Cytotoxic α-Halogenoacrylic Derivatives of Distamycin A and Congeners

Italo Beria, Pier Giovanni Baraldi, Paolo Cozzi, Marina Caldarelli, Cristina Geroni, Sergio Marchini, Nicola Mongelli, Romeo Romagnoli

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

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 α-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 α-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.

Original languageEnglish
Pages (from-to)2611-2623
Number of pages13
JournalJournal of Medicinal Chemistry
Volume47
Issue number10
DOIs
Publication statusPublished - May 6 2004

Fingerprint

Derivatives
Glutathione
DNA
Binders
Tumors
Antineoplastic Agents
Neoplasms
Genes
Phase II Clinical Trials
Thymine
stallimycin
brostallicin
Alkylating Agents
Alkylation
DNA-Binding Proteins
Adenine
Cytotoxicity
Hematopoietic Stem Cells
Toxicology
DNA Damage

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Beria, I., Baraldi, P. G., Cozzi, P., Caldarelli, M., Geroni, C., Marchini, S., ... Romagnoli, R. (2004). Cytotoxic α-Halogenoacrylic Derivatives of Distamycin A and Congeners. Journal of Medicinal Chemistry, 47(10), 2611-2623. https://doi.org/10.1021/jm031051k

Cytotoxic α-Halogenoacrylic Derivatives of Distamycin A and Congeners. / Beria, Italo; Baraldi, Pier Giovanni; Cozzi, Paolo; Caldarelli, Marina; Geroni, Cristina; Marchini, Sergio; Mongelli, Nicola; Romagnoli, Romeo.

In: Journal of Medicinal Chemistry, Vol. 47, No. 10, 06.05.2004, p. 2611-2623.

Research output: Contribution to journalArticle

Beria, I, Baraldi, PG, Cozzi, P, Caldarelli, M, Geroni, C, Marchini, S, Mongelli, N & Romagnoli, R 2004, 'Cytotoxic α-Halogenoacrylic Derivatives of Distamycin A and Congeners', Journal of Medicinal Chemistry, vol. 47, no. 10, pp. 2611-2623. https://doi.org/10.1021/jm031051k
Beria, Italo ; Baraldi, Pier Giovanni ; Cozzi, Paolo ; Caldarelli, Marina ; Geroni, Cristina ; Marchini, Sergio ; Mongelli, Nicola ; Romagnoli, Romeo. / Cytotoxic α-Halogenoacrylic Derivatives of Distamycin A and Congeners. In: Journal of Medicinal Chemistry. 2004 ; Vol. 47, No. 10. pp. 2611-2623.
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