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1.
Bioorg Med Chem ; 106: 117733, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38704960

RESUMO

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.


Assuntos
Complexo de Endopeptidases do Proteassoma , Inibidores de Proteassoma , Relação Estrutura-Atividade , Complexo de Endopeptidases do Proteassoma/metabolismo , Complexo de Endopeptidases do Proteassoma/química , Inibidores de Proteassoma/farmacologia , Inibidores de Proteassoma/química , Inibidores de Proteassoma/síntese química , Humanos , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , Subunidades Proteicas/antagonistas & inibidores , Subunidades Proteicas/metabolismo , Subunidades Proteicas/química , Estrutura Molecular
2.
Chem Pharm Bull (Tokyo) ; 72(6): 547-558, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38866476

RESUMO

Iridoids, which are a class of monoterpenoids, are attractive synthetic targets due to their diversely substituted cis-fused cyclopenta[c]pyran skeletons. Additionally, various biological activities of iridoids raise the value of synthetic studies on this class of compounds. Here, our synthetic efforts toward 11-noriridoids; (±)-umbellatolide B (6), (±)-10-O-benzoylglobularigenin (9) and 1-O-pentenylaucubigenin (34) are described. For the efficient synthesis of target compounds, common synthetic intermediates (tricyclic enones 17 and 26) were prepared by the Pauson-Khand reaction. The cleavage of the acetal bond on the tricyclic enones and 1,2-reduction introduced the two hydroxy groups on the cyclopentane ring of the core scaffold. Furthermore, the C3-C4 olefin part was constructed by the syn-elimination of a thiocarbonate moiety to obtain 34. The developed synthetic routes for 6, 9, and 34 will be useful for the preparation of iridoid analogs that have a polyfunctionalized core skeleton.


Assuntos
Iridoides , Iridoides/síntese química , Iridoides/química , Estrutura Molecular , Estereoisomerismo
3.
J Org Chem ; 88(15): 11367-11371, 2023 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-37466434

RESUMO

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.

4.
Bioorg Med Chem Lett ; 37: 127847, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33571648

RESUMO

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.


Assuntos
Bibliotecas de Moléculas Pequenas/química , Difusão , Membranas Artificiais , Estrutura Molecular , Permeabilidade , Solubilidade
5.
Bioorg Med Chem Lett ; 30(2): 126839, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31848042

RESUMO

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.


Assuntos
Antígenos Virais/química , Proteínas Nucleares/química , Nucleossomos/química , Peptídeos Cíclicos/uso terapêutico , Humanos , Estrutura Molecular , Peptídeos Cíclicos/farmacologia
6.
Chembiochem ; 20(16): 2046-2053, 2019 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-31062458

RESUMO

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 complex 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.


Assuntos
Complexo Repressor Polycomb 2/metabolismo , Histonas/química , Histonas/metabolismo , Humanos , Metilação , Complexo Repressor Polycomb 2/química , Conformação Proteica
7.
Genes Cells ; 22(5): 424-435, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28326644

RESUMO

We developed transgenic (Tg) rats that express human CD4, CCR5, CXCR4, CyclinT1, and CRM1 genes. Tg rat macrophages were efficiently infected with HIV-1 and supported production of infectious progeny virus. By contrast, both rat primary CD4+ T cells and established T cell lines expressing human CD4, CCR5, CyclinT1, and CRM1 genes were infected inefficiently, but this was ameliorated by inhibition of cyclophilin A. The infectivity of rat T cell-derived virus was lower than that of human T cell-derived virus.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Ciclina T/metabolismo , Infecções por HIV/imunologia , Carioferinas/metabolismo , Macrófagos/imunologia , Receptores Citoplasmáticos e Nucleares/metabolismo , Animais , Linfócitos T CD4-Positivos/virologia , Linhagem Celular , Células Cultivadas , Ciclina T/genética , Suscetibilidade a Doenças , HIV-1/patogenicidade , Humanos , Carioferinas/genética , Macrófagos/virologia , Ratos , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Receptores Citoplasmáticos e Nucleares/genética , Proteína Exportina 1
8.
J Org Chem ; 83(13): 7085-7101, 2018 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-29457732

RESUMO

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.


Assuntos
Depsipeptídeos/química , Depsipeptídeos/síntese química , Solventes/química , Cianetos/química , Esterificação , Lactonas/química , Estrutura Molecular , Propanóis/química , Estereoisomerismo
10.
Chem Pharm Bull (Tokyo) ; 66(1): 84-95, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29311516

RESUMO

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.


Assuntos
Monossacarídeos/síntese química , Nucleotídeos/síntese química , Oligopeptídeos/síntese química , Técnicas de Síntese em Fase Sólida , Uridina Difosfato Ácido N-Acetilmurâmico/análogos & derivados , Conformação Molecular , Monossacarídeos/química , Nucleotídeos/química , Oligopeptídeos/química , Uridina Difosfato Ácido N-Acetilmurâmico/síntese química , Uridina Difosfato Ácido N-Acetilmurâmico/química
11.
Bioorg Med Chem ; 25(14): 3623-3630, 2017 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-28528081

RESUMO

Plinabulin and KPU-300 are promising anti-microtubule agents; however, the low water solubility of these compounds (<0.1µg/mL) has limited their pharmaceutical advantages. Here, we developed five water-soluble derivatives of plinabulin and KPU-300 with a click strategy using disodium salts of amino acids. The mother skeleton, diketopiperazine (DKP), was transformed into a monolactim-type alkyne and a copper-catalyzed alkyne azide cycloaddition (CuAAC) combined azides that was derived from amino acids as a water-solubilizing moiety. The conversion of carboxyl groups into disodium salts greatly improved the water solubility by 0.8 million times compared to the solubility of the parent molecules. In addition, the α-amino acid side chains of the water-solubilizing moieties affected both the water solubility and the half-lives of the compounds during enzymatic hydrolysis. Our effort to develop a variety of water-soluble derivatives using the click strategy has revealed that the replaceable water-solubilizing moieties can alter molecular solubility and stability under enzymatic hydrolysis. With this flexibility, we are approaching to the in vivo study using water-soluble derivative.


Assuntos
Aminoácidos/química , Benzofenonas/química , Dicetopiperazinas/química , Sais/química , Água/química , Alcinos/química , Azidas/química , Catálise , Química Click , Cobre/química , Reação de Cicloadição , Dicetopiperazinas/síntese química , Dicetopiperazinas/metabolismo , Meia-Vida , Hidrólise , Sódio/química , Solubilidade
12.
Bioconjug Chem ; 27(7): 1606-13, 2016 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-27304609

RESUMO

Although several approaches for making antibody-drug conjugates (ADC) have been developed, it has yet to be reported that an antibody binding peptide such as Z33 from protein A is utilized as the pivotal unit to generate the noncovalent-type ADC (NC-ADC). Herein we aim to establish a novel probe for NC-ADC by synthesizing the Z33-conjugated antitumor agent, plinabulin. Due to the different solubility of two components, including hydrophobic plinabulin and hydrophilic Z33, an innovative method with a solid-supported disulfide coupling reagent is required for the synthesis of the target compounds with prominent efficiency (29% isolated yield). We demonstrate that the synthesized hybrid exhibits a binding affinity against the anti-HER2 antibody (Herceptin) and the anti-CD71 antibody (6E1) (Kd = 46.6 ± 0.5 nM and 4.5 ± 0.56 µM, respectively) in the surface plasmon resonance (SPR) assay. In the cell-based assays, the hybrid provides a significant cytotoxicity in the presence of Herceptin against HER2 overexpressing SKBR-3 cells, but not against HER2 low-expressing MCF-7 cells. Further, it is noteworthy that the hybrid in combination with Herceptin induces cytotoxicity against Herceptin-resistant SKBR-3 (SKBR-3HR) cells. Similar results are obtained with the 6E1 antibody, suggesting that the synthesized hybrid can be widely applicable for NC-ADC using the antibody of interest. In summary, a series of evidence presented here strongly indicate that NC-ADCs have high potential for the next generation of antitumor agents.


Assuntos
Antineoplásicos/metabolismo , Dicetopiperazinas/metabolismo , Imunoconjugados/metabolismo , Imunoconjugados/farmacologia , Imunoglobulina G/metabolismo , Pró-Fármacos/metabolismo , Humanos , Imunoconjugados/química , Células MCF-7 , Solubilidade , Água/química
13.
Biopolymers ; 106(4): 440-5, 2016 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-26567043

RESUMO

Neuromedin U (NMU), an anorexigenic peptide, has attracted attention as a candidate for development of drugs against obesity. We recently developed several potent hexapeptidic agonists derived from NMU that share a common Pro-Arg-Asn-NH2 (PRN) sequence at their C-termini and found that the amide bond between Arg and Asn is rapidly degraded in serum. In this study, we determined that the key enzyme responsible for this biodegradation was thrombin. Both irreversible and reversible thrombin inhibitors (PPACK and argatroban, respectively) enhanced the serum stability of both hexapeptidic agonists and human NMU itself as an inherent ligand. In addition, rapid degradation did not occur in citrated human plasma because thrombin was not activated under these conditions. Furthermore, we found that an N-terminal 2-thienylacetyl group in hexapeptidic agonists enhanced recognition by thrombin. These findings will be valuable for future investigations of the biological functions of NMU in vivo. © 2015 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 440-445, 2016.


Assuntos
Clorometilcetonas de Aminoácidos/química , Neuropeptídeos/química , Ácidos Pipecólicos/química , Trombina , Arginina/análogos & derivados , Humanos , Hidrólise , Soro/química , Sulfonamidas , Trombina/antagonistas & inibidores , Trombina/química
14.
Org Biomol Chem ; 13(11): 3186-9, 2015 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-25657109

RESUMO

A new solid-phase disulfide ligation method is developed to prepare a disulfide peptide from two types of Cys-containing peptide fragments with minimum purification steps. In combination with the subsequent intramolecular amide bond formation, a cyclic nonapeptide, oxytocin, was efficiently synthesized as a fundamental model for more complex cyclic peptides.


Assuntos
Dissulfetos/química , Peptídeos Cíclicos/síntese química , Piridinas/química , Estrutura Molecular , Peptídeos Cíclicos/química
15.
Sci Rep ; 14(1): 7628, 2024 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-38561454

RESUMO

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.


Assuntos
Neoplasias do Colo , Equinomicina , Humanos , Animais , Camundongos , Equinomicina/farmacologia , Neoplasias do Colo/tratamento farmacológico , Subunidade alfa do Fator 1 Induzível por Hipóxia
16.
Bioorg Med Chem ; 21(2): 412-24, 2013 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-23245752

RESUMO

We describe here the design, synthesis and biological evaluation of a series of molecules toward the development of novel peptidomimetic inhibitors of SARS-CoV 3CL(pro). A docking study involving binding between the initial lead compound 1 and the SARS-CoV 3CL(pro) motivated the replacement of a thiazole with a benzothiazole unit as a warhead moiety at the P1' site. This modification led to the identification of more potent derivatives, including 2i, 2k, 2m, 2o, and 2p, with IC(50) or K(i) values in the submicromolar to nanomolar range. In particular, compounds 2i and 2p exhibited the most potent inhibitory activities, with K(i) values of 4.1 and 3.1 nM, respectively. The peptidomimetic compounds identified through this process are attractive leads for the development of potential therapeutic agents against SARS. The structural requirements of the peptidomimetics with potent inhibitory activities against SARS-CoV 3CL(pro) may be summarized as follows: (i) the presence of a benzothiazole warhead at the S1'-position; (ii) hydrogen bonding capabilities at the cyclic lactam of the S1-site; (iii) appropriate stereochemistry and hydrophobic moiety size at the S2-site and (iv) a unique folding conformation assumed by the phenoxyacetyl moiety at the S4-site.


Assuntos
Desenho de Fármacos , Oligopeptídeos/síntese química , Inibidores de Proteases/síntese química , Proteínas Virais/antagonistas & inibidores , Benzotiazóis/química , Sítios de Ligação , Cisteína Endopeptidases/química , Cisteína Endopeptidases/metabolismo , Ligação de Hidrogênio , Simulação de Acoplamento Molecular , Oligopeptídeos/química , Oligopeptídeos/metabolismo , Inibidores de Proteases/química , Inibidores de Proteases/metabolismo , Ligação Proteica , Estrutura Terciária de Proteína , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/metabolismo , Relação Estrutura-Atividade , Proteínas Virais/metabolismo
17.
Chem Pharm Bull (Tokyo) ; 61(9): 889-901, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23995353

RESUMO

Certain antimicrotubule agents displaying colchicine-like tubulin-depolymerizing activity can act as both cytotoxic and vascular-disrupting agents (VDAs). VDAs constitute a new class of anticancer drugs and are currently in clinical trials. We have developed a VDA clinical candidate (phase II) diketopiperazine (DKP)-type antimicrotubule agent called plinabulin (7) derived from the natural DKP phenylahistin (5), which displays colchicine-like tubulin-depolymerizing activity. To develop more potent antimicrotubule DKP derivatives, we performed an intensive structure-activity relationship study examining the phenyl group of compound 7. This study identified more potent DKP derivatives (2,5-difluoro derivatives [29] and benzophenone derivatives [36]) with vascular-disrupting activities. The benzophenone moiety of compound 36 was further modified to yield the most potent cytotoxic derivative yet discovered, the 4-fluorobenzophenone derivative 38 m, which inhibited the growth of HT-29 cells in vitro at subnanomolar levels. As both VDAs and cytotoxic agents, these potent DKP derivatives are valuable second-generation drug candidates. The chemical biology of plinabulin was examined by designing and synthesizing biotin-tagged photoaffinity probes 40-42 that could be used to indicate the binding mode of compound 7 with tubulin. A tubulin photoaffinity labeling study suggested that compound 7 binds at the interface between the α- and ß-tubulins near the colchicine-binding site and not inside the colchicine-binding cavity. A water-soluble prodrug of the poorly water-soluble 7 was next designed in an effort to improve the pharmacokinetics and chemotherapeutic indices. The lead compound 56 revealed high water solubility and a half-life profile appropriate for an injected drug.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Dicetopiperazinas/química , Dicetopiperazinas/farmacologia , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologia , Benzofenonas/química , Benzofenonas/farmacologia , Células HT29 , Humanos , Neoplasias/tratamento farmacológico , Marcadores de Fotoafinidade/química , Marcadores de Fotoafinidade/metabolismo , Tubulina (Proteína)/metabolismo
18.
Chem Commun (Camb) ; 59(82): 12306-12309, 2023 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-37753573

RESUMO

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.

19.
Bioorg Med Chem ; 20(14): 4279-89, 2012 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-22727370

RESUMO

KPU-105 (4), a potent anti-microtubule agent that contains a benzophenone was derived from the diketopiperazine-type vascular disrupting agent (VDA) plinabulin 3, which displays colchicine-like tubulin depolymerization activity. To develop derivatives with more potent anti-microtubule and cytotoxic activities, we further modified the benzophenone moiety of 4. Accordingly, we obtained a 4-fluorobenzophenone derivative 16j that inhibited tumor cell growth in vitro with a subnanomolar IC(50) value against HT-29 cells (IC(50)=0.5 nM). Next, the effect of 16j on mitotic spindles was evaluated in HeLa cells. Treatment with 3nM of 16j partially disrupted the interphase microtubule network. By contrast, treatment with the same concentration of CA-4 barely affected the microtubule network, indicating that 16j exhibited more potent anti-mitotic effects than did CA-4.


Assuntos
Antineoplásicos/síntese química , Benzofenonas/química , Dicetopiperazinas/química , Microtúbulos/química , Moduladores de Tubulina/síntese química , Antineoplásicos/química , Antineoplásicos/toxicidade , Benzofenonas/síntese química , Proliferação de Células/efeitos dos fármacos , Colchicina/química , Cristalografia por Raios X , Dicetopiperazinas/síntese química , Dicetopiperazinas/toxicidade , Células HT29 , Células HeLa , Humanos , Microtúbulos/metabolismo , Conformação Molecular , Relação Estrutura-Atividade , Moduladores de Tubulina/química , Moduladores de Tubulina/toxicidade
20.
Chem Pharm Bull (Tokyo) ; 60(7): 877-81, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22790821

RESUMO

Plinabulin (1) is a potent anti-microtubule agent, however, its low water solubility has to be improved for the advantage in pharmacokinetics and chemotherapy. In this report, the replaceable water-solubilizing moiety of the water-soluble prodrug of plinabulin (1) was investigated. The properties of the water-soluble prodrugs of plinabulin (1), in which the water-solubilizing part was replaced with a new functionality, were evaluated. The newly introduced water-solubilizing moiety provided interesting effects on the water solubility and half-life of the prodrugs.


Assuntos
Dicetopiperazinas/química , Pró-Fármacos/química , Dicetopiperazinas/síntese química , Dicetopiperazinas/metabolismo , Esterases/metabolismo , Meia-Vida , Hidrólise , Pró-Fármacos/síntese química , Pró-Fármacos/metabolismo , Solubilidade , Água
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