A Polyamine-Based Dinitro-Naphthalimide Conjugate as Substrates for Polyamine Transporters Preferentially Accumulates in Cancer Cells and Minimizes Side Effects in vitro and in vivo.

Jing Ma,Lili Hou,Songqiang Xie,Chaojie Wang,Jianing Liu,Kexin Yue,Qi Ma,Man Shi,Yingguang Li,Jiajia Wang,Linrong Li,Sitong Liu,Sihan Zhao,Peng George Wang,Zhuoqing Xi,Hanfang Liu,Shudi Guo,Zhiyong Tian

doi:10.3389/fchem.2020.00166

Abstract

Naphthalimides, such as amonafide and mitonafide in clinical trials, have been developed as antitumor agents for orthotopic tumor. However, the serious side effects in cancer patients limit their applications. Herein, a new class of polyamine-based naphthalimide conjugates 5a-5c, 7a-7b, and 11a-11b with and without the alkylation of the distant nitrogen in the polyamine chain were synthesized and the mechanism was determined. Compared with amonafide, dinitro-naphthalimide conjugate 5c with a 4,3-cyclopropyl motif preferentially accumulates in cancer cells and minimizes side effects in vitro and in vivo. More importantly, 5c at the dosage of as low as 3 mg/kg (57.97%) displays better antitumor effects than the positive control amonafide (53.27%) at 5 mg/kg in vivo. And a remarkably elevated antitumor activity and a reduced toxicity are also observed for 5c at 5 mg/kg (65.90%). The upregulated p53 and the apoptotic cells (73.50%) indicate that the mechanism of 5c to induce apoptosis may result from its enhanced DNA damage. Further investigation indicates that in addition to target DNA, 5c can modulate the polyamine homeostasis by upregulating polyamine oxidase (PAO) in a different way from that of amonafide. And also by targeting PTs overexpressed in most of cancer cells, 5c downregulates the contents of Put, Spd, and Spm, which are in favor of suppressing fast-growing tumor cells. Our study implies a promising strategy for naphthalimide conjugates to treat hepatic carcinoma with notable activities and reduced toxicities at a low dosage.

Highlights

As the sixth most prevalent malignancy, hepatocellular carcinoma (HCC) is a kind of cancer that is found too late and has a high mortality worldwide (Forner et al, 2012; Dou et al, 2016)
We summarized the structure-activity relationship (SAR) of 5a-5c, 7a-7b, and 11a-11b with and without the classical unsymmetrically-substituted polyamine analogs CHENSpm and CPENSpm (Casero and Marton, 2007; Casero et al, 2018; Phanstiel, 2018) (Figure 1 and Scheme 1)
We found that polyamine-based dinitro-naphthalimide conjugates 5a-5c (RF 0.43–1.67) can overcome cisplatin resistance efficiently, the RF values of which are 2–9-folds lower than that of cisplatin (RF = 3.67)

Summary

Introduction

As the sixth most prevalent malignancy, hepatocellular carcinoma (HCC) is a kind of cancer that is found too late and has a high mortality worldwide (Forner et al, 2012; Dou et al, 2016). 90% of cancer patients with HCC cannot survive for more than 5 years even after the treatment by anticancer drugs (Chen et al, 2016; Siegel et al, 2016). (Li et al, 2016) it is urgent to develop novel drugs with enhanced activities and reduced toxicities at a relatively low dosage. One of the major reasons why amonafide and mitonafide cannot be used widely is because they can have serious side effects in cancer patients. The design of novel naphthalimide therapeutic agents with reduced toxicity represents an area that is in need of urgent attention

Methods

Results

Conclusion