Physical and biological characteristics of the antitumor drug actinomycin D analogues derivatized at N-methyl-L-valine residues.
The crystal structure of the DNA-actinomycin D (AMD) complex and a simple molecular modeling study indicated that AMD analogues derivatized at N-methyl-L-valine residues (fifth amino acid residue in the cyclic depsipeptide of AMD) could bind to DNA as strongly as the parent AMD. The analogues in which N-methyl-L-valine residues were replaced with L- and D-forms of N-methylvalines, N-methylthreonines, N-methylphenylalanies, N-methyltyrosines, and N-methyl-O-methyltyrosines have been totally synthesized. The characteristics of binding of the analogues to various DNAs including DNA-1 [d(TATATATGCATATATA)], DNA-2 [d(TATATACGCGTATATA)], DNA-3 [d(ATATATAGCTATATAT)], and DNA-4 [d(ATATATGGCCATATAT)] have been examined by using visible absorption spectrum methods. The association constants calculated from the absorption spectra indicate that the modifications of the N-methyl-L-valine residues in the AMD molecule do affect the DNA binding characteristics of the analogues. The L-aromatic analogues bind slightly better than the L-aliphatic analogues except for binding to DNA-1 (-TGCA-), whereas the D-aliphatic analogues bind consistently better than the D-aromatic analogues. In the L-form analogues, the L-Tyr analogue has the highest overall association constant, whereas the D-Val analogue has the highest association constant among the D-form analogues. In spite of substitution of bulky aromatic groups, the D-aromatic analogues bind to the DNA-1 quite well. However, D-aromatic analogues have significantly reduced their binding capacities to the other DNAs, indicating that the substitution of the D-aromatic residues creates a unique four-base sequence preference (-TGCA-). The RNA polymerase inhibitory activities of the AMD analogues in vivo have been examined using human cells (HeLa). All AMD analogues except for the L-Thr analogues severely inhibit RNA synthesis at relatively low drug concentrations. The D-Val, L-OMT, L-Phe, and D-Phe analogues inhibit RNA synthesis more strongly than the natural antibiotic (AMD itself).
Takusagawa
F
F
Department of Biochemistry, University of Kansas, Lawrence 66045, USA.
Wen
L
L
Chu
W
W
Li
Q
Q
Takusagawa
K T
KT
Carlson
R G
RG
Weaver
R F
RF
D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D004247:DNA / Q000378:metabolism*; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors*; D003609:Dactinomycin / Q000031:analogs & derivatives* / Q000494:pharmacology; D015195:Drug Design; D006367:HeLa Cells; D006801:Humans; D008958:Models, Molecular; D009691:Nucleic Acid Denaturation; D019384:Nucleic Acid Synthesis Inhibitors / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D009838:Oligodeoxyribonucleotides / Q000737:chemistry / Q000378:metabolism*; D012995:Solubility; D013053:Spectrophotometry; D013696:Temperature; D014158:Transcription, Genetic / Q000187:drug effects; D014633:Valine / Q000031:analogs & derivatives
D000903:Antibiotics, Antineoplastic; D019384:Nucleic Acid Synthesis Inhibitors; D009838:Oligodeoxyribonucleotides; D003609:Dactinomycin; D004247:DNA; D012321:DNA-Directed RNA Polymerases; D014633:Valine