ABSTRACT
Development of selective or dual proteasome subunit inhibitors based on syringolin B as a scaffold is described. We focused our efforts on a structure-activity relationship study of inhibitors with various substituents at the 3-position of the macrolactam moiety of syringolin B analogue to evaluate whether this would be sufficient to confer subunit selectivity by using sets of analogues with hydrophobic, basic and acidic substituents, which were designed to target Met45, Glu53 and Arg45 embedded in the S1 subsite, respectively. The structure-activity relationship study using systematic analogues provided insight into the origin of the subunit-selective inhibitory activity. This strategy would be sufficient to confer subunit selectivity regarding ß5 and ß2 subunits.
ABSTRACT
Colorectal cancer is the third most commonly diagnosed cancer and the second leading cause of cancer-related death, thus a novel chemotherapeutic agent for colon cancer therapy is needed. In this study, analogues of echinomycin, a cyclic peptide natural product with potent toxicity to several human cancer cell lines, were synthesized, and their biological activities against human colon cancer cells were investigated. Analogue 3 as well as 1 inhibit HIF-1α-mediated transcription. Notably, transcriptome analysis indicated that the cell cycle and its regulation were involved in the effects on cells treated with 3. Analogue 3 exhibited superior in vivo efficacy to echinomycin without significant toxicity in mouse xenograft model. The low dose of 3 needed to be efficacious in vivo is also noteworthy and our data suggest that 3 is an attractive and potentially novel agent for the treatment of colon cancer.
Subject(s)
Colonic Neoplasms , Echinomycin , Humans , Animals , Mice , Echinomycin/pharmacology , Colonic Neoplasms/drug therapy , Hypoxia-Inducible Factor 1, alpha SubunitABSTRACT
A new compound, a derivative of 3,4,5-trimethoxy-N-phenyl benzamide bearing an 8''-methylimidazopyridine moiety, is found to demonstrate neuroprotective effects by preventing cell death caused by oxidative stress. The compound possesses high solubility and metabolic stability, and inhibits MPTP-induced effects in vivo, indicating high potential as a therapeutic drug for Parkinson's disease.
ABSTRACT
Solid-phase total synthesis of nannocystin Ax (1) was disclosed. A coupling reaction between a peptide and a polyketide moiety was conducted on a solid support, and macrocyclization was achieved by Mitsunobu cyclization. The established synthetic route was efficient to prepare its analogues, which contain different types of peptide moieties.
ABSTRACT
Post-translational modifications (PTMs) of histones play a key role in epigenetic regulation. Unraveling the roles of each epigenetic mark can provide new insights into their biological mechanisms. On the other hand, it is generally difficult to prepare homogeneously-modified histones/nucleosomes to investigate their specific functions. Therefore, synthetic approaches to acquire precisely mimicked histones/nucleosomes are in great demand, and further development of this research field is anticipated. In this review, synthetic strategies to modify histones/nucleosomes, including cysteine modifications, transformations of dehydroalanine residues and lysine acylation using a catalyst system, are cited. In addition, the functional evaluation of synthetically modified histones/nucleosomes is described.
Subject(s)
Histones , Nucleosomes , Epigenesis, Genetic , Histones/chemistry , Histones/genetics , Histones/metabolism , Protein Processing, Post-TranslationalABSTRACT
The aging population has had an impact on society in recent decades. Aging-associated health issues are a particularly challenging aspect to regulate. Therefore, the extension of healthy life expectancy by the application of biologically active compounds is an attractive research topic in the fields of medicinal chemistry, chemical biology, and also organic synthesis. Herein, the first total synthesis of acaulide, acaulone A and 10-keto-acaudiol A is described. These compounds were originally isolated from a culture of Acaulium sp. H-JQSF. Acaulide exhibits anti-osteoporosis activity in a prednisolone-induced osteoporotic zebrafish model; hence, this natural product is expected to be a new lead compound for anti-osteoporosis drugs. The characteristic acaulide skeletons were synthesized via late-stage Michael addition inspired by the proposed biosynthetic pathways. The conformational analysis of the 14-membered macrodiolide revealed the specific conformation that enabled the late-stage stereoselective functionalization.
Subject(s)
Biological Products/chemical synthesis , Bone Density Conservation Agents , Chemistry, Organic/methods , Chemistry, Pharmaceutical/methods , Drug Development/methods , Polyketides/chemical synthesis , Animals , Ascomycota , Biological Products/pharmacology , Biological Products/therapeutic use , Disease Models, Animal , Humans , Organic Chemistry Phenomena , Osteoporosis/drug therapy , Polyketides/pharmacology , Polyketides/therapeutic use , ZebrafishABSTRACT
To develop methodology to predict the potential druggability of middle molecules, we examined the structure, solubility, and permeability relationships of a diverse library (HKDL ver.1) consisting of 510 molecules (359 natural product derivatives, 76 non-natural products, 46 natural products, and 29 non-natural product derivatives). The library included peptides, depsipeptides, macrolides, and lignans, and 476 of the 510 compounds had a molecular weight in the range of 500-2000 Da. The solubility and passive diffusion velocity of the middle molecules were assessed using the parallel artificial membrane permeability assay (PAMPA). Quantitative values of solubility of 471 molecules and passive diffusion velocity of 287 molecules were obtained, and their correlations with the structural features of the molecules were examined. Based on the results, we propose a method to predict the passive diffusion characteristics of middle molecules from their three-dimensional structural features.
Subject(s)
Small Molecule Libraries/chemistry , Diffusion , Membranes, Artificial , Molecular Structure , Permeability , SolubilityABSTRACT
Iridoids are a large family of monoterpenoids found in traditional medicinal plants and show significant effects for the human species. In addition to their wide range of biological activities, such as neuroprotective and antitumor activities, the cis-fused bicyclic ring systems of iridoids are still attractive as synthetic targets to apply novel synthetic methodologies. Accordingly, recent progress regarding the biosynthesis and chemical synthesis of iridoids is covered in this minireview. Identification of new enzymes for the iridoid biosynthesis in Catharanthus roseus and ingenious synthetic strategies for the construction of the iridoid skeleton are described.
Subject(s)
Iridoids/chemical synthesis , Iridoids/metabolism , Animals , Humans , Iridoids/chemistry , Molecular StructureABSTRACT
The synthesis and biological evaluation of analogues of uridylpeptide antibiotics were described, and the molecular interaction between the 3'-hydroxy analogue of mureidomycin A (3'-hydroxymureidomycin A) and its target enzyme, phospho-MurNAc-pentapeptide transferase (MraY), was analyzed in detail. The structure-activity relationship (SAR) involving MraY inhibition suggests that the side chain at the urea-dipeptide moiety does not affect the MraY inhibition. However, the anti-Pseudomonas aeruginosa activity is in great contrast and the urea-dipeptide motif is a key contributor. It is also suggested that the nucleoside peptide permease NppA1A2BCD is responsible for the transport of 3'-hydroxymureidomycin A into the cytoplasm. A systematic SAR analysis of the urea-dipeptide moiety of 3'-hydroxymureidomycin A was further conducted and the antibacterial activity was determined. This study provides a guide for the rational design of analogues based on uridylpeptide antibiotics.
Subject(s)
Anti-Bacterial Agents/metabolism , Dipeptides/metabolism , Enzyme Inhibitors/metabolism , Uridine/analogs & derivatives , Uridine/metabolism , Amino Acid Sequence , Anti-Bacterial Agents/chemical synthesis , Bacterial Proteins/antagonists & inhibitors , Bacterial Proteins/chemistry , Bacterial Proteins/metabolism , Dipeptides/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Microbial Sensitivity Tests , Molecular Docking Simulation , Molecular Structure , Protein Binding , Pseudomonas aeruginosa/drug effects , Sequence Alignment , Staphylococcus aureus/enzymology , Structure-Activity Relationship , Transferases/antagonists & inhibitors , Transferases/chemistry , Transferases/metabolism , Transferases (Other Substituted Phosphate Groups) , Urea/analogs & derivatives , Urea/metabolismABSTRACT
Acaulide and acaulone A, which contain 14-membered macrodiolides, were isolated from a culture of Acaulium sp. H-JQSF. The antiosteoporosis activity of acaulide is expected to contribute to drug discovery research for an aging society. We herein report the first total synthesis of acaulide, acaulone A, and 10-keto-acaudiol A. Acaulide and acaulone A were synthesized via the late stage Michael addition to the 14-membered macrodiolide, which was inspired by plausible biosynthetic pathways. This approach succeeded in the construction of the acaulide skeleton, which revealed the specific conformation of the 14-membered macrodiolide for late stage functionalization.
ABSTRACT
The first total synthesis of echinomycin (1) was accomplished by featuring the late-stage construction of the thioacetal moiety via Pummerer rearrangement and simultaneous cyclization, as well as two-directional elongation of the peptide chains to construct a C2-symmetrical bicyclic octadecadepsipeptide bridged with a sulfide linkage. This strategy can be applicable to a variety of echinomycin analogues.
Subject(s)
Echinomycin/chemical synthesis , Echinomycin/analogs & derivatives , Echinomycin/chemistry , Molecular Structure , StereoisomerismABSTRACT
Tunicamycins, which are nucleoside natural products, inhibit both bacterial phospho-N-acetylmuraminic acid (MurNAc)-pentapeptide translocase (MraY) and human UDP-N-acetylglucosamine (GlcNAc): polyprenol phosphate translocase (GPT). The improved synthesis and detailed biological evaluation of an MraY-selective inhibitor, 2, where the GlcNAc moiety was modified to a MurNAc amide, has been described.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Bacterial Proteins/antagonists & inhibitors , Transferases/antagonists & inhibitors , Tunicamycin/chemical synthesis , Tunicamycin/pharmacology , Bacterial Proteins/chemistry , Cell Line , Chemistry Techniques, Synthetic , Humans , Models, Molecular , Molecular Conformation , Molecular Structure , Structure-Activity Relationship , Transferases/chemistry , Transferases (Other Substituted Phosphate Groups)ABSTRACT
Kaposi's sarcoma-associated herpesvirus (KSHV) is known to be a carcinogenic agent that causes AIDS-associated Kaposi's sarcoma (KS). When KSHV infects host's cells, one of the virus's proteins, latency-associated nuclear antigen 1 (LANA), binds to the host's nucleosomes to retain episomes and create latency circumstances. Although the infectious mechanism of KSHV is partly elucidated, the development of drug candidates for targeting KS is ongoing. In this study, we developed cyclic peptides corresponding to an N-terminal LANA sequence that disrupt the LANA-nucleosome interaction. The cyclic peptides showed a different secondary structure compared to their corresponding linear peptide derivatives, which suggests that our cyclization strategy imitates the N-terminal LANA binding conformation on nucleosomes.
Subject(s)
Antigens, Viral/chemistry , Nuclear Proteins/chemistry , Nucleosomes/chemistry , Peptides, Cyclic/therapeutic use , Humans , Molecular Structure , Peptides, Cyclic/pharmacologyABSTRACT
Functional regulation of a protein complex is generally difficult because information of the target complex as a whole is limited. However, regulation of a protein complex is important for understanding complicated biological events in cells and therapeutic possibilities. This concept article introduces the potential for the functional regulation of a multiprotein complex, polycomb repressive complexâ 2 (PRC2), by developing chemical modulators. Functional regulatory mechanisms of PRC2 are described by using protein interaction information found through structural analyses. Subsequently, possibilities of novel chemical modulator development of PRC2 based on structural insights into the complex and related interactions are discussed.
Subject(s)
Polycomb Repressive Complex 2/metabolism , Histones/chemistry , Histones/metabolism , Humans , Methylation , Polycomb Repressive Complex 2/chemistry , Protein ConformationABSTRACT
A structure-activity relationship study on three classes of polymyxin analogues focusing on hydrophobicity was conducted.
Subject(s)
Anti-Bacterial Agents/pharmacology , Polymyxins/pharmacology , Pseudomonas aeruginosa/drug effects , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Dose-Response Relationship, Drug , Hydrophobic and Hydrophilic Interactions , Microbial Sensitivity Tests , Molecular Conformation , Molecular Structure , Polymyxins/analogs & derivatives , Polymyxins/chemistry , Structure-Activity RelationshipABSTRACT
Full details of our synthetic studies toward plusbacin A3 (1), which is a depsipeptide with antibacterial activity, and its dideoxy derivative are described. To establish an efficient synthetic route of 1, a solvent-dependent diastereodivergent Joullié-Ugi three-component reaction (JU-3CR) was used to construct trans-Pro(3-OH) in a small number of steps. Two strategies were investigated toward the total synthesis. In the first synthetic strategy, the key steps were the trans-selective JU-3CR and a macrolactonization at the final stage of the synthesis. The JU-3CR using alkyl isocyanides in 1,1,1,3,3,3-hexafluoroisopropanol provided the trans products, and the coupling of the fragments to prepare the macrocyclization precursor proceeded smoothly. However, attempts toward the macrolactonization did not provide the desired product. Then, the second strategy that included esterification in an initial stage was investigated. Methods for constructing trans-Pro(3-OH) were examined using a convertible isocyanide, which could be converted to a carboxylic acid required for the following amidation. Ester bond formation was achieved through an intermolecular coupling using a hydroxyl-Asp derivative and the corresponding alcohol, and the amidation afforded a linear depsipeptide. The macrolactamization of the linear peptide gave the cyclic depsipeptide, and then the global deprotection accomplished the total synthesis of 1 and its dideoxy derivative.
Subject(s)
Depsipeptides/chemistry , Depsipeptides/chemical synthesis , Solvents/chemistry , Cyanides/chemistry , Esterification , Lactones/chemistry , Molecular Structure , Propanols/chemistry , StereoisomerismABSTRACT
A solid-phase synthesis of Park nucleotide as well as lipids I and II analogues, which is applicable to the synthesis of a range of analogues, is described in this work. This technique allows highly functionalized macromolecules to be modularly labeled. Multiple steps are used in a short time (4 d) with a single purification step to synthesize the molecules by solid-phase synthesis.
Subject(s)
Monosaccharides/chemical synthesis , Nucleotides/chemical synthesis , Oligopeptides/chemical synthesis , Solid-Phase Synthesis Techniques , Uridine Diphosphate N-Acetylmuramic Acid/analogs & derivatives , Molecular Conformation , Monosaccharides/chemistry , Nucleotides/chemistry , Oligopeptides/chemistry , Uridine Diphosphate N-Acetylmuramic Acid/chemical synthesis , Uridine Diphosphate N-Acetylmuramic Acid/chemistryABSTRACT
The total synthesis of tunicamycin V is described. This strategy is based on the initial construction of tunicaminyluracil, which is regarded to play an important role in the observed biological activities. The key to the synthesis was a Mukaiyama aldol reaction followed by a furan-oxidation to construct the undecose skeleton, a [3,3] sigmatropic rearrangement of a cyanate, and a highly selective trehalose-type glycosylation.
ABSTRACT
The total synthesis of plusbacin A3 (1) has been accomplished using a solvent-dependent diastereodivergent Joullié-Ugi three-component reaction (JU-3CR) as a key step. Two trans-3-hydroxy-l-proline residues were constructed by combining the JU-3CR with a convertible isocyanide strategy. Subsequent peptide coupling and macrolactamization afforded plusbacin A3. Investigating the antibacterial activity of 1 compared with that of its dideoxy analogue revealed that the threo-ß-hydroxyaspartic acid residues are essential for antibacterial activity. Notably, there is a low potential for the development of resistance in S. aureus against plusbacin A3.