Non-Phosphorus Lipids As New Antitumor Drug Prototypes

The main classes of antitumor drugs (antimetabolites, anthracyclines, taxanes, and alkylating agents) act via DNA damage, inhibit DNA synthesis, and/or represent antimicrotubule agents. The phosphorus-containing alkyl glycerolipids induce death of tumor cells of various tissue origin, whereas nonmalignant counterparts are less damaged. One serious drawback of these compounds is their hemolytic activity, that is, disruption of red blood cells. Moreover, intracellular phospholipases can hydrolyze the phosphorus-containing glycerolipids and reduce their antitumor potency. This justifies the search for new antitumor, nonhemolytic phosphorus-free lipids. Modifications of the hydrophobic and polar groups yielded new lipid-based agents. In particular, the replacement of the hydrophilic phosphate group with a carbohydrate residue yielded a new chemotype of glycosylated glycerolipids. Further developments resulted in a series of non-phosphorus cationic, polycationic, and neutral glycoglycerolipids. New non-phosphorus lipids retained the antiproliferative and cytotoxic properties similarly to edelfosine and other alkyl phosphoglycerolipids. Importantly, the hemolytic activity was negligible or absent. This review analyzes the structure–activity relationship within the class of non-phosphorus glycerolipids as the original antitumor drug candidates.