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1.
Angew Chem Int Ed Engl ; 60(26): 14252-14271, 2021 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-32392399

RESUMO

Pactamycin and jogyamycin are aminocyclopentitol natural products, where each core carbon bears a stereodefined alcohol or amine moiety. Their structural complexity, coupled with the diversity of functional groups coexisting in a condensed space, make them fascinating synthetic targets in their own right. Pactamycin and its derivatives bind to the 30S ribosomal subunit and display activity against parasites responsible for drug-resistant malaria and African sleeping sickness; however, efforts to develop their therapeutic potential have been hampered by their cellular toxicity. Interestingly, bioengineered analogues display differences in selectivity and toxicity towards mammalian cells, spurring efforts to develop flexible strategies to thoroughly probe structure-activity relationships (SAR), particularly in analogues lacking the C7 hydroxyl group of pactamycin. This review compares and contrasts approaches towards pactamycin and jogyamycin, including two successful total syntheses of the former. The implications of each route for preparing analogues to inform SAR and lead to compounds with increased selectivity for binding malarial over human ribosomes are briefly discussed.


Assuntos
Pactamicina/análogos & derivados , Pactamicina/síntese química , Humanos , Estrutura Molecular , Pactamicina/química , Estereoisomerismo
2.
J Org Chem ; 84(21): 14092-14100, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31578059

RESUMO

Jogyamycin is a member of the aminocyclopentitol class of natural products that exhibits significant antiprotozoal activities against diseases that include African sleeping sickness and malaria. Herein, we report a route to the core of this natural product via an underutilized Ichikawa rearrangement as a key step. This route efficiently forms the cyclopentane ring from simple and easily accessible starting materials and rapidly installs the C1/C4/C5 polar functional groups. In addition, this strategy shows excellent potential for the preparation of analogues of jogyamycin to study how structural changes impact the selectivity in binding to the ribosome.


Assuntos
Pactamicina/análogos & derivados , Técnicas de Química Sintética , Pactamicina/química , Estereoisomerismo
3.
Nat Chem Biol ; 15(8): 795-802, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31308531

RESUMO

Glycosylation is a common modification reaction in natural product biosynthesis and has been known to be a post-assembly line tailoring process in glycosylated polyketide biosynthesis. Here, we show that in pactamycin biosynthesis, glycosylation can take place on an acyl carrier protein (ACP)-bound polyketide intermediate. Using in vivo gene inactivation, chemical complementation and in vitro pathway reconstitution, we demonstrate that the 3-aminoacetophenone moiety of pactamycin is derived from 3-aminobenzoic acid by a set of discrete polyketide synthase proteins via a 3-(3-aminophenyl)3-oxopropionyl-ACP intermediate. This ACP-bound intermediate is then glycosylated by an N-glycosyltransferase, PtmJ, providing a sugar precursor for the formation of the aminocyclopentitol core structure of pactamycin. This is the first example of glycosylation of a small molecule while tethered to a carrier protein. Additionally, we demonstrate that PtmO is a hydrolase that is responsible for the release of the ACP-bound product to a free ß-ketoacid that subsequently undergoes decarboxylation.


Assuntos
Proteínas de Transporte/metabolismo , Pactamicina/biossíntese , Streptomyces/metabolismo , Proteínas de Bactérias , Proteínas de Transporte/química , Clonagem Molecular , Regulação Bacteriana da Expressão Gênica , Policetídeo Sintases/genética , Policetídeo Sintases/metabolismo , Policetídeos/química , Ligação Proteica
4.
Org Lett ; 21(10): 3554-3557, 2019 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-31058517

RESUMO

The first total synthesis of pactalactam was accomplished using substrate-controlled stereoselective aziridination and regioselective aziridine ring-opening to construct three continuous amino groups on an octasubstituted cyclopentane core. The cyclopentane framework was obtained by ring-closing metathesis and aldol coupling using a l-threonine-derived oxazoline compound. Cyclic urea formation, m-acetylphenyl group introduction by Chan-Lam coupling, and primary alcohol-selective acylation yielded the reported pactalactam structure. The presence of pactalactam in the fermentation broth of pactamycin-producing bacteria was also confirmed.


Assuntos
Álcoois/química , Aziridinas/química , Ciclopentanos/química , Imidazolidinas/síntese química , Pactamicina/síntese química , Acilação , Imidazolidinas/química , Estrutura Molecular , Pactamicina/química
5.
Chembiochem ; 20(19): 2458-2462, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31059166

RESUMO

Pactamycin is an antibiotic produced by Streptomyces pactum with antitumor and antimalarial properties. Pactamycin has a unique aminocyclitol core that is decorated with 3-aminoacetophenone, 6-methylsaliciate, and an N,N-dimethylcarbamoyl group. Herein, we show that the adenylation enzyme PctU activates 3-aminobenzoic acid (3ABA) with adenosine triphosphate and ligates it to the holo form of the discrete acyl carrier protein PctK to yield 3ABA-PctK. Then, 3ABA-PctK is N-glycosylated with uridine diphosphate-N-acetyl-d-glucosamine (UDP-GlcNAc) by the glycosyltransferase PctL to yield GlcNAc-3ABA-PctK. Because 3ABA is known to be a precursor of the 3-aminoacetophenone moiety, PctU appears to be a gatekeeper that selects the appropriate 3-aminobenzoate starter unit. Overall, we propose that acyl carrier protein-bound glycosylated 3ABA derivatives are biosynthetic intermediates of pactamycin biosynthesis.


Assuntos
Adenina/metabolismo , Adenilato Quinase/metabolismo , Enzimas/metabolismo , Glicosiltransferases/metabolismo , Pactamicina/biossíntese , Uridina Difosfato N-Acetilglicosamina/metabolismo , meta-Aminobenzoatos/metabolismo , Proteínas de Bactérias/metabolismo
6.
J Med Chem ; 62(18): 8412-8428, 2019 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-31026161

RESUMO

Molecules isolated from natural sources including bacteria, fungi, and plants are a long-standing source of therapeutics that continue to add to our medicinal arsenal today. Despite their potency and prominence in the clinic, complex natural products often exhibit a number of liabilities that hinder their development as therapeutics, which may be partially responsible for the current trend away from natural product discovery, research, and development. However, advances in synthetic biology and organic synthesis have inspired a new generation of natural product chemists to tackle powerful undeveloped scaffolds. In this Perspective, we will present case studies demonstrating the historical and current focus on making targeted, but significant, changes to natural product scaffolds via biosynthetic gene cluster manipulation, total synthesis, semisynthesis, or a combination of these methods, with a focus on increasing activity, decreasing toxicity, or improving chemical and pharmacological properties.


Assuntos
Produtos Biológicos/farmacologia , Neoplasias/tratamento farmacológico , Antibacterianos/farmacologia , Benzoquinonas/farmacologia , Linhagem Celular Tumoral , Química Orgânica , Química Farmacêutica/tendências , Glicopeptídeos/química , Humanos , Lactamas Macrocíclicas/farmacologia , Macrolídeos/farmacologia , Família Multigênica , Pactamicina/farmacologia , Peptídeos/farmacologia , Polienos/química , Biologia Sintética/tendências , Tetraciclinas/farmacologia
7.
Appl Microbiol Biotechnol ; 103(11): 4337-4345, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31025074

RESUMO

The antitumor antibiotic pactamycin is a highly substituted aminocyclopentitol-derived secondary metabolite produced by the soil bacterium Streptomyces pactum. It has exhibited potent antibacterial, antitumor, antiviral, and antiprotozoal activities. Despite its outstanding biological activities, the complex chemical structure and broad-spectrum toxicity have hampered its development as a therapeutic, limiting its contribution to biomedical science to a role as a molecular probe for ribosomal function. However, a detailed understanding of its biosynthesis and how the biosynthesis is regulated has made it possible to tactically design and produce new pactamycin analogues, some of which have shown improved pharmacological properties. This mini-review describes the biosynthesis, regulation, engineered production, and biological activities of pactamycin and its congeners. It also highlights the suitability of biosynthetic methods as a feasible approach to generate new analogues of complex natural products and underscores the importance of utilizing biosynthetic enzymes as tools for chemoenzymatic production of structurally diverse bioactive compounds.


Assuntos
Antibióticos Antineoplásicos/biossíntese , Vias Biossintéticas/genética , Regulação Bacteriana da Expressão Gênica , Pactamicina/biossíntese , Streptomyces/genética , Streptomyces/metabolismo , Anti-Infecciosos/metabolismo , Anti-Infecciosos/farmacologia , Antibióticos Antineoplásicos/farmacologia , Engenharia Metabólica/métodos , Pactamicina/farmacologia
8.
Nat Prod Rep ; 36(3): 430-457, 2019 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-30183796

RESUMO

Covering: up to mid-2018 Pyridoxal 5'-phosphate (PLP) is a versatile organic cofactor used to catalyze diverse reactions on amino acid, oxoacid, and amine substrates. Here we review the reactions catalyzed by PLP-dependent enzymes, highlighting enzymes reported in the natural product biosynthetic literature. We describe enzymes that catalyze transaminations, Claisen-like condensations, and ß- and γ-eliminations and substitutions, along with epimerizations, decarboxylations, and transaldolations. Finally, we describe a newly reported group of O2-, PLP-dependent enzymes. Altogether, natural product biosynthesis showcases the incredible versatility of PLP-dependent transformations for building chemical complexity.


Assuntos
Produtos Biológicos/metabolismo , Fosfato de Piridoxal/fisiologia , Imidazóis , Lactamas/metabolismo , Lipoproteínas/biossíntese , Macrolídeos/metabolismo , Oligopeptídeos/biossíntese , Pactamicina/biossíntese , Saxitoxina/biossíntese , Tiazóis/metabolismo , Tionas/metabolismo
9.
Appl Microbiol Biotechnol ; 102(24): 10589-10601, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30276712

RESUMO

Pactamycin, a structurally unique aminocyclitol natural product isolated from Streptomyces pactum, has potent antibacterial, antitumor, and anti-protozoa activities. However, its production yields under currently used culture conditions are generally low. To understand how pactamycin biosynthesis is regulated and explore the possibility of improving pactamycin production in S. pactum, we investigated the transcription regulations of pactamycin biosynthesis. In vivo inactivation of two putative pathway-specific regulatory genes, ptmE and ptmF, resulted in mutant strains that are not able to produce pactamycin. Genetic complementation using a cassette containing ptmE and ptmF integrated into the S. pactum chromosome rescued the production of pactamycin. Transcriptional analysis of the ΔptmE and ΔptmF strains suggests that both genes control the expression of the whole pactamycin biosynthetic gene cluster. However, attempts to overexpress these regulatory genes by introducing a second copy of the genes in S. pactum did not improve the production yield of pactamycin. We discovered that pactamycin biosynthesis is sensitive to phosphate regulation. Concentration of inorganic phosphate higher than 2 mM abolished both the transcription of the biosynthetic genes and the production of the antibiotic. Draft genome sequencing of S. pactum and bioinformatics studies revealed the existence of global regulatory genes, e.g., genes that encode a two-component PhoR-PhoP system, which are commonly involved in secondary metabolism. Inactivation of phoP did not show any significant effect to pactamycin production. However, in the phoP::aac(3)IV mutant, pactamycin biosynthesis is not affected by external inorganic phosphate concentration.


Assuntos
Proteínas de Bactérias/genética , Regulação Bacteriana da Expressão Gênica , Pactamicina/biossíntese , Streptomyces/genética , Streptomyces/metabolismo , Proteínas de Bactérias/metabolismo , Duplicação Gênica , Perfilação da Expressão Gênica , Teste de Complementação Genética , Genoma Bacteriano , Mutação , Óperon , Fosfatos/metabolismo , Streptomyces/crescimento & desenvolvimento
10.
Org Lett ; 20(13): 3938-3942, 2018 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-29939033

RESUMO

The use of ß-nitroenamines as a new class of acceptors in the enantioselective Pd-catalyzed trimethylenemethane cycloaddition afforded differentiated 1,2-dinitrogen bearing cyclopentanes with three contiguous stereocenters. The utility of these acceptors was demonstrated with the efficient construction of the core of jogyamycin and aminocyclopentitols. Further elaboration of the cycloadducts provided a concise synthetic approach toward joygamycin.


Assuntos
Pactamicina/análogos & derivados , Catálise , Reação de Cicloadição , Metano/análogos & derivados , Estrutura Molecular , Pactamicina/síntese química , Paládio , Estereoisomerismo
11.
Org Lett ; 20(2): 397-400, 2018 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-29319326

RESUMO

Pactamycin is a structurally unique aminocyclitol antibiotic with broad-spectrum cell growth inhibitory activity. To explore the bountiful activity of the aminocyclitol core of pactamycin, an efficient, modular, and asymmetric synthesis of aminocyclopentitols resembling the pactamycin pharmacophore has been developed employing a SmI2-mediated imino-pinacol coupling strategy. Two of the compounds exhibited antitumor activity against A375 melanoma cells.


Assuntos
Pactamicina/química , Antibacterianos , Estrutura Molecular
12.
Chembiochem ; 19(2): 126-130, 2018 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-29148266

RESUMO

The unique five-membered aminocyclitol core of the antitumor antibiotic pactamycin originates from d-glucose, so unprecedented enzymatic modifications of the sugar intermediate are involved in the biosynthesis. However, the order of the modification reactions remains elusive. Herein, we examined the timing of introduction of an amino group into certain sugar-derived intermediates by using recombinant enzymes that were encoded in the pactamycin biosynthesis gene cluster. We found that the NAD+ -dependent alcohol dehydrogenase PctP and pyridoxal 5'-phosphate dependent aminotransferase PctC converted N-acetyl-d-glucosaminyl-3-aminoacetophonone into 3'-amino-3'-deoxy-N-acetyl-d-glucosaminyl-3-aminoacetophenone. Further, N-acetyl-d-glucosaminyl-3-aminophenyl-ß-oxopropanoic acid ethyl ester was converted into the corresponding 3'-amino derivative. However, PctP did not oxidize most of the tested d-glucose derivatives, including UDP-GlcNAc. Thus, modification of the GlcNAc moiety in pactamycin biosynthesis appears to occur after the glycosylation of aniline derivatives.


Assuntos
Biocatálise , Oxirredutases/metabolismo , Pactamicina/biossíntese , Açúcares/metabolismo , Transaminases/metabolismo , Glicosilação , Pactamicina/química , Streptomyces/enzimologia , Açúcares/química
13.
ACS Chem Biol ; 12(2): 362-366, 2017 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-28060484

RESUMO

ß-Ketoacyl-acyl carrier protein (ß-Ketoacyl-ACP) synthase (KAS) III catalyzes the first step in fatty acid biosynthesis, involving a Claisen condensation of the acetyl-CoA starter unit with the first extender unit, malonyl-ACP, to form acetoacetyl-ACP. KAS III-like proteins have also been reported to catalyze acyltransferase reactions using coenzyme A esters or discrete ACP-bound substrates. Here, we report the in vivo and in vitro characterizations of a KAS III-like protein (PtmR), which directly transfers a 6-methylsalicylyl moiety from an iterative type I polyketide synthase to an aminocyclopentitol unit in pactamycin biosynthesis. PtmR is highly promiscuous, recognizing a wide array of S-acyl-N-acetylcysteamines as substrates to produce a suite of pactamycin derivatives with diverse alkyl and aromatic features. The results suggest that KAS III-like proteins may be used as versatile tools for modifications of complex natural products.


Assuntos
3-Oxoacil-(Proteína de Transporte de Acila) Sintase/metabolismo , Pactamicina/biossíntese , Catálise , Coenzima A/metabolismo , Estrutura Molecular , Pactamicina/química
14.
Biopolymers ; 107(4)2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27858985

RESUMO

The bacterial ribosome has many functional ribosomal RNA (rRNA) sites. We have computationally analyzed the rRNA regions involved in the interactions between the 30S and 50S subunits. Various properties of rRNA such as solvent accessibility, opening energy, hydrogen bonding pattern, van der Waals energy, thermodynamic stability were determined. Based on these properties we selected rRNA targets for hybridization with complementary 2'-O-methyl oligoribonucleotides (2'-OMe RNAs). Further, the inhibition efficiencies of the designed ribosome-interfering 2'-OMe RNAs were tested using a ß-galactosidase assay in a translation system based on the E. coli extract. Several of the oligonucleotides displayed IC50 values below 1 µM, which were in a similar range as those determined for known ribosome inhibitors, tetracycline and pactamycin. The calculated opening and van der Waals stacking energies of the rRNA targets correlated best with the inhibitory efficiencies of 2'-OMe RNAs. Moreover, the binding affinities of several oligonucleotides to both 70S ribosomes and isolated 30S and 50S subunits were measured using a double-filter retention assay. Further, we applied heat-shock chemical transformation to introduce 2'-OMe RNAs to E. coli cells and verify inhibition of bacterial growth. We observed high correlation between IC50 in the cell-free extract and bacterial growth inhibition. Overall, the results suggest that the computational analysis of potential rRNA targets within the conformationally dynamic regions of inter-subunit bridges can help design efficient antisense oligomers to probe the ribosome function.


Assuntos
Oligonucleotídeos/metabolismo , RNA Ribossômico/metabolismo , Sequência de Bases , Sítios de Ligação , Desenho Assistido por Computador , Escherichia coli/efeitos dos fármacos , Escherichia coli/genética , Escherichia coli/metabolismo , Conformação de Ácido Nucleico , Oligonucleotídeos/química , Pactamicina/química , Pactamicina/metabolismo , Pactamicina/farmacologia , Ligação Proteica , Biossíntese de Proteínas/efeitos dos fármacos , Estrutura Terciária de Proteína , RNA Ribossômico/antagonistas & inibidores , RNA Ribossômico/química , Subunidades Ribossômicas Maiores de Bactérias/química , Subunidades Ribossômicas Maiores de Bactérias/metabolismo , Subunidades Ribossômicas Menores de Bactérias/química , Subunidades Ribossômicas Menores de Bactérias/metabolismo
15.
Chembiochem ; 17(17): 1585-8, 2016 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-27305101

RESUMO

Pactamycin is a bacteria-derived aminocyclitol antibiotic with a wide-range of biological activity. Its chemical structure and potent biological activities have made it an interesting lead compound for drug discovery and development. Despite its unusual chemical structure, many aspects of its formation in nature remain elusive. Using a combination of genetic inactivation and metabolic analysis, we investigated the tailoring processes of pactamycin biosynthesis in Streptomyces pactum. The results provide insights into the sequence of events during the tailoring steps of pactamycin biosynthesis and explain the unusual production of various pactamycin analogues by S. pactum mutants. We also identified two new pactamycin analogues that have better selectivity indexes than pactamycin against malarial parasites.


Assuntos
Antibióticos Antineoplásicos/biossíntese , Pactamicina/análogos & derivados , Pactamicina/biossíntese , Streptomyces/metabolismo , Antibióticos Antineoplásicos/química , Conformação Molecular , Pactamicina/química , Streptomyces/genética
16.
Org Lett ; 18(2): 284-7, 2016 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-26741730

RESUMO

Oxidative allene amination provides rapid access to densely functionalized amine-containing stereotriads through highly reactive bicyclic methyleneaziridine intermediates. This strategy has been demonstrated as a viable approach for the construction of the densely functionalized aminocyclitol core of jogyamycin, a natural product with potent antiprotozoal activity. Importantly, the flexibility of oxidative allene amination will enable the syntheses of modified aminocyclitol analogues of the jogyamycin core.


Assuntos
Pactamicina/análogos & derivados , Pactamicina/síntese química , Alcadienos/química , Aminação , Aminas/química , Estrutura Molecular , Oxirredução , Pactamicina/química , Pactamicina/farmacologia , Estereoisomerismo , Streptomyces/química
17.
Chembiochem ; 16(17): 2484-90, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26426567

RESUMO

Mutational analysis of the pyridoxal 5'-phosphate (PLP)-dependent enzyme PctV was carried out to elucidate the multi-step reaction mechanism for the formation of 3-aminobenzoate (3-ABA) from 3-dehydroshikimate (3-DSA). Introduction of mutation K276R led to the accumulation of a quinonoid intermediate with an absorption maximum at 580 nm after the reaction of pyridoxamine 5'-phosphate (PMP) with 3-DSA. The chemical structure of this intermediate was supported by X-ray crystallographic analysis of the complex formed between the K276R mutant and the quinonoid intermediate. These results clearly show that a quinonoid intermediate is involved in the formation of 3-ABA. They also indicate that Lys276 (in the active site of PctV) plays multiple roles, including acid/base catalysis during the dehydration reaction of the quinonoid intermediate.


Assuntos
Oxirredutases/metabolismo , Pactamicina/biossíntese , Sítios de Ligação , Biocatálise , Domínio Catalítico , Cristalografia por Raios X , Cinética , Simulação de Dinâmica Molecular , Mutagênese Sítio-Dirigida , Oxirredutases/química , Oxirredutases/genética , Pactamicina/química , Fosfato de Piridoxal/química , Ácido Chiquímico/análogos & derivados , Ácido Chiquímico/química , Ácido Chiquímico/metabolismo , Espectrofotometria Ultravioleta , meta-Aminobenzoatos/química , meta-Aminobenzoatos/metabolismo
18.
PLoS One ; 10(5): e0125322, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25938491

RESUMO

Pactamycin, although putatively touted as a potent antitumor agent, has never been used as an anticancer drug due to its high cytotoxicity. In this study, we characterized the effects of two novel biosynthetically engineered analogs of pactamycin, de-6MSA-7-demethyl-7-deoxypactamycin (TM-025) and 7-demethyl-7-deoxypactamycin (TM-026), in head and neck squamous cell carcinoma (HNSCC) cell lines SCC25 and SCC104. Both TM-025 and TM-026 exert growth inhibitory effects on HNSCC cells by inhibiting cell proliferation. Interestingly, unlike their parent compound pactamycin, the analogs do not inhibit synthesis of nascent protein in a cell-based assay. Furthermore, they do not induce apoptosis or autophagy in a dose- or a time-dependent manner, but induce mild senescence in the tested cell lines. Cell cycle analysis demonstrated that both analogs significantly induce cell cycle arrest of the HNSCC cells at S-phase resulting in reduced accumulation of G2/M-phase cells. The pactamycin analogs induce expression of cell cycle regulatory proteins including master regulator p53, its downstream target p21Cip1/WAF1, p27kip21, p19, cyclin E, total and phospho Cdc2 (Tyr15) and Cdc25C. Besides, the analogs mildly reduce cyclin D1 expression without affecting expression of cyclin B, Cdk2 and Cdk4. Specific inhibition of p53 by pifithrin-α reduces the percentage of cells accumulated in S-phase, suggesting contribution of p53 to S-phase increase. Altogether, our results demonstrate that Pactamycin analogs TM-025 and TM-026 induce senescence and inhibit proliferation of HNSCC cells via accumulation in S-phase through possible contribution of p53. The two PCT analogs can be widely used as research tools for cell cycle inhibition studies in proliferating cancer cells with specific mechanisms of action.


Assuntos
Carcinoma de Células Escamosas/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Neoplasias de Cabeça e Pescoço/patologia , Hidrocarbonetos Fluorados/farmacologia , Pactamicina/análogos & derivados , Fase S/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismo , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Relação Dose-Resposta a Droga , Inativação Gênica/efeitos dos fármacos , Humanos , Modelos Biológicos , Pactamicina/farmacologia , Biossíntese de Proteínas/efeitos dos fármacos , Carcinoma de Células Escamosas de Cabeça e Pescoço , Regulação para Cima/efeitos dos fármacos
19.
Bioorg Med Chem ; 23(8): 1849-57, 2015 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-25792144

RESUMO

The synthesis and biological analysis of a number of novel congeners of the aminocyclopentitol pactamycin is described. Specific attention was paid to the preparation of derivatives at crucial synthetic branch points of the parent structure, and biological assays revealed a number of insights into the source of pactamycin's biological activity. Additionally, the encapsulation of pactamycin and select derivatives into the PRINT© nanoparticle technology was investigated as a proof-of-concept, and evidence of bioactivity modulation through nanoparticle delivery is demonstrated. This work has provided heretofore unrealized access to a large number of novel compounds for further evaluation.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Pactamicina/análogos & derivados , Pactamicina/farmacologia , Antineoplásicos/administração & dosagem , Linhagem Celular Tumoral , Portadores de Fármacos/química , Humanos , Nanopartículas/química , Neoplasias/tratamento farmacológico , Pactamicina/administração & dosagem
20.
Elife ; 32014 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-24913268

RESUMO

Malaria inflicts an enormous burden on global human health. The emergence of parasite resistance to front-line drugs has prompted a renewed focus on the repositioning of clinically approved drugs as potential anti-malarial therapies. Antibiotics that inhibit protein translation are promising candidates for repositioning. We have solved the cryo-EM structure of the cytoplasmic ribosome from the human malaria parasite, Plasmodium falciparum, in complex with emetine at 3.2 Å resolution. Emetine is an anti-protozoan drug used in the treatment of ameobiasis that also displays potent anti-malarial activity. Emetine interacts with the E-site of the ribosomal small subunit and shares a similar binding site with the antibiotic pactamycin, thereby delivering its therapeutic effect by blocking mRNA/tRNA translocation. As the first cryo-EM structure that visualizes an antibiotic bound to any ribosome at atomic resolution, this establishes cryo-EM as a powerful tool for screening and guiding the design of drugs that target parasite translation machinery.


Assuntos
Emetina/química , Plasmodium falciparum/metabolismo , Ribossomos/química , Ribossomos/ultraestrutura , Animais , Antimaláricos/química , Sítios de Ligação , Microscopia Crioeletrônica , Citoplasma/metabolismo , Desenho de Fármacos , Eritrócitos/parasitologia , Humanos , Modelos Moleculares , Pactamicina/química , Ligação Proteica , RNA Mensageiro/metabolismo , Proteínas Ribossômicas/química
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