Novel Piperidinedione Analogs as Inhibitors of Breast Cancer Cell Growth

Abstract

We previously reported the utility of antineoplaston‐A10 (3‐phenylacetylamino‐2,6‐piperidinedione) as an endogenous cancer protector and immune modulator in breast cancer patients (Cancer Lett., 2000, 157, 57). In this study, four new piperidinedione A10 analogs were synthesized and tested for their antimitotic activity on a human breast cancer cell line against the prototype A10 and the antibreast cancer drug tamoxifen. Moreover, the DNA binding capacity of such compounds was evaluated against A10. (E)‐3‐(4‐Nitrocinnamoylamino)‐2,6‐piperidinedione “3B” and (E)‐3‐(4‐hydroxycinnamoylamino)‐2,6‐piperidinedione “3D” were several‐fold more potent antiproliferative agents than A10 and tamoxifen. They also had significantly higher capacity to bind DNA than A10. Conversely, (E)‐3‐(cinnamoylamino)‐2,6‐piperidinedione “3A” and (E)‐3‐(4‐methoxycinnamoylamino)‐2,6‐piperidinedione) “3C” had weaker biological profiles than the lead compound A10. Detailed synthetic, spectroscopic, and biological data are reported.

Transcriptional inhibition of the estrogen response element by antiestrogenic piperidinediones correlates with intercalation into DNA measured by energy calculations

“…Conversely, hydrolysis of the piperidinedione ring of A10 yields PAG. Early work indicated that A10 had reproducible but weak antineoplastic activity which encouraged us to design more active analogs [26][27][28]. Our design strategy was based upon observations that hormone antagonists fit at least partially within the same site in DNA as agonists [50].…”

“…The piperidinedione derivatives used in this study included 3-phenylacetylamino-2,6-piperidinedione (A10), phydroxy-A10 (p-OH A10), 3-(4-nitrocinnamoylamino)-2,6-piperidinedione (B3) [28], phenylacetylglutamine (PAG), phenylacetate (PA), and p-chlorophenylacetate (CPA) (Fig. 1).…”

“…Chu of the University of Georgia [27]. B3 was synthesized by Laila Abou-Zeid at the Medical College of Georgia [28]. PA and CPA were purchased from Sigma Chemical Company (St. Louis, MO).…”

“…[26]. The prototype compound 3-phenylacetylamino-2,6-piperidinedione (designated A10) was originally shown to possess anticancer activity in a variety of in vitro and animal models [27][28][29]. Moreover, an increasing number of piperidinediones and closely related compounds (see structures in Fig.…”

“…1) were demonstrated to have antineoplastic effects, including analogs that have been used in the treatment of breast cancer [30][31][32]. A10 was shown to fit between base pairs (intercalate) in DNA, along with more active A10 analogs that were designed from our modeling studies [27,28]. A good correlation was also observed between the fit of A10 derivatives intercalated in DNA, their actual DNA binding capacity measured experimentally and their antiproliferative effects on estrogen-dependent breast cancer growth [28,32].…”