Antileukemic activity of synthetic daunomycinone derivatives bearing modifications in the glycosidic moiety.
The antileukemic activities of the daunomycinone glycosides synthesized in our laboratories (compounds 4 and 7, code names S12 and S13, respectively) were characterized in L1210 cells in vitro. S13 inhibits tumor cell proliferation and viability at day 4 (IC50: 150-200 nM) more effectively than S12 (IC50: 250-450 nM), suggesting that the 4'-trifluoracetamido substitution of the glycosidic moiety of these 3'-halo daunonycinone derivatives has greater antitumor potential than the 4'-azido substitution. Since S12 and S13 do not increase but rather decrease the mitotic index of L1210 cells at 24 hours, they are not antitubulin drugs but might arrest the early stages of cell cycle progression. Pretreatments for 1.5-3 hours with S12 and S13 are sufficient to partially inhibit the rates of DNA and RNA syntheses (IC50: 4-10 microM) determined over 30- to 60-minute periods of pulse-labeling in L 1210 cells in vitro, but these daunomycinone glycosides alter neither the cellular transport of purine and pyrimidine nucleosides nor the rate of protein synthesis. After 24 hours, the concentration-dependent induction of DNA cleavage by S13 reaches a plateau at 10 microM but the weaker S12 requires 48 hours to maximally stimulate DNA cleavage like S13. The mechanism by which S13 induces DNA fragmentation is inhibited by actinomycin D, cycloheximide, benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone, benzyloxycarbonyl-Ile-Glu-Thr-Asp-fluoromethyl ketone, N-tosyl-L-phenylalanine chloromethyl ketone and ZnSO4, suggesting that S13 triggers apoptosis by caspase and endonuclease activation. Since microM concentrations of S12 and S13 are cytostatic and cytotoxic, but do not sufficiently inhibit RNA and protein syntheses to block their own ability to sustain the active process of apoptosis and DNA fragmentation, such 3'-halo daunomycinone glycosides might be valuable to develop new means of polychemotherapy.
Perchellet
E M
EM
Kansas State University, Division of Biology, Manhattan 66506-4901, USA.
Sperfslage
B J
BJ
McIlvain
C J
CJ
Aligiannis
N
N
Pouli
N
N
Marakos
P
P
Skaltsounis
A L
AL
Perchellet
J P
JP
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002352:Carrier Proteins / Q000037:antagonists & inhibitors; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004273:DNA, Neoplasm / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D003630:Daunorubicin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006027:Glycosides / Q000138:chemical synthesis / Q000494:pharmacology*; D006131:Growth Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D007939:Leukemia L1210 / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors; D008938:Mitosis / Q000187:drug effects; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D033703:Nucleoside Transport Proteins; D012334:RNA, Neoplasm / Q000037:antagonists & inhibitors / Q000096:biosynthesis
D000903:Antibiotics, Antineoplastic; D002352:Carrier Proteins; D004273:DNA, Neoplasm; D006027:Glycosides; D006131:Growth Inhibitors; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D033703:Nucleoside Transport Proteins; D012334:RNA, Neoplasm; D003630:Daunorubicin