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1.
Bioorg Med Chem Lett ; 27(5): 1304-1310, 2017 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-28117205

RESUMO

The magnitude of expression of cathepsin L, often upregulated in the tumor microenvironment, correlates with the invasive and metastatic nature of certain tumors. Inhibition of cathepsin L represents an emerging strategy for the treatment of metastatic cancer. A potent, small-molecule inhibitor (referred to as KGP94) of cathepsin L, and new KGP94 analogues were synthesized. (3,5-Dibromophenyl)-(3-hydroxyphenyl) ketone thiosemicarbazone (22), with an IC50 value of 202nM, exhibited similar inhibitory activity against cathepsin L compared to KGP94 (IC50=189nM). Due to limited aqueous solubility of KGP94, a water-soluble phosphate salt (KGP420) was prepared in order to facilitate future in vivo studies. Enzymatic hydrolysis with alkaline phosphatase (ALP) demonstrated that the phosphate prodrug, KGP420, was readily converted to the parent compound, KGP94.


Assuntos
Catepsina L/antagonistas & inibidores , Organofosfatos/química , Pró-Fármacos/síntese química , Pró-Fármacos/farmacologia , Tiossemicarbazonas/síntese química , Tiossemicarbazonas/farmacologia , Tioureia/análogos & derivados , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Estrutura Molecular , Pró-Fármacos/química , Sais/síntese química , Sais/farmacologia , Solubilidade , Tiossemicarbazonas/química , Tioureia/síntese química , Tioureia/química , Tioureia/farmacologia , Água/química
2.
Bioorg Med Chem ; 23(21): 6974-92, 2015 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-26462052

RESUMO

Upregulation of cathepsin L in a variety of tumors and its ability to promote cancer cell invasion and migration through degradation of the extracellular matrix suggest that cathepsin L is a promising biological target for the development of anti-metastatic agents. Based on encouraging results from studies on benzophenone thiosemicarbazone cathepsin inhibitors, a series of fourteen benzoylbenzophenone thiosemicarbazone analogues were designed, synthesized, and evaluated for their inhibitory activity against cathepsins L and B. Thiosemicarbazone inhibitors 3-benzoylbenzophenone thiosemicarbazone 1, 1,3-bis(4-fluorobenzoyl)benzene thiosemicarbazone 8, and 1,3-bis(2-fluorobenzoyl)-5-bromobenzene thiosemicarbazone 32 displayed the greatest potency against cathepsin L with low IC50 values of 9.9 nM, 14.4 nM, and 8.1 nM, respectively. The benzoylbenzophenone thiosemicarbazone analogues evaluated were selective in their inhibition of cathepsin L compared to cathepsin B. Thiosemicarbazone analogue 32 inhibited invasion through Matrigel of MDA-MB-231 breast cancer cells by 70% at 10 µM. Thiosemicarbazone analogue 8 significantly inhibited the invasive potential of PC-3ML prostate cancer cells by 92% at 5 µM. The most active cathepsin L inhibitors from this benzoylbenzophenone thiosemicarbazone series (1, 8, and 32) displayed low cytotoxicity toward normal primary cells [in this case human umbilical vein endothelial cells (HUVECs)]. In an initial in vivo study, 3-benzoylbenzophenone thiosemicarbazone (1) was well-tolerated in a CDF1 mouse model bearing an implanted C3H mammary carcinoma, and showed efficacy in tumor growth delay. Low cytotoxicity, inhibition of cell invasion, and in vivo tolerability are desirable characteristics for anti-metastatic agents functioning through an inhibition of cathepsin L. Active members of this structurally diverse group of benzoylbenzophenone thiosemicarbazone cathepsin L inhibitors show promise as potential anti-metastatic, pre-clinical drug candidates.


Assuntos
Antineoplásicos/síntese química , Catepsina L/antagonistas & inibidores , Inibidores de Cisteína Proteinase/síntese química , Tiossemicarbazonas/química , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Benzofenonas/química , Sítios de Ligação , Catepsina B/antagonistas & inibidores , Catepsina B/metabolismo , Catepsina L/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Inibidores de Cisteína Proteinase/farmacologia , Inibidores de Cisteína Proteinase/uso terapêutico , Desenho de Fármacos , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Concentração Inibidora 50 , Isomerismo , Cinética , Neoplasias Mamárias Animais/tratamento farmacológico , Camundongos , Simulação de Acoplamento Molecular , Estrutura Terciária de Proteína , Tiossemicarbazonas/farmacologia , Tiossemicarbazonas/uso terapêutico , Transplante Heterólogo
3.
ACS Cent Sci ; 8(8): 1145-1158, 2022 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-36032774

RESUMO

Genomic studies and experiments with permeability-deficient strains have revealed a variety of biological targets that can be engaged to kill Gram-negative bacteria. However, the formidable outer membrane and promiscuous efflux pumps of these pathogens prevent many candidate antibiotics from reaching these targets. One such promising target is the enzyme FabI, which catalyzes the rate-determining step in bacterial fatty acid biosynthesis. Notably, FabI inhibitors have advanced to clinical trials for Staphylococcus aureus infections but not for infections caused by Gram-negative bacteria. Here, we synthesize a suite of FabI inhibitors whose structures fit permeation rules for Gram-negative bacteria and leverage activity against a challenging panel of Gram-negative clinical isolates as a filter for advancement. The compound to emerge, called fabimycin, has impressive activity against >200 clinical isolates of Escherichia coli, Klebsiella pneumoniae, and Acinetobacter baumannii, and does not kill commensal bacteria. X-ray structures of fabimycin in complex with FabI provide molecular insights into the inhibition. Fabimycin demonstrates activity in multiple mouse models of infection caused by Gram-negative bacteria, including a challenging urinary tract infection model. Fabimycin has translational promise, and its discovery provides additional evidence that antibiotics can be systematically modified to accumulate in Gram-negative bacteria and kill these problematic pathogens.

5.
ACS Infect Dis ; 7(2): 493-505, 2021 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-33522241

RESUMO

Fusidic acid (FA) is a potent steroidal antibiotic that has been used in Europe for more than 60 years to treat a variety of infections caused by Gram-positive pathogens. Despite its clinical success, FA requires significantly elevated dosing (3 g on the first day, 1.2 g on subsequent days) to minimize resistance, as FA displays a high resistance frequency, and a large shift in minimum inhibitory concentration is observed for resistant bacteria. Despite efforts to improve on these aspects, all previously constructed derivatives of FA have worse antibacterial activity against Gram-positive bacteria than the parent natural product. Here, we report the creation of a novel FA analogue that has equivalent potency against clinical isolates of Staphylococcus aureus (S. aureus) and Enterococcus faecium (E. faecium) as well as an improved resistance profile in vitro when compared to FA. Importantly, this new compound displays efficacy against an FA-resistant strain of S. aureus in a soft-tissue murine infection model. This work delineates the structural features of FA necessary for potent antibiotic activity and demonstrates that the resistance profile can be improved for this scaffold and target.


Assuntos
Antibacterianos , Ácido Fusídico , Animais , Antibacterianos/farmacologia , Farmacorresistência Bacteriana , Ácido Fusídico/farmacologia , Camundongos , Testes de Sensibilidade Microbiana , Staphylococcus aureus
6.
Nat Microbiol ; 5(1): 67-75, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31740764

RESUMO

Gram-negative bacterial infections are a significant public health concern, and the lack of new drug classes for these pathogens is linked to the inability of most drug leads to accumulate inside Gram-negative bacteria1-7. Here, we report the development of a web application-eNTRyway-that predicts compound accumulation (in Escherichia coli) from its structure. In conjunction with structure-activity relationships and X-ray data, eNTRyway was utilized to re-design Debio-1452-a Gram-positive-only antibiotic8-into versions that accumulate in E. coli and possess antibacterial activity against high-priority Gram-negative pathogens. The lead compound Debio-1452-NH3 operates as an antibiotic via the same mechanism as Debio-1452, namely potent inhibition of the enoyl-acyl carrier protein reductase FabI, as validated by in vitro enzyme assays and the generation of bacterial isolates with spontaneous target mutations. Debio-1452-NH3 is well tolerated in vivo, reduces bacterial burden in mice and rescues mice from lethal infections with clinical isolates of Acinetobacter baumannii, Klebsiella pneumoniae and E. coli. This work provides tools for the facile discovery and development of high-accumulating compounds in E. coli, and a general blueprint for the conversion of Gram-positive-only compounds into broad-spectrum antibiotics.


Assuntos
Antibacterianos/farmacologia , Descoberta de Drogas/métodos , Enoil-(Proteína de Transporte de Acila) Redutase (NADH)/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Animais , Antibacterianos/química , Antibacterianos/farmacocinética , Benzofuranos/química , Benzofuranos/farmacocinética , Benzofuranos/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Enoil-(Proteína de Transporte de Acila) Redutase (NADH)/genética , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Escherichia coli/efeitos dos fármacos , Escherichia coli/metabolismo , Bactérias Gram-Negativas/metabolismo , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Pironas/química , Pironas/farmacocinética , Pironas/farmacologia , Software , Relação Estrutura-Atividade
7.
Eur J Med Chem ; 58: 568-72, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23168380

RESUMO

Kinetic analysis of the mode of inhibition of cathepsin L by KGP94, a lead compound from a privileged library of functionalized benzophenone thiosemicarbazone derivatives, demonstrated that it is a time-dependent, reversible, and competitive inhibitor of the enzyme. These results are consistent with the formation of a transient covalent bond, and are supported by molecular modeling that places the thiocarbonyl of the inhibitor in proximity to the thiolate moiety of the enzyme active site Cys25. KGP94 significantly decreased the activity of cathepsin L toward human type I collagen, and impeded both migration and invasion of MDA-MB-231 human breast cancer cells. Growth retardation was achieved in vivo against both recently implanted and established tumours using a C3H mouse mammary carcinoma model.


Assuntos
Antineoplásicos/farmacologia , Catepsina L/antagonistas & inibidores , Inibidores de Cisteína Proteinase/farmacologia , Neoplasias Mamárias Experimentais/tratamento farmacológico , Tiossemicarbazonas/farmacologia , Tioureia/análogos & derivados , Animais , Antineoplásicos/química , Catepsina L/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Inibidores de Cisteína Proteinase/química , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Feminino , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Tiossemicarbazonas/química , Tioureia/química , Tioureia/farmacologia
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