Synthesis, biological activity and DNA interaction of anilinoacridine and bithiazole peptide derivatives related to the anti-tumor drugs m-AMSA and bleomycin.
The synthesis of two depsipeptides including a peptide metal-chelating moiety (Gly-His-Lys) and a moiety with DNA affinity, namely either glycyl-anilino-9-aminoacridine 1 or 2'-(2-aminoethyl)-4-methoxycarbonyl-2",4'-bithiazole 2, has been carried out. The goal was to introduce separately on the same molecule the two factors contributing to the biological activity of many anti-tumor drugs. The interaction of both drugs with DNA has been studied and the acridine ring of 1 was found to intercalate in the double helix. The production of free radicals has been evidenced by spin-trapping for 1 although both compounds were revealed to be good copper-chelating agents. In vitro cytostatic activity and inhibition of [3H]-thymidine incorporation were obtained for 1 while 2 exhibited no activity in both tests. In view of these results, it can be pointed out that the anti-tumor properties of such drugs rely (1) on their ability to reach and to bind DNA and (2) on redox mechanisms involving interactions between the drugs, metals and molecular oxygen. The latter phenomenon leads to the formation of active radical species, able to degrade the DNA.
Morier-Teissier
E
E
INSERM U.16, Lille, France.
Bailly
C
C
Bernier
J L
JL
Houssin
R
R
Helbecque
N
N
Catteau
J P
JP
Colson
P
P
Houssier
C
C
Hénichart
J P
JP
D000609:Aminoacridines / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D000677:Amsacrine / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000378:metabolism; D001761:Bleomycin / Q000494:pharmacology*; D002417:Cattle; D002614:Chelating Agents; D055598:Chemical Phenomena; D002621:Chemistry; D003300:Copper; D004247:DNA / Q000187:drug effects* / Q000378:metabolism; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004354:Drug Screening Assays, Antitumor; D005609:Free Radicals; D006358:Hot Temperature; D007364:Intercalating Agents; D007939:Leukemia L1210 / Q000473:pathology; D051379:Mice; D009691:Nucleic Acid Denaturation / Q000187:drug effects; D009842:Oligopeptides / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D010084:Oxidation-Reduction; D013050:Spectrometry, Fluorescence; D013057:Spectrum Analysis; D013844:Thiazoles / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000473:pathology; D014783:Viscosity
D000609:Aminoacridines; D000677:Amsacrine; D000970:Antineoplastic Agents; D001761:Bleomycin; D002614:Chelating Agents; D003300:Copper; D004247:DNA; D004273:DNA, Neoplasm; D005609:Free Radicals; D007364:Intercalating Agents; D009842:Oligopeptides; D013844:Thiazoles; C060635:N-(glycyl-histidyl-lysyl)-2-(4''-methoxycarbonyl-2'',4'-bithiazol-2'-yl)ethylamine; C060634:Gly-ACA