Synthesis and anticancer activities of 6-amino amonafide derivatives.

Norton, J; Witschi, M; Luong, L; Kawamura, A; Ghosh, S; Stack, MS; Sim, E; Avram, M; Appella, D; Huang, S

Journal article

Synthesis and anticancer activities of 6-amino amonafide derivatives.

Abstract:: Amonafide is a DNA intercalator and topoisomerase II inhibitor in clinical development for the treatment of neoplastic diseases. Amonafide contains a free arylamine, which causes it to be metabolized in humans by N-acetyl transferase-2 (NAT2) into a toxic form. To eliminate the NAT2 acetylation of amonafide while retaining the anticancer properties, we have synthesized nine derivatives that are structurally similar to amonafide that should not be acetylated. Eight derivatives have arylamines at the 6-position (vs. 5-position of amonafide) and one derivative completely lacks the arylamine. The derivative with a free amine in the 6-position and one with a substituted amine in the 6-position are not acetylated, whereas amonafide is extensively acetylated as determined by an NAT2 assay. The biological activities of these compounds were evaluated to determine whether they behaved similarly to amonafide in purified systems and in vitro. We found that three compounds had similar cancer cell-selective growth inhibition to amonafide, while retaining similar subcellular localization, DNA intercalation and topoisomerase II inhibition activities. In addition, these compounds were able to eliminate a marker of metastatic potential, the perinucleolar compartment. These three compounds (named numonafides) might thus allow for better patient management than those treated with amonafide; hence, they should be developed further as potential clinical replacements for amonafide or as novel anticancer drugs.

Publication status:: Published

Actions

Email

Email this record

Send the bibliographic details of this record to your email address.

Your Email
Please enter the email address that the record information will be sent to.

-
Your message (optional)
Please add any additional information to be included within the email.
Share
Cite

Cite this record

APA Style

Norton, J., Witschi, M., Luong, L., Kawamura, A., Ghosh, S., Stack, M. S., Sim, E., Avram, M., Appella, D., & Huang, S. (2008). Synthesis and anticancer activities of 6-amino amonafide derivatives. Anti-Cancer Drugs, 19(1), 23–36.

MLA Style

Norton, J, et al. “Synthesis and Anticancer Activities of 6-Amino Amonafide Derivatives.” Anti-Cancer Drugs, vol. 19, no. 1, 2008, pp. 23–36.

Chicago Style

Norton, J, M Witschi, L Luong, et al. 2008. “Synthesis and Anticancer Activities of 6-Amino Amonafide Derivatives.” Anti-Cancer Drugs 19 (1): 23–36.
Print