Design, Synthesis, and Evaluation of Novel 3-Carboranyl-1,8-Naphthalimide Derivatives as Potential Anticancer Agents

Abstract

We synthesized a series of novel 3-carboranyl-1,8-naphthalimide derivatives, mitonafide and pinafide analogs, using click chemistry, reductive amination and amidation reactions and investigated their in vitro effects on cytotoxicity, cell death, cell cycle, and the production of reactive oxygen species in a HepG2 cancer cell line. The analyses showed that modified naphthalic anhydrides and naphthalimides bearing ortho- or meta-carboranes exhibited diversified activity. Naphthalimides were more cytotoxic than naphthalic anhydrides, with the highest IC50 value determined for compound 9 (3.10 µM). These compounds were capable of inducing cell cycle arrest at G0/G1 or G2M phase and promoting apoptosis, autophagy or ferroptosis. The most promising conjugate 35 caused strong apoptosis and induced ROS production, which was proven by the increased level of 2′-deoxy-8-oxoguanosine in DNA. The tested conjugates were found to be weak topoisomerase II inhibitors and classical DNA intercalators. Compounds 33, 34, and 36 fluorescently stained lysosomes in HepG2 cells. Additionally, we performed a similarity-based assessment of the property profile of the conjugates using the principal component analysis. The creation of an inhibitory profile and descriptor-based plane allowed forming a structure–activity landscape. Finally, a ligand-based comparative molecular field analysis was carried out to specify the (un)favorable structural modifications (pharmacophoric pattern) that are potentially important for the quantitative structure–activity relationship modeling of the carborane–naphthalimide conjugates.

Implications of Oxidative Stress in Glioblastoma Multiforme Following Treatment with Purine Derivatives

“…ROS accumulation could damage DNA directly and cause oxidative lesions; 8-oxo-dG could be a reliable biomarker of OS [42]. Under normal conditions, a genome has one 8-oxo-dG molecule per 10 5 -10 6 guanosines, which is equivalent to thousands of 8-oxo-dG molecules per cell [102]. We found that all the tested compounds significantly elevated the number of 8-oxo-dG molecules as compared to control cells; this finding complements the above considerations and confirms that both the adenosine derivatives induce OS in T98G cells (Figure 8).…”

Design of DNA Intercalators Based on 4-Carboranyl-1,8-Naphthalimides: Investigation of Their DNA-Binding Ability and Anticancer Activity

“…As reported earlier, the introduction of boron clusters into drug molecules could improve the activity toward resistant forms [16][17][18][19] or to obtain hitherto unknown nematicidal activity [20]. Structures of mitonafide, pinafide, and 1,8-naphthalimides modified with a carborane cluster [8,9].…”

“…In our work, we have described thus far the methods used to synthesize naphthalimides modified with carborane or metallacarborane groups through the modification of imide (Figure 1) [8] and bearing the carborane group at position 3 of the ring [9]. We observed that the attachment site of the boron cluster to the naphthalimide moiety, type of the boron cluster, and structure of the linker between the boron cluster and the heteroaromatic ring system influenced various cytotoxic activities against HepG2 cancer cells.…”

Carboranes as unique pharmacophores in antitumor medicinal chemistry

“…In boron neutron capture therapy (BNCT), the first step is the selective accumulation of 10 B-containing compounds in cancer cells, which can be irradiated by low-energy and harmless thermal neutrons. 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 Subsequently, 10 B atoms break up into α particles and lithium nuclei, yielding high linear energy transfer (LET) particles ( Figure 2 ). 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 As a result, 10 B-containing cancer cells can be destroyed by the high-LET particles.…”

“… 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 Subsequently, 10 B atoms break up into α particles and lithium nuclei, yielding high linear energy transfer (LET) particles ( Figure 2 ). 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 As a result, 10 B-containing cancer cells can be destroyed by the high-LET particles. In contrast, the surrounding normal/healthy cells can survive because of the limited path length of these particles of only 5–9 μm, which is smaller than the diameter of a general cell.…”