-dioxo-3-yl diphenyl phosphate (ASUD-diphenyl phosphate) is described for the synthesis of N-protected amino acid-ASUD esters which are active esters useful in the synthesis of peptides. This compound was synthesized by reacting N-hydroxy-3-azaspiro[5,5]undecane-2,4-dione (HO-ASUD) with diphenyl chlorophosphate in the presence of a base at room temperature and was obtained in high yields. The ASUD-diphenyl phosphate reagent reacts with N-protected amino acids under mild conditions to give the corresponding ASUD active esters, while preserving the enantiomeric purity of the amino acid. The new reagent is a stable crystalline compound and eliminates the need for DCC, a potent skin allergen, used previously for the synthesis of N-protected amino acid-ASUD ester.
- Rao, B. Leelamaheswara,Nowshuddin, Shaik,Jha, Anjali,Divi, Murali K.,Rao
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p. 487 - 491
(2016/06/06)
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- Combinatorial synthesis of oxazol-thiazole bis-heterocyclic compounds
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A combinatorial library of novel oxazol-thiazole bis-heterocycles was synthesized in good to excellent overall yields with high purity using a solution and solid-phase parallel synthesis approach. Oxazole amino acids, prepared from serine methyl ester and
- Murru, Siva,Nefzi, Adel
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- Parallel synthesis of bis-oxazole peptidomimetics
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The parallel synthesis of bis-oxazole peptidomimetics starting from Boc-aminoacids and Serine-methyl ester is described. This work presents the synthesis of oxazole aminoacid building blocks in solution phase and their utilization for the solid phase pept
- Murru, Siva,Dooley, Colette T.,Nefzi, Adel
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supporting information
p. 7062 - 7064
(2013/12/04)
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- CIDOFOVIR PEPTIDE CONJUGATES AS PRODRUGS
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Cidofovir-based compounds having an amino acid, dipeptide or tripeptide attached to a cidofovir or cyclic cidofovir framework. The compounds show enhanced oral bioavailability and increased binding to the PepT1 transporter. The present invention also provides compositions and methods for treating virus infections, and a method of preparing cidofovir.
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Page/Page column 14
(2008/06/13)
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- Pd(0)-catalyzed Heck-type arylation of didehydropeptides
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Pd(0)-catalyzed Heck-type arylation of several didehydropeptides has been studied and the process has been found to be a viable method for the synthesis of the corresponding arylated products stereoselectively but in moderate yields. Copyright Taylor & Fr
- Chattopadhyay, Shital K.,Pal, Benoy K.,Biswas, Suman
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p. 1167 - 1175
(2007/10/03)
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- Total synthesis of trunkamide A, a novel thiazoline-based prenylated cyclopeptide metabolite from Lissoclinum sp.
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Full details of a total synthesis of the doubly prenylated cyclic peptide trunkamide A of marine origin, and also its C45 epimer, are described.
- McKeever, Benedict,Pattenden, Gerald
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p. 2713 - 2727
(2007/10/03)
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- Total synthesis of the prenylated cyclopeptide trunkamide A, a cytotoxic metabolite from Lissoclinum sp.
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A total synthesis of the doubly prenylated cyclic peptide trunkamide A of marine origin, and also its C45 epimer, is described.
- McKeever, Benedict,Pattenden, Gerald
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p. 2573 - 2577
(2007/10/03)
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- Allyltrichlorostannane additions to chiral dipeptide aldehydes
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The first examples of successful allylsilane additions to chiral dipeptide aldehydes are described. Treatment of allylsilanes with tin tetrachloride at room temperature affords allyltrichlorostannane intermediates that reacts with dipeptide aldehydes to give 1,2-syn-homoallylic alcohols, potential intermediates for the synthesis of hydroxyethylene dipeptide isosteres.
- Dias, Luiz C.,Ferreira, Edílson
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p. 7159 - 7162
(2007/10/03)
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- A new approach to the synthesis of di- and tripeptides with unnatural amino acids using organozinc chemistry
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Di- and tripeptides which incorporate an iodoalanine unit at the C-terminus can be converted into the corresponding organozinc reagents upon treatment with activated zinc. These C-terminal di- and tripeptide organozinc reagents react with electrophiles either under palladium catalysis, or by prior transmetallation to a zinc/copper reagent, to give di- and tripeptides incorporating non-proteinogenic amino acids without loss of stereochemical purity.
- Dunn, Michael J.,Jackson, Richard F. W.
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p. 13905 - 13914
(2007/10/03)
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- Peptide derivative
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A peptide derivative useful as substrates for determining enzymatic activities have the following formula STR1 wherein R1 is a group selected from the group consisting of seryl, phenylalanyl-seryl, threonyl and leucyl-threonyl groups, and Rsub
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