3.8.2.2. Category 2: Activation through Acid- or Base-Catalyzed Ring Opening
In this strategy, the designed molecules have one special structural feature in common. The common feature is the cyclic unstable enediyne which has been made stable by the fusion of a locking device. The locking device is usually a small ring, such as an epoxide, a β-lactam, or even an isooxazoline ring. All of these molecules are equipped with pH-based triggering devices, which unlock them by opening the small ring. With the removal of strain, the molecules become active under ambient conditions.
Inspired by the chemistry of the natural dynemicins, Nicolaouet et al. first reported the synthesis of a series of analogues in which the flow of electrons to open the epoxide ring was blocked by the incorporation of protecting groups in potential donors. In one such design, the pivaloyl group was used to protect the free phenolic -OH group to generate the enediyne A. Base-promoted hydrolysis produced the free phenolic form B, which is capable of promoting the epoxide ring opening via the flow of electrons followed by BC to give diradical D which can cleave DNA (Scheme 66).
Scheme 66. Base-mediated deprotection and activation of dynemicin model enediynes.
Similar to dynemicin, electrons can also flow from the ring nitrogen if its lone pair is free. On that basis, the enediyne F was synthesized by Nicolaou and co-workers. The interesting feature of this molecule is that the nucleophilic N atom is made non-nucleophilic by protection with a 2-(phenylsulphonyl) ethoxy carbonyl group. The group falls off upon treatment with mild bases, thus leading to the generation of free amine G the lone pair of which is being free flows toward the direction of epoxide, which then opens up. With the release of strain, the resulting compound I shows BC under ambient conditions (Scheme 67). The produced diradical J have DNA-cleaving activity at micromolar concentrations, resulting in the formation of both relaxed and linear forms of DNA.
Scheme 67. Base-catalyzed β-elimination and activation of Dynemicin model enediyne.
The sensitivity of epoxide rings under acidic conditions was exploited by Unno and co-workers in their designed dynemicin analogues. Thus, several novel analogues designated by structure K were made, and their DNA-cleaving potential under acidic conditions was evaluated. It was demonstrated that the size and electronic character of the substituents (R1 and R2) at the C9 position critically influenced the DNA-cleaving ability of the synthesized enediynes. The compounds represented by K were shown to undergo BC under acidic conditions (Scheme 68). A similar cascade of reactions involving ring opening and BC may operate in cancer cells because they are sufficiently acidic with pH less than 7.
Scheme 68. Acid-catalyzed ring opening of epoxide and activation of enediyne.
From previous discussions, it is clear that, among the various small ring systems, Nature has picked up the epoxide ring to lock the unstable enediynes, with the reason being the easy unlocking of these systems by opening of the strained epoxide ring by an acid-catalyzed process or opening because of an inward flow of electrons.