In vitro and in vivo antitumor effects of novel actinomycin D analogs with amino acid substituted in the cyclic depsipeptides.
Peptides
; 31(4): 568-73, 2010 Apr.
Article
em En
| MEDLINE
| ID: mdl-20045716
ABSTRACT
The actinomycin D (AMD) analogs in which the D-valine residues (the second amino acid residue in the cyclic depsipeptide of AMD) and the N-methyl-L-valine residues (the fifth amino acid residue in the cyclic depsipeptide of AMD) were replaced with D-Phe or l- and D-forms N-methylvalines, N-methylisoleucine, N-methylleucine, N-methylphenylalanine, N-methylalanine, and sarcosine were synthesized. The antimicrobial activity and cytotoxic activities of these compounds in vitro were investigated. The results showed that most D-valine substituted analogs had much lower antimicrobial activity and cytotoxic activities in vitro than AMD itself, but three N-methyl-L-valine substituted analogs had comparable or even more remarkable cytotoxic activities in vitro than AMD. Acute toxicities and antitumor effects of the N-methyl-L-valine substituted analogs in mice were also examined. The result showed that the acute toxicity of compound 4 L-methylleucine(5)-AMD analog is comparable to AMD itself and that of compound 3(L-Methylisoleucine(5)-AMD analog) is slightly more toxic, about 1.25-fold than AMD. However, the acute toxicity of compound 5 D-methylleucine5-AMD analog is about 2-fold lower than AMD. This suggested that the N-methyl-D-amino acid replacement in the cyclic ring might play a vital role in their decreased acute toxicities, and perhaps the N-methyl-D-leucine substituent is more favorable, though there may be a slight loss of antitumor activity. This finding may be helpful for the design and development of more potent antitumor agents together with low acute toxicity, and suggests that the N-methyl-D-leucine substituent has the potential to be used as antitumor drug lead.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Dactinomicina
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Linhagem Celular Tumoral
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Depsipeptídeos
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Antibióticos Antineoplásicos
Limite:
Animals
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Humans
Idioma:
En
Revista:
Peptides
Ano de publicação:
2010
Tipo de documento:
Article