ABSTRACT
As the importance of RNA as a therapeutic target has become increasingly recognized, the need for new chemotypes able to bind RNA has grown in significance. We hypothesized that diketopiperazines (DKPs), common substructures in natural products and protein-targeting therapeutic agents, could serve as effective scaffolds for targeting RNA. To confirm this hypothesis, we designed and synthesized two analogs, one incorporating a DKP and one not, of compounds previously demonstrated to bind an RNA critical to the life cycle of HIV-1 with high affinity and specificity. Prior to compound synthesis, calculations employing density functional methods and molecular mechanics conformational searches were used to confirm that the DKP could present functionality in a similar (albeit not identical) orientation to the non DKP-containing compound. We found that both the DKP-containing and parent compound had similar affinities to the target RNA as measured by surface plasmon resonance (SPR). Both compounds were found to have modest but equal anti-HIV activity. These results establish the feasibility of using DKPs to target RNA.
Subject(s)
Anti-HIV Agents/pharmacology , Biological Products/pharmacology , Diketopiperazines/pharmacology , HIV/drug effects , RNA, Viral/drug effects , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/chemistry , Biological Products/chemical synthesis , Biological Products/chemistry , Density Functional Theory , Diketopiperazines/chemical synthesis , Diketopiperazines/chemistry , Microbial Sensitivity Tests , Molecular StructureABSTRACT
Asymmetric construction of dithiodiketopiperazines on otherwise achiral scaffolds remains a pivotal synthetic challenge encountered in many biologically significant natural products. Herein, we report the first total syntheses of (-)-glionitrin A/B and revise the absolute configurations. Emerging from the study is a novel oxidative sulfenylation of triketopiperazines that enables asymmetric formation of dithiodiketopiperazines on sensitive substrates. The concise route paves the way for further studies on the potent antimicrobial and antitumor activities of glionitrin A and the intriguing ability of glionitrin B to inhibit invasive ability of cancer cells.
Subject(s)
Diketopiperazines/chemical synthesis , Piperazines/chemistry , Anti-Infective Agents/chemical synthesis , Anti-Infective Agents/chemistry , Density Functional Theory , Diketopiperazines/chemistry , Molecular Conformation , Oxidation-Reduction , Stereoisomerism , Sulfur/chemistryABSTRACT
Bioactive molecules that enhance or induce osteogenic potential of bone precursor cells have shown vital roles in bone tissue engineering. Herein, we report the design and synthesis of a novel diketopiperazine (DT) that induces osteoblastic differentiation of pre-osteoblasts and bone-marrow-derived stem cells in vitro and enhances the osteogenic potential of cryogel matrix. Such functional diketopiperazines can serve as potential scaffolds for bone healing and regeneration.
Subject(s)
Cell Differentiation/drug effects , Cryogels/chemistry , Diketopiperazines/pharmacology , Osteogenesis/drug effects , Peptides, Cyclic/pharmacology , Tissue Scaffolds/chemistry , Animals , Cell Proliferation/drug effects , Diketopiperazines/chemical synthesis , Diketopiperazines/toxicity , Mesenchymal Stem Cells/drug effects , Mice , Osteoblasts/drug effects , Peptides, Cyclic/chemical synthesis , Peptides, Cyclic/toxicity , Taurine/analogs & derivatives , Taurine/pharmacology , Taurine/toxicity , Tissue Engineering/methodsABSTRACT
Cyclodipeptides (CDPs) or 2,5-diketopiperazines (DKPs) can exert a variety of biological activities and display pronounced resistance against enzymatic hydrolysis as well as a propensity towards self-assembly into gels, relative to the linear-dipeptide counterparts. They have attracted great interest in a variety of fields spanning from functional materials to drug discovery. This concise review will analyze the latest advancements in their synthesis, self-assembly into gels, and their more innovative applications.
Subject(s)
Diketopiperazines/chemical synthesis , Dipeptides/chemistry , Peptides, Cyclic/chemical synthesis , Diketopiperazines/chemistry , Gels/chemistry , Green Chemistry Technology , Microwaves , Molecular Structure , Peptides, Cyclic/chemistryABSTRACT
The activity of pharmacologically active compounds can be increased by presenting a drug in a defined conformation, which fits exactly into the binding pocket of its target. Herein, the piperazine scaffold was conformationally restricted by substituted C2- or C3-bridges across the 2- and 6-position. At first, a three-step, one-pot procedure was developed to obtain reproducibly piperazine-2,6-diones with various substituents at the N-atoms in high yields. Three strategies for bridging of piperazine-2,6-diones were pursued: 1. The bicyclic mixed ketals 8-benzyl-6-ethoxy-3-(4-methoxybenzyl)-6-(trimethylsilyloxy)-3,8-diazabicyclo[3.2.1]octane-2,4-diones were prepared by Dieckmann analogous cyclization of 2-(3,5-dioxopiperazin-2-yl)acetates. 2. Stepwise allylation, hydroboration and oxidation of piperazine-2,6-diones led to 3-(3,5-dioxopiperazin-2-yl)propionaldehydes. Whereas reaction of such an aldehyde with base provided the bicyclic alcohol 9-benzyl-6-hydroxy-3-(4-methoxybenzyl)-3,9-diazabicyclo[3.3.1]nonane-2,4-dione in only 10 % yield, the corresponding sulfinylimines reacted with base to give N-(2,4-dioxo-3,9-diazabicyclo[3.3.1]nonan-6-yl)-2-methylpropane-2-sulfinamides in >66 % yield. 3. Transformation of a piperazine-2,6-dione with 1,4-dibromobut-2-ene and 3-halo-2-halomethylprop-1-enes provided 3,8-diazabicyclo[3.2.1]octane-2,4-dione and 3,9-diazabicyclo[3.3.1]nonane-2,4-dione with a vinyl group at the C2- or a methylene group at the C3-bridge, respectively. Since bridging via sulfinylimines and the one-pot bridging with 3-bromo-2-bromomethylprop-1-ene gave promising yields, these strategies will be exploited for the synthesis of novel receptor ligands bearing various substituents in a defined orientation at the carbon bridge.
Subject(s)
Azabicyclo Compounds/chemical synthesis , Diketopiperazines/chemical synthesis , Cyclization , Molecular StructureABSTRACT
The in vitro conversion of (1S,3S)-1-dimethoxylethyl-1,2,3,4-tetrahydro-ß-carboline-3-carboxylic acid, (1S,3S)-DCCA, in rat plasma is monitored by HPLC-FT-ICR-MS. We show that the in vitro conversion of (1S,3S)-DCCA in rat plasma for 1 h leads to forming (6S/12aS)-bisdimethoxyethylheptachpyridone, reflecting intermolecular condensation of (1S,3S)-DCCA, and the in vitro conversion of (6S/12aS)-bisdimethoxyethylheptachpyridone in rat plasma for 1 h leads to forming (6S/12aS)-heptachpyridone, reflecting hydrolysis of (6S/12aS)-bisdimethoxyethylheptachpyridone. At a dose of 1.0 µmol/kg (6S/12aS)-heptachpyridone orally inhibits venous thrombosis and arterial thrombosis in vivo. Bleeding time, clotting time and international normalized ratio show that at this dose (6S/12aS)-heptachpyridone has no bleeding risk, does not lengthen clotting time and does not change the exogenous coagulation pathway. We also show that the reactions promoted by rat plasma are easy to practice by chemical synthesis. Thus our findings build a bridge across the in vivo conversion and the application.
Subject(s)
Carbazoles/therapeutic use , Diketopiperazines/therapeutic use , Fibrinolytic Agents/therapeutic use , Venous Thrombosis/drug therapy , Animals , Blood/metabolism , Carbazoles/chemical synthesis , Carbazoles/metabolism , Diketopiperazines/chemical synthesis , Diketopiperazines/metabolism , Fibrinolytic Agents/chemical synthesis , Fibrinolytic Agents/metabolism , Hydrolysis , Male , Rats, Sprague-Dawley , Vena Cava, Inferior/drug effectsABSTRACT
Histone deacetylases (HDACs) as attractive targets in many diseases therapies has been studied extensively, and its application in cancer research is the most important. Here, we developed a series of derivatives containing natural 2,5-diketopiperazine (DKP) skeleton. Several compounds exhibited distinct HDAC1 inhibitory activities, in particular 2a (IC50 = 405 nM). The selectivity profile for representative 2a indicated that this series of compounds had a preference for HDAC1-3. Additionally, 2a showed the best growth inhibitory activities against K562 and HL-60 tumor cell line with IC50 values of 4.23 and 4.16 µM, respectively. This work may lay the foundation for developing DKP-based HDAC inhibitors as a potential anticancer agent.
Subject(s)
Antineoplastic Agents/pharmacology , Diketopiperazines/pharmacology , Drug Discovery , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylases/metabolism , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Diketopiperazines/chemical synthesis , Diketopiperazines/chemistry , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , HL-60 Cells , Histone Deacetylase Inhibitors/chemical synthesis , Histone Deacetylase Inhibitors/chemistry , Humans , K562 Cells , Molecular Docking Simulation , Molecular Structure , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
A series of linear and cyclic peptidomimetics composed of a cell-penetrating peptide and a non-natural, bifunctional 2,5-diketopiperazine scaffold is reported. Conformational studies revealed well-defined helical structures in micellar medium for linear structures, while cyclic peptidomimetics were more flexible. Biological investigations showed higher membrane-activity of cyclic derivatives allowing their use as shuttles for anti-cancer drugs.
Subject(s)
Antineoplastic Agents/pharmacology , Cell-Penetrating Peptides/chemistry , Daunorubicin/pharmacology , Diketopiperazines/chemistry , Drug Carriers/chemistry , Cell Survival , Cell-Penetrating Peptides/chemical synthesis , Diketopiperazines/chemical synthesis , Drug Carriers/chemical synthesis , HeLa Cells , Humans , Micelles , Peptidomimetics/chemical synthesis , Peptidomimetics/chemistry , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Sodium Dodecyl Sulfate/chemistry , StereoisomerismABSTRACT
Covering: Up to mid-2019 Cyclodipeptide synthases (CDPSs) catalyse the formation of cyclodipeptides using aminoacylated-tRNA as substrates. The recent characterization of large sets of CDPSs has revealed that they can produce highly diverse products, and therefore have great potential for use in the production of different 2,5-diketopiperazines (2,5-DKPs). Sequence similarity networks (SSNs) are presented as a new, efficient way of classifying CDPSs by specificity and identifying new CDPS likely to display novel specificities. Several strategies for further increasing the diversity accessible with these enzymes are discussed here, including the incorporation of non-canonical amino acids by CDPSs and use of the remarkable diversity of 2,5-DKP-tailoring enzymes discovered in recent years.
Subject(s)
Biotechnology/methods , Diketopiperazines/chemical synthesis , Peptide Synthases/chemistry , Peptide Synthases/metabolism , Protein Engineering/methods , Amino Acids/chemistry , Diketopiperazines/metabolism , Substrate SpecificityABSTRACT
The co-crystal structure of Compound 6b with tubulin was prepared and solved for indicating the binding mode and for further optimization. Based on the co-crystal structures of tubulin with plinabulin and Compound 6b, a total of 27 novel A/B/C-rings plinabulin derivatives were designed and synthesized. Their biological activities were evaluated against human lung cancer NCI-H460 cell line. The optimum phenoxy-diketopiperazine-type Compound 6o exhibited high potent cytotoxicity (IC50â¯=â¯4.0â¯nM) through SAR study of three series of derivatives, which was more potent than plinabulin (IC50â¯=â¯26.2â¯nM) and similar to Compound 6b (IC50â¯=â¯3.8â¯nM) against human lung cancer NCI-H460 cell line. Subsequently, the Compound 6o was evaluated against other four human cancer cell lines. Both tubulin polymerization assay and immunofluorescence assay showed that Compound 6o could inhibit microtubule polymerization efficiently. Furthermore, theoretical calculation of the physical properties and molecular docking were elucidated for these plinabulin derivatives. The binding mode of Compound 6o was similar to Compound 6b based on the result of molecular docking. The theoretical calculated LogPo/w and PCaco of Compound 6o were better than Compound 6b, which could enhance its cytostatic activity. Therefore, Compound 6o might be developed as a novel potent anti-microtubule agent.
Subject(s)
Antineoplastic Agents/pharmacology , Diketopiperazines/pharmacology , Drug Development , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Cell Survival/drug effects , Crystallography, X-Ray , Diketopiperazines/chemical synthesis , Diketopiperazines/chemistry , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Models, Molecular , Molecular Structure , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
Cyclic dipeptides, 2,5-diketopiperazines (DKPs), are well-known bioactive and taste compounds in food. DKPs have also been reported in various foods and particularly, Pro-containing DKPs (cyclo(-X-Pro)) are more predominant in heated and fermented foods than other type of DKPs. However, the mechanism underlying the preferential formation of Pro-containing DKPs in food remains uncertain. Herein, we attempted to elucidate the effects of reaction conditions and the mechanism of DKPs formation. The reaction conditions (heating time, heating temperature, and pH) and amino acid sequence of the linear peptides were important for the DKPs formation from linear peptides. In addition, Pro-containing DKPs were significantly formed from linear peptides with the second amino acid from the N-terminus being Pro. Based on these results, the underlying mechanism of the enrichment of Pro-containing DKPs in foods was proposed.
Subject(s)
Dipeptides/chemistry , Peptides, Cyclic/chemistry , Proline/analysis , Amino Acid Sequence , Diketopiperazines/chemical synthesis , Diketopiperazines/standards , Hot Temperature , Hydrogen-Ion Concentration , Protein Conformation , Reference StandardsABSTRACT
Structurally complex and bioactive ent-kaurane diterpenoids have well-characterized biological functions and have drawn widespread attention from chemists for many decades. However, construction of highly oxidized forms of such diterpenoids still presents considerable challenges to synthetic chemists. Herein, we report the first total syntheses of C19 oxygenated spiro-lactone ent-kauranoids, including longirabdiol, longirabdolactone, and effusin. A concise synthesis of the common intermediate used for all three syntheses was enabled via three free-radical-based reactions: (1) a newly devised tandem decarboxylative cyclization/alkenylation sequence that forges the cis-19, 6-lactone concomitantly with vicinal alkenylation, (2) a Ni-catalyzed decarboxylative Giese reaction that constructs C10 quaternary center stereoselectively, and (3) a vinyl radical cyclization that generates a rigid bicyclo[3.2.1]octane. A series of late-stage oxidations from the common intermediate then provided each of the natural products in turn. Further biological evaluation of these synthetic natural products reveals broad anticancer activities.
Subject(s)
Diketopiperazines/chemical synthesis , Diterpenes, Kaurane/chemical synthesis , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cyclization , Decarboxylation , Diketopiperazines/pharmacology , Diterpenes, Kaurane/pharmacology , Drug Screening Assays, Antitumor , Esterification , Humans , Oxidation-Reduction , StereoisomerismABSTRACT
We present a chemical methylome analysis platform to evaluate the inhibitory activity of small molecules towards poorly characterized protein methyltransferases (PMTs), facsilitating to identify syn-HyPA-ETP-2 as a non-histone arginine methyltransferase inhibitor.
Subject(s)
Diketopiperazines/pharmacology , Enzyme Inhibitors/pharmacology , Protein-Arginine N-Methyltransferases/antagonists & inhibitors , Animals , Diketopiperazines/chemical synthesis , Diketopiperazines/chemistry , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , HEK293 Cells , Heterogeneous-Nuclear Ribonucleoprotein K , Humans , Mice , Organoselenium Compounds/chemistry , Piperazines/chemistry , Ribonucleoproteins/metabolism , S-Adenosylmethionine/analogs & derivatives , S-Adenosylmethionine/chemistry , StereoisomerismSubject(s)
Anti-Bacterial Agents/pharmacology , Antifungal Agents/pharmacology , Antimicrobial Cationic Peptides/pharmacology , Bacteria/drug effects , Candida/drug effects , Diketopiperazines/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Antifungal Agents/chemical synthesis , Antifungal Agents/chemistry , Antimicrobial Cationic Peptides/chemical synthesis , Antimicrobial Cationic Peptides/chemistry , Diketopiperazines/chemical synthesis , Diketopiperazines/chemistry , Humans , Microbial Sensitivity TestsABSTRACT
We report herein the scalable total synthesis of the secondary metabolite, mycocyclosin, initially isolated from Mycobacterium tuberculosis. Mycocylosin bears a highly strained 3,3'-dityrosine biaryl system which arises biosynthetically from an intramolecular oxidative dehydrogenative cross-coupling of cyclo(l-Tyr-l-Tyr) (cYY) catalyzed by the P450 enzyme CYP121. CYP121 is found exclusively in M. tuberculosis. Scalable access to mycocyclosin and related derivatives via a Pd(II)-catalyzed macrocyclization is anticipated to facilitate the biological evaluation of these compounds as novel tuberculosis antimicrobials.
Subject(s)
Diketopiperazines/chemical synthesis , Molecular Structure , Mycobacterium tuberculosis , Oxidation-ReductionABSTRACT
Novel multifunctional 3,6-Diphenyl-1,4-bis(phenylsulfonyl)piperazine-2,5-dione derivatives were designed and synthesized for the treatment of Alzheimer's disease (AD). The designed scaffold has blood brain barrier penetrating ability, acetylcholinesterase (AChE) and matrix metalloproteinase-2 (MMP-2) inhibition potential. Compounds 52 and 46 showed very significant inhibition against AChE, IC50â¯=â¯32.45⯱â¯0.044, 28.65⯱â¯0.029, BuChE, IC50â¯=â¯157.95⯱â¯0.264, 160.58⯱â¯0.082 and MMP-2, IC50â¯=â¯36.83⯱â¯0.015, 19.57⯱â¯0.005 (nM). In the enzyme kinetics study, lead molecule 46 showed non-competitive inhibition of AChE with Kiâ¯=â¯7â¯nM and competitive inhibition of MMP-2 with Kiâ¯=â¯20â¯nM. Compounds 52 and 46 inhibited AChE-induced Aß aggregation at 20⯵M. The compounds also exhibited in-vitro antioxidant potential in DPPH assay. Further, compound 46 was found to be a promising neuroprotective agent in MC65â¯cells. Lead molecule 46 significantly enhanced working memory in scopolamine induced amnesia animal model at dose of 5â¯mg/kg dose. The mitochondrial membrane potential was restored in animals when treated with compounds 52 and 46.
Subject(s)
Alzheimer Disease/drug therapy , Diketopiperazines/pharmacology , Enzyme Inhibitors/pharmacology , Neuroprotective Agents/pharmacology , Acetylcholinesterase/metabolism , Alzheimer Disease/metabolism , Butyrylcholinesterase/metabolism , Diketopiperazines/chemical synthesis , Diketopiperazines/chemistry , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Matrix Metalloproteinase 2/metabolism , Molecular Structure , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/chemistry , Structure-Activity RelationshipABSTRACT
We previously synthesized new 5-thienyl-substituted 2-aminobenzamide-type HDAC1, 2 inhibitors with the (4-ethyl-2,3-dioxopiperazine-1-carboxamido) methyl group. K-560 (1a) protected against neuronal cell death in a Parkinson's disease model by up-regulating the expression of XIAP. This finding prompted us to design new K-560-related compounds. We examined the structure activity relationship (SAR) for the neuronal protective effects of newly synthesized and known K-560 derivatives after cerebral ischemia. Among them, K-856 (8), containing the (4-methyl-2,5-dioxopiperazin-1-yl) methyl group, exhibited a promising neuronal survival activity. The SAR study strongly suggested that the attachment of a monocyclic 2,3- or 2,5-diketopiperazine group to the 2-amino-5-aryl (but not 2-nitro-5-aryl) scaffold is necessary for K-560-related compounds to exert a potent neuroprotective effect.
Subject(s)
Diketopiperazines/chemical synthesis , Histone Deacetylase Inhibitors/chemical synthesis , Neurons/cytology , Neuroprotective Agents/chemical synthesis , Animals , Benzamides/chemistry , Brain Ischemia/drug therapy , Cell Death/drug effects , Cell Line , Diketopiperazines/chemistry , Diketopiperazines/pharmacology , Histone Deacetylase Inhibitors/chemistry , Histone Deacetylase Inhibitors/pharmacology , Humans , Models, Biological , Molecular Structure , Neurons/drug effects , Neuroprotective Agents/chemistry , Neuroprotective Agents/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
The highly convergent total synthesis of dimeric diketopiperazine alkaloids (+)-asperazine A and (+)-pestalazine B is described. A critical aspect of our expedient route was the development of a directed regio- and diastereoselective C3-N1' coupling of complex tetracyclic diketopiperazine components. This late-stage heterodimerization reaction was made possible by design of tetracyclic diketopiperazines that allow C3-carbocation coupling of the electrophilic component to the N1' locus of the nucleophilic fragment. The application of this new coupling reaction to the first total synthesis of (+)-asperazine A led to our revision of the sign and magnitude of the optical rotation for the reported structure.
Subject(s)
Diketopiperazines/chemical synthesis , Indole Alkaloids/chemical synthesis , Alkaloids/chemical synthesis , Chemistry Techniques, Synthetic/methods , Dimerization , StereoisomerismABSTRACT
This article focuses on our investigation of the molecular structure characteristics of diketopiperazines (DKPs), and application of these findings to the development of novel functional molecules. DKPs bearing a benzyl moiety are known to adopt a folded conformation, in which the benzyl moiety is folded over the DKP ring. In order to investigate the driving force behind the folded conformation, we synthesized DKPs bearing a benzyl moiety with different para-substituents, and demonstrated that the folded conformation likely arose from intramolecular CH/π interactions, based on the electronic effects of para-substituents on the benzyl group in 1H NMR spectroscopy. On the other hand, N4-methylation of DKPs bearing a benzyl moiety was found to change their folded conformation to an extended conformation, based on single crystal X-ray crystallography and 1H NMR spectroscopy analysis. Next, we attempted to synthesize both hydroxamate-type siderophores containing the DKP ring: rhodotorulic acid and erythrochelin. Facile synthesis of rhodotorulic acid and its N,N'-dimethylated derivative was achieved by microwave-assisted cyclization of the corresponding dipeptide precursors. Interestingly, N,N'-dimethylated rhodotorulic acid was found to be more soluble in various organic solvents than rhodotorulic acid. Moreover, erythrochelin was synthesized for the first time, and its metal-chelating ability with not only Fe(III) but also Mg(II) was confirmed based on electrospray ionization mass spectrometry (ESI-MS) analysis. Finally, we synthesized DKPs bearing a primary amino group, and found that they could catalyze the asymmetric aldol reaction between hydroxyacetone and p-nitrobenzaldehyde.
Subject(s)
Diketopiperazines/chemistry , Diketopiperazines/chemical synthesis , Molecular Conformation , Aldehydes/chemistry , Catalysis , Chelating Agents , Crystallography, X-Ray , Cyclization , Magnetic Resonance Spectroscopy , Methylation , Microwaves , Oligopeptides/chemical synthesis , Organic Chemistry Phenomena , Piperazines/chemical synthesis , Solvents , Spectrometry, Mass, Electrospray IonizationABSTRACT
The synthesis of barettin, a selective serotonin receptor inhibitor and potent antibiofouling natural product, is described. The synthesis starts with the diketopiperazine nucleus intact and the side chains are installed using iterative aldol condensations. The route represents a general strategy for synthesis of a wide array of mono-alkylidene diketopiperazine structures, including those derived from non-canonical amino acid residues.