Synthesis, cytotoxicity and antitumor activity of some new simplified pyrazole analogs of the antitumor agent CC-1065. Effect of an hydrophobic group on antitumor activity.
Three simplified pyrazole analogs (7-9) of the antitumor agents CC-1065, were synthesized. In in vitro assays, against L1210 cell lines all derivatives showed a cytotoxicity in a pM range, values close to the natural target compound (+)-CC-1065. In in vivo tests, against disseminate L1210 leukemia cells, synthesized compounds showed a good potency (O.D. 300 micrograms/Kg) but no activity. These observations further validate the effect of the hydrophilic and/or hydrophobic characteristics of the substituents present on the molecules, confirming the relevance of this phenomena on in vivo activity. In fact in this case the increase of hydrophobic characteristics of the molecules produce the loss of activity, probably due to a worse bioavailability of the drugs in animals.
Baraldi
P G
PG
Dipartimento di Scienze Farmaceutiche, Università di Ferrara, Italy.
Cacciari
B
B
Guiotto
A
A
Romagnoli
R
R
Spalluto
G
G
Zaid
A N
AN
Cozzi
P
P
Geroni
C
C
Mongelli
N
N
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D000080890:Duocarmycins; D007211:Indoles; D007933:Leucomycins / Q000737:chemistry* / Q000494:pharmacology; D007939:Leukemia L1210 / Q000188:drug therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D015394:Molecular Structure; D011720:Pyrazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D000080890:Duocarmycins; D007211:Indoles; D007933:Leucomycins; D011720:Pyrazoles; C018782:CC 1065