PNU 157977: a new potent antitumour agent exhibiting low in vivo toxicity in mice injected with L1210 leukaemia cells.
The design, synthesis, in vitro and in vivo activity against L1210 murine leukaemia of the dibromo nitrogen mustard derivative of 2, called PNU 157977, is described and the structure-activity relationship discussed. This dibromo derivative is almost two orders of magnitude more cytotoxic than the dichloro counterpart having the same oligopeptidic chain (IC50 2.7 ng/ml versus 225 ng/ml), and it showed in vivo an increased survival time which is 5- and 3-fold longer than that of tallimustine and 2 (and T/C 750 versus 133 and 213) respectively. Moreover PNU 157977 shows activity against the M5076 solid tumour markedly inferior to that of the closely analogous 2. Footprinting experiments conducted using the oestrogen receptor PCR probe as the footprinting target molecule show that PNU 157977 possesses a different sequence-specific alkylation and greater cleavage activity than either 2 or tallimustine.
Baraldi
P G
PG
Dipartimento di Scienze Farmaceutiche, Università di Ferrara, Italy. pgb@ifeuniv.unife.it
Balboni
G
G
Romagnoli
R
R
Spalluto
G
G
Cozzi
P
P
Geroni
C
C
Mongelli
N
N
Rutigliano
C
C
Bianchi
N
N
Gambari
R
R
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology* / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D018983:DNA Footprinting; D004214:Distamycins / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D015195:Drug Design; D007939:Leukemia L1210 / Q000188:drug therapy*; D051379:Mice; D009368:Neoplasm Transplantation; D009588:Nitrogen Mustard Compounds / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D011960:Receptors, Estrogen / Q000187:drug effects / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D018906:Antineoplastic Agents, Alkylating; D004214:Distamycins; D009588:Nitrogen Mustard Compounds; C119563:PNU 157977; D011960:Receptors, Estrogen; C066900:tallimustine