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Dimerizable Redox‐Sensitive Triazine‐Based Cationic Lipids for in vitro Gene Delivery

Introduction of a missing gene into the cell nucleus (transfection), followed by its expression by the natural machinery of the cell, is a very well-established strategy to produce proteins. This process can also be used therapeutically to produce proteins needed to heal a certain pathological condition (gene therapy). However, achievement of efficient transfection remains a challenging endeavor. A number of transfection methods have been developed, essentially based on the use of viruses, chemical reagents (for example, cationic lipids and polymers), or physical methods (mechanical stimulation, electroporation, magnetic field induced, etc.). All of these transfection strategies have advantages and drawbacks, but it is apparent that the use of chemical reagents is a very attractive option, because of their ready availability (many transfection reagents are commercial products), their versatility (they can be used to transfect different kinds of cells with genetic material having a wide range of dimensions), low toxicity for the operator (viruses can be pathogenic), and simple experimental use. The main drawback with chemicals as transfectants is connected with their generally low performance, both in terms of number of cells which are transfected and alive at the end of the process and in terms of duration of the transfection. For this reason, chemical transfection reagents must be effective and with limited cytotoxicity, but also cheap and readily prepared from inexpensive, nonexotic starting materials to be competitive and of potential practical use. With these premises, it is not surprising that calcium phosphate is still widely used to achieve transfection, particularly with “difficult” and resistant cells, in addition to popular “organic” reagents (which are generally cationic liposomes comprised of a cationic lipid and a neutral, helper lipid for example, cholesterol) such as Lipofectamine, DOTAP, and related compounds. Although a number of active ingredients for transfection have been recently described in the literature, few of them are truly innovative in terms of structure. In this paper we present a conceptually new family of cationic lipids for transfection featuring a triazine scaffold, which allows for an easy derivatization, with three functionally different amino side chains: 1) a linear C12–C16 chain (the lipophilic tail), 2) a 3-propylammonium chain which acts as polar head, 3) a redox-sensitive dimerizable 2-thioethyl chain (according to the so-called disulfide-linker strategy). The corresponding disulfide dimers have been synthesized and evaluated as well. The new triazine-based transfectants feature very simple preparation from inexpensive materials, and the triazine core allows for a smooth introduction of structural diversity by means of subsequent nucleophilic dechloroaminations of the starting trichlorotriazine by different amines. Most importantly, these triazine-based cationic lipids exhibit low cytotoxicity and high transfection efficiency on a variety of eukaryotic cells, even without any formulation with helper lipids. The lead thiol compound 4, having a C14 chain, was synthesized in multigram amounts as portrayed in Scheme 1.