title: In vitro and in vivo antitumor effects of novel actinomycin D analogs with amino acid substituted in the cyclic depsipeptides.
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.
authors.affiliation: Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Institute of Biochemistry and Molecular Biology, School of Life Sciences, and State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 South Tianshui Road, Lanzhou 730000, PR China. zhangbz@lzu.edu.cn
authors.forename: Bang-zhi
authors.initials: BZ
authors.lastname: Zhang
authors.forename: Kai-rong
authors.initials: KR
authors.lastname: Wang
authors.forename: Jie-xi
authors.initials: JX
authors.lastname: Yan
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Jing-jing
authors.initials: JJ
authors.lastname: Song
authors.forename: Jing-man
authors.initials: JM
authors.lastname: Ni
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
mesh_terms: D019943:Amino Acid Substitution; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D000890:Anti-Infective Agents / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D000903:Antibiotics, Antineoplastic / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor / Q000187:drug effects*; D053938:DNA Fragmentation; D003609:Dactinomycin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D047630:Depsipeptides / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051379:Mice; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure
chemical_list: D000596:Amino Acids; D000890:Anti-Infective Agents; D000903:Antibiotics, Antineoplastic; D047630:Depsipeptides; D003609:Dactinomycin