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2.
J Nat Prod ; 84(2): 195-203, 2021 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-33534559

RESUMO

Separating the immunosuppressive activity of FK506 (1) from its neurotrophic activity is required to develop FK506 analogues as drugs for the treatment of neuronal diseases. Two new FK506 analogues, 9-deoxo-36,37-dihydro-prolylFK506 (2) and 9-deoxo-31-O-demethyl-36,37-dihydro-prolylFK506 (3) containing a proline moiety instead of the pipecolate ring at C-1 and modifications at the C-9/C-31 and C-36-C-37 positions, respectively, were biosynthesized, and their biological activities were evaluated. The proline substitution in 9-deoxo-36,37-dihydroFK506 and 9-deoxo-31-O-demethyl-36,37-dihydroFK506 reduced immunosuppressive activity by more than 120-fold, as previously observed. Compared with FK506 (1), 2 and 3 exhibited ∼1.2 × 105- and 2.2 × 105-fold reductions in immunosuppressive activity, respectively, whereas they retained almost identical neurite outgrowth activity. Furthermore, these compounds significantly increased the strength of synaptic transmission, confirming that replacement of the pipecolate ring with a proline is critical to reduce the strong immunosuppressive activity of FK506 (1) while enhancing its neurotrophic activity.


Assuntos
Crescimento Neuronal/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Tacrolimo/análogos & derivados , Animais , Células Cultivadas , Fermentação , Hipocampo/citologia , Imunossupressores , Camundongos Endogâmicos ICR , Estrutura Molecular , Ácidos Pipecólicos , Streptomyces/metabolismo
3.
J Nat Prod ; 83(2): 277-285, 2020 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-32073848

RESUMO

The cultivation of a Streptomyces sp. SD53 strain isolated from the gut of the silkworm Bombyx mori produced two macrolactam natural products, piceamycin (1) and bombyxamycin C (2). The planar structures of 1 and 2 were identified by a combination of NMR, MS, and UV spectroscopic analyses. The absolute configurations were assigned based on chemical and chromatographic methods as well as ECD calculations. A new chromatography-based experimental method for determining the configurations of stereogenic centers ß to nitrogen atoms in macrolactams was established and successfully applied in this report. These compounds exhibited significant bioactivities against the silkworm entomopathogen Bacillus thuringiensis and various human pathogens as well as human cancer cell lines. In particular, piceamycin potently inhibited Salmonella enterica and Proteus hauseri with MIC values of 0.083 µg/mL and 0.025 µg/mL, respectively. The biosynthetic pathway involved in the formation of the cyclopentenone moiety in piceamycin is discussed.


Assuntos
Antibacterianos/farmacologia , Produtos Biológicos/química , Lactamas Macrocíclicas/química , Streptomyces/química , Antibacterianos/química , Produtos Biológicos/metabolismo , Vias Biossintéticas , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Proteus/química , Estereoisomerismo
4.
J Nat Prod ; 82(8): 2078-2086, 2019 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-31321978

RESUMO

A reduction in the strong immunosuppressive activity of FK506 (1) is essential for developing this compound as an antifungal agent. Seven new FK506 analogues modified at both the FK506-binding protein 12- and the calcineurin-binding regions were biosynthesized. 9-DeoxoFK520 (7) exhibited a >900-fold reduction in the in vitro immunosuppressive activity but maintained significant antifungal activity, indicating that the C-9 and C-21 positions are critical for separation of immunosuppressive and antifungal activities. 7 exhibited robust synergistic antifungal activity with fluconazole. FK506 (1) is a 23-membered macrolide produced by several Streptomyces species and is used as an immunosuppressive drug to prevent the rejection of transplanted organs. FK506 has also exhibited antifungal, neuroprotective, and neuroregenerative activities. In humans, FK506 binds to FK506-binding protein (FKBP) 12, and the resulting FKBP12-FK506 complex interacts with a Ca2+-calmodulin-dependent phosphatase, calcineurin (CaN). Inactivation of CaN by forming the FKBP12-FK506-CaN ternary complex prevents the activation of nuclear factor of activated T cells (NF-AT), inhibiting the production of interleukin-2 and subsequent T-cell proliferation. This CaN signaling pathway also plays a critical role in the growth and pathogenesis of major fungal pathogens such as Cryptococcus neoformans, Candida albicans, and Aspergillus fumigatus. Therefore, the synthesis of FK506 analogues that can discriminate human FKBP12/CaN from its fungal counterparts may separate antifungal activity from the immunosuppressive activity, thereby allowing the development of a novel antifungal agent.


Assuntos
Antifúngicos/metabolismo , Antifúngicos/farmacologia , Tacrolimo/análogos & derivados , Tacrolimo/farmacologia , Animais , Antifúngicos/química , Aspergillus fumigatus/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Cryptococcus neoformans/efeitos dos fármacos , Humanos , Imunossupressores/química , Imunossupressores/farmacologia , Testes de Sensibilidade Microbiana , Estrutura Molecular , Tacrolimo/química , Tacrolimo/metabolismo
5.
Org Lett ; 21(6): 1804-1808, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30801193

RESUMO

Bombyxamycins A and B (1 and 2) were discovered from a silkworm gut Streptomyces bacterium. Spectroscopic analysis and multiple-step chemical derivatization identified them as 26-membered cyclic lactams with polyene features. Bombyxamycin A showed significant antibacterial and antiproliferative effects. The bombyxamycin biosynthetic gene cluster was identified by genetic analysis. Gene deletion experiments confirmed that the cytochrome P450 BomK is responsible for the generation of 2, which unprecedentedly bears tetrahydrofuran in its macrocyclic ring.


Assuntos
Bombyx/química , Sistema Enzimático do Citocromo P-450/genética , Intestinos/fisiologia , Lactamas Macrocíclicas/isolamento & purificação , Animais , Sistema Enzimático do Citocromo P-450/química , Lactamas Macrocíclicas/química , Lactamas Macrocíclicas/metabolismo , Estrutura Molecular , Família Multigênica
6.
Artigo em Inglês | MEDLINE | ID: mdl-30181374

RESUMO

FK506 (tacrolimus) is an FDA-approved immunosuppressant indicated for the prevention of allograft rejections in patients undergoing organ transplants. In mammals, FK506 inhibits the calcineurin-nuclear factor of activated T cells (NFAT) pathway to prevent T-cell proliferation by forming a ternary complex with its binding protein, FKBP12, and calcineurin. FK506 also exerts antifungal activity by inhibiting calcineurin, which is essential for the virulence of human-pathogenic fungi. Nevertheless, FK506 cannot be used directly as an antifungal drug due to its immunosuppressive action. In this study, we analyzed the cytotoxicity, immunosuppressive activity, and antifungal activity of four FK506 analogs, 31-O-demethyl-FK506, 9-deoxo-FK506, 9-deoxo-31-O-demethyl-FK506, and 9-deoxo-prolyl-FK506, in comparison with that of FK506. The four FK506 analogs generally possessed lower cytotoxicity and immunosuppressive activity than FK506. The FK506 analogs, except for 9-deoxo-prolyl-FK506, had strong antifungal activity against Cryptococcus neoformans and Candida albicans, which are two major invasive pathogenic yeasts, due to the inhibition of the calcineurin pathway. Furthermore, the FK506 analogs, except for 9-deoxo-prolyl-FK506, had strong antifungal activity against the invasive filamentous fungus Aspergillus fumigatus Notably, 9-deoxo-31-O-demethyl-FK506 and 31-O-demethyl-FK506 exhibited robust synergistic antifungal activity with fluconazole, similar to FK506. Considering the antifungal efficacy, cytotoxicity, immunosuppressive activity, and synergistic effect with commercial antifungal drugs, we selected 9-deoxo-31-O-demethyl-FK506 for further evaluation of its in vivo antifungal efficacy in a murine model of systemic cryptococcosis. Although 9-deoxo-31-O-demethyl-FK506 alone was not sufficient to treat the cryptococcal infection, when it was used in combination with fluconazole, it significantly extended the survival of C. neoformans-infected mice, confirming the synergistic in vivo antifungal efficacy between these two agents.


Assuntos
Antifúngicos/farmacologia , Tacrolimo/análogos & derivados , Tacrolimo/farmacologia , Animais , Aspergilose/tratamento farmacológico , Aspergilose/microbiologia , Aspergillus fumigatus/efeitos dos fármacos , Calcineurina/farmacologia , Inibidores de Calcineurina/farmacologia , Candida albicans/efeitos dos fármacos , Candidíase/tratamento farmacológico , Candidíase/microbiologia , Células Cultivadas , Criptococose/tratamento farmacológico , Criptococose/microbiologia , Cryptococcus neoformans/efeitos dos fármacos , Feminino , Fluconazol/farmacologia , Imunossupressores/farmacologia , Masculino , Camundongos , Testes de Sensibilidade Microbiana/métodos , Proteína 1A de Ligação a Tacrolimo/farmacologia
7.
ACS Comb Sci ; 19(4): 262-270, 2017 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-28191923

RESUMO

Anthracyclines, such as doxorubicin, are effective anticancer drugs composed of a tetracyclic polyketide aglycone and one or more deoxysugar moieties, which play a critical role in their biological activity. A facile one-pot combinatorial biosynthetic system was developed for the generation of a range of glycosylated derivatives of anthracyclines. Cocultivation of Streptomyces venezuelae mutants producing two anthracycline aglycones with eight different nucleotide deoxysugar-producing S. venezuelae mutants that coexpress a substrate-flexible glycosyltransferase led to the generation of 16 aklavinone or ε-rhodomycinone glycosides containing diverse deoxysugar moieties, seven of which are new. This demonstrates the potential of the one-pot combinatorial biosynthetic system based on cocultivation as a facile biological tool capable of combining diverse aglycones and deoxysugars to generate structurally diverse polyketides carrying engineered sugars for drug discovery and development.


Assuntos
Antraciclinas/metabolismo , Desoxiaçúcares/biossíntese , Glicosídeos/biossíntese , Nucleotídeos/metabolismo , Policetídeos/metabolismo , Streptomyces/metabolismo , Técnicas de Química Combinatória , Glicosilação , Glicosiltransferases/metabolismo , Mutação , Naftacenos/metabolismo , Streptomyces/genética
8.
J Nat Prod ; 79(8): 2014-21, 2016 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-27453999

RESUMO

The S-adenosyl-l-methionine-dependent O-methyltransferases TylE and TylF catalyze the last two methylation reactions in the tylosin biosynthetic pathway of Streptomyces fradiae. It has long been known that the TylE-catalyzed C2‴-O-methylation of the 6-deoxy-d-allose bound to demethylmacrocin or demethyllactenocin precedes the TylF-catalyzed C3‴-O-methylation of the d-javose (C2‴-O-methylated 6-deoxy-d-allose) attached to macrocin or lactenocin. This study reveals the unexpected substrate promiscuity of TylE and TylF responsible for the biosynthesis of d-mycinose (C3‴-O-methylated d-javose) in tylosin through the identification of a new minor intermediate 2‴-O-demethyldesmycosin (2; 3‴-methyl-demethyllactenocin), which lacks a 2‴-O-methyl group on the mycinose moiety of desmycosin, along with 2‴-O-demethyltylosin (1; 3‴-methyl-demethylmacrocin) that was previously detected from the S. fradiae mutant containing a mutation in the tylE gene. These results unveil the unique substrate flexibility of TylE and TylF and demonstrate their potential for the engineered biosynthesis of novel glycosylated macrolide derivatives.


Assuntos
Hexoses/biossíntese , Metiltransferases/metabolismo , Streptomyces/enzimologia , Tilosina/metabolismo , Antibacterianos/metabolismo , Hexoses/química , Leucomicinas/metabolismo , Metilação , Estrutura Molecular , Mutação , S-Adenosilmetionina/metabolismo , Streptomyces/genética , Tilosina/análogos & derivados
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