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1.
Molecules ; 26(19)2021 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-34641567

RESUMO

The search for novel antimycobacterial drugs is a matter of urgency, since tuberculosis is still one of the top ten causes of death from a single infectious agent, killing more than 1.4 million people worldwide each year. Nine Amaryllidaceae alkaloids (AAs) of various structural types have been screened for their antimycobacterial activity. Unfortunately, all were considered inactive, and thus a pilot series of aromatic esters of galanthamine, 3-O-methylpancracine, vittatine and maritidine were synthesized to increase biological activity. The semisynthetic derivatives of AAs were screened for their in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Ra and two other mycobacterial strains (M. aurum, M. smegmatis) using a modified Microplate Alamar Blue Assay. The most active compounds were also studied for their in vitro hepatotoxicity on the hepatocellular carcinoma cell line HepG2. In general, the derivatization of the original AAs was associated with a significant increase in antimycobacterial activity. Several pilot derivatives were identified as compounds with micromolar MICs against M. tuberculosis H37Ra. Two derivatives of galanthamine, 1i and 1r, were selected for further structure optimalization to increase the selectivity index.


Assuntos
Alcaloides de Amaryllidaceae/síntese química , Antibacterianos/síntese química , Mycobacterium tuberculosis/efeitos dos fármacos , Alcaloides de Amaryllidaceae/efeitos adversos , Alcaloides de Amaryllidaceae/farmacologia , Antibacterianos/efeitos adversos , Antibacterianos/farmacologia , Células Hep G2 , Humanos , Testes de Sensibilidade Microbiana
2.
Med Res Rev ; 33(2): 439-55, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22419031

RESUMO

The anticancer activity of Amaryllidaceae isocarbostyrils is well documented. At pharmacological concentrations, that is, approximately 1 µM in vitro and approximately 10 mg/kg in vivo, narciclasine displays marked proapoptotic and cytotoxic activity, as does pancratistatin, and significant in vivo anticancer effects in various experimental models, but it is also associated with severe toxic side effects. At physiological doses, that is, approximately 50 nM in vitro and approximately 1 mg/kg in vivo, narciclasine is not cytotoxic but cytostatic and displays marked anticancer activity in vivo in experimental models of brain cancer (including gliomas and brain metastases), but it is not associated with toxic side effects. The cytostatic activity of narciclasine involves the impairment of actin cytoskeleton organization by targeting GTPases, including RhoA and the elongation factor eEF1A. We have demonstrated that chronic treatments of narciclasine (1 mg/kg) significantly increased the survival of immunodeficient mice orthotopically xenografted with highly invasive human glioblastomas and apoptosis-resistant brain metastases, including melanoma- and non-small-cell-lung cancer- (NSCLC) related brain metastases. Thus, narciclasine is a potentially promising agent for the treatment of primary brain cancers and various brain metastases. To date, efforts to develop synthetic analogs with anticancer properties superior to those of narciclasine have failed; thus, research efforts are now focused on narciclasine prodrugs.


Assuntos
Alcaloides de Amaryllidaceae/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/enzimologia , GTP Fosfo-Hidrolases/efeitos dos fármacos , Terapia de Alvo Molecular , Fenantridinas/uso terapêutico , Alcaloides de Amaryllidaceae/efeitos adversos , Alcaloides de Amaryllidaceae/farmacologia , Animais , Apoptose/efeitos dos fármacos , Neoplasias Encefálicas/patologia , Estudos de Coortes , Citotoxinas/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , GTP Fosfo-Hidrolases/metabolismo , Glioblastoma/tratamento farmacológico , Glioblastoma/enzimologia , Glioblastoma/patologia , Humanos , Técnicas In Vitro , Melanoma/tratamento farmacológico , Melanoma/enzimologia , Melanoma/patologia , Camundongos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Fenantridinas/efeitos adversos , Fenantridinas/farmacologia , Relação Estrutura-Atividade , Transplante Heterólogo , Resultado do Tratamento
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