Water-soluble fullerene derivatives have a big potential for biomedical applications due to their pronounced antiviral, antioxidant, antitumor, neuroprotective, antiamyloid and antibacterial activities. In this lecture, we will summarize the results of our recent studies on the synthesis, in vitro and in vivo biological activity studies of differently functionalized water-soluble fullerene derivatives.

We developed a series of efficient and selective methods for the synthesis of multifunctionalized C₆₀ and C₇₀ derivatives. In particular, we proposed a dozen of new reactions for facile conversion of readily available C₆₀Cl₆ and C₇₀Cl_8/10 precursors to a variety of individual water-soluble fullerene derivatives bearing 4 to 16 solubilizing groups [1-6]. These new synthetic approaches substantially decreased the cost of water-soluble fullerene compounds and made them available in bulk quantities for biological studies.

The synthesized water-soluble fullerene derivatives demonstrated highly promising antiviral properties against human immunodeficiency virus (HIV-1, HIV-2), cytomegalovirus, herpes simplex and influenza viruses with the efficiency parameters exceeding that of commercial antiviral drugs [1-6]. Importantly, some of the fullerene derivatives were shown to inhibit simultaneously several viral enzymes; such multi-target behavior enables efficient antiviral action and suppresses significantly the formation of drug resistance.

Several compounds demonstrated pronounced antitumor effects on lung and brain cancer (glioblastoma) models in vitro and in vivo. The cancer cell death was caused by either autophagy or apoptosis [7, 8]. It has also been shown that some of the water-soluble fullerene derivatives stimulated the proliferation of neural stem cells and were able to restore the damage to the central nervous system in vivo [8].

The polycarboxylic water-soluble fullerene derivatives were able to destroy Ab(1-42) amyloid fibrils in vitro and improved cognitive functions of animals in vivo, thus featuring the potential of these compounds for the treatment of neurodegenerative diseases [9-10]. Several water-soluble fullerene derivatives bearing positively charged functional groups suppressed E. coli and other pathogenic bacteria [6].

Some specific fullerene derivatives were able to regulate intracellular homeostasis of reactive oxygen species, while their role (cytotoxicant or superoxide scavenger and a potential cytoprotector) was determined by the type of solubilizing addends attached to the cage [11]. Unprecedentedly, a fullerene derivative with the attached phosphoric acid residues was able to induce myogenic differentiation of human stem cells, which normally develop in adipocytes [1].

Most of the designed fullerene-based compounds show low cytotoxicity in different cell lines (HELF, MDCK, Vero, TZM-bl, etc.) and also low acute toxicity in mice (BDF1 mice) [1-7]. Thus, water-soluble fullerene derivatives can be considered as promising lead compounds for multiple pharmaceutical applications.

This work was supported by Russian Science Foundation (project 22-43-08005).

References:

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