PHYSICAL AND BIOLOGICAL CHARACTERISTICS OF THE ANTITUMOR DRUG ACTINOMYCIN-D ANALOGS DERIVATIZED AT N-METHYL-L-VALINE RESIDUES

Citation
F. Takusagawa et al., PHYSICAL AND BIOLOGICAL CHARACTERISTICS OF THE ANTITUMOR DRUG ACTINOMYCIN-D ANALOGS DERIVATIZED AT N-METHYL-L-VALINE RESIDUES, Biochemistry, 35(40), 1996, pp. 13240-13249
Citations number
41
Categorie Soggetti
Biology
Journal title
ISSN journal
00062960
Volume
35
Issue
40
Year of publication
1996
Pages
13240 - 13249
Database
ISI
SICI code
0006-2960(1996)35:40<13240:PABCOT>2.0.ZU;2-8
Abstract
The crystal structure of the DNA-actinomycin D (AMD) complex and a sim ple 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-methylphenylal anines, N-methyltyrosines, and N-methyl-O-methyltyrosines have been to tally synthesized. The characteristics of binding of the analogues to various DNAs including DNA-1 [d(TATATATGCATATATA)], DNA-2 [d(TATATACGC GTATATA)], 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 m olecule do affect the DNA binding characteristics of the analogues. Th e L-aromatic analogues bind slightly better than the L-aliphatic analo gues;except for binding to DNA-1 (-TGCA-), whereas the D-aliphatic ana logues bind consistently better than the D-aromatic analogues. In the L-form analogues, the L-Tyr analogue has the highest overall associati on constant, whereas the D-Val analogue has the highest association co nstant among the D-form analogues. In spite of substitution of bulky a romatic groups, the D-aromatic analogues bind to the DNA-I quite well. However, D-aromatic analogues have significantly reduced their bindin g capacities to the other DNAs, indicating that the substitution of th e 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 analogue s except for the L-Thr analogues severely inhibit RNA synthesis at rel atively low drug concentrations. The D-Val, L-OMT, L-Phe, and D-Phe an alogues inhibit RNA synthesis more strongly than the natural antibioti c (AMD itself).