Cytotoxic alpha-halogenoacrylic derivatives of distamycin A and congeners.
The mechanism of action of many antitumor agents involves DNA damage, either by direct binding of the drug to DNA or to DNA-binding proteins. However, most of the DNA-interacting agents have only a limited degree of sequence specificity, which implies that they may hit all the cellular genes. DNA minor groove binders, among which the derivatives of distamycin A play an important role, could provide significant improvement in cancer management, increasing gene specificity, due to high selectivity of interaction with thymine-adenine (TA) rich sequences. We now report and discuss the synthesis, the in vitro and in vivo activities, and some mechanistic features of alpha-halogenoacrylamido derivatives of distamycin A. The final result of this work was the selection of brostallicin 17 (PNU-166196). Brostallicin, presently in phase II clinical trials, shows a broad spectrum of antitumor activity and an apoptotic effect higher than distamycin derivative tallimustine. An important in vitro toxicological feature of brostallicin is the very good ratio between myelotoxicity on human haematopoietic progenitor cells and cytotoxicity on tumor cells, in comparison with clinically tested DNA minor groove binders. A peculiarity of brostallicin is its in vitro reactivity in the DNA alkylation assays only in the presence of glutathione. Moreover brostallicin's antitumor activity, both in in vitro and in vivo tumor models, is higher in the presence of increased levels of glutathione/glutathione-S-tranferases. These findings contribute to the definition of brostallicin as a novel anticancer agent that differs from other minor groove binders and alkylating agents for both the profile of activity and the mechanism of action and to classify the alpha-bromoacrylamido derivatives of distamycin as a new class of cytotoxics. Moreover, due to its interaction with glutathione, brostallicin may have a role for the tailored treatment of tumors characterized by constitutive or therapy-induced overexpression of glutathione/glutathione-S-tranferase levels.
Beria
Italo
I
Pharmacia Italia S.p.A., Discovery Research Oncology, Viale Pasteur 10, 20014 Nerviano, Milan, Italy. italo.beria@pharmacia.com
Baraldi
Pier Giovanni
PG
Cozzi
Paolo
P
Caldarelli
Marina
M
Geroni
Cristina
C
Marchini
Sergio
S
Mongelli
Nicola
N
Romagnoli
Romeo
R
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D004214:Distamycins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005978:Glutathione / Q000378:metabolism; D006146:Guanidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
D000970:Antineoplastic Agents; D004214:Distamycins; D006146:Guanidines; D011758:Pyrroles; C030000:stallimycin; D005978:Glutathione; C455279:brostallicin