3.9.2.4. Category 4: Photo-activation of Locked or Acyclic Enediyne

The basis of this design strategy relies on the use of photo-cleavable protecting groups. This group masks the nucleophilic character of an amine or a phenolic hydroxyl group. The protecting group falls off upon photolysis and then liberates the free amine or phenol. Then, the free amine or the phenol allows flow of electrons which results in the opening of a strained ring-like epoxide. Thus, the strain is released. As a result, the enediynes get activated toward BC under ambient conditions.

This idea was best demonstrated in the design of a model compound reported by Nicolaou et al. (Scheme 93). Thus, the compound A under photolytic conditions got converted into the diol D via the intermediacy of the quinone−methide C formed by epoxide ring opening. With the release of strain, the compound D underwent BC. The addition of an external nucleophile, such as EtOH or EtSH, led to the isolation of the cycloaromatized product.

Scheme 93. Photodeprotection and activation of the dynemicin model.

Another design based on similar idea was devised by Wender et al. who synthesized a 5-nitroveratryloxy (N -Voc)-protected dynemicin analogue E (Scheme 94). Compound E is photochemically activable dynemicin analogue that underwent cycloaromatization upon irradiation with wavelengths greater than 300 nm. The ability of this compound to DNA cleavage was also demonstrated. It was also observed that the enediyne E is also activated toward thermal BC by treatment with acid, which opens up the epoxide. Thus, the molecule is equipped with a dual triggering mechanism, pH as well as light.

Scheme 94. Photodeprotection and activation of the dynemicin model.

The design of molecules with an acyclic framework to be activated in a similar way is based on the fact that cyclic 10-membered azaenediyne spontaneously cyclizes under ambient conditions with a decent half-life ( t _1/2 = 36 h at 30°C). Taking the idea from this fact, a new design strategy has been adopted in which an acyclic enediyne having an amino group in one arm of the enediyne is protected in the form of N -Voc or β-lactam. Cleavage of N -Voc or opening of the β-lactam ring releases the nucleophilic nitrogen free which then undergoes intramolecular attack to close the cycle. The latter with appropriate size then undergoes BC. The resulting diradical in this process shows DNA cleavage or antibacterial property.

Thus, Basak et al. designed an acyclic enediyne molecule with a photo-cleavable amine protecting group that is stable at biological temperatures but is convertible to a cyclic 10-membered enediyne after a triggering reaction. This in situ generated cyclic enediyne could then be capable of showing DNA cleavage activity upon BC (Scheme 95). Thus, they have synthesized the enediyne A, where the photocleavable protecting group satisfies two criteria: (a) it suppresses the nucleophilicity of the nitrogen, and (b) it is removed by photolysis. The compound A upon irradiation at 365 nm was able to induce single-strand cleavage of plasmid DNA. It is also to be mentioned that the ketone A also caused partial DNA damage under non-irradiating conditions. However, the efficiency of cleavage was ~2.5 times less compared to that observed for the in situ generated cyclic enediyne C which could be produced after deprotection of the protecting group of A and an intramolecular ring closure by nucleophilic attack by free –NH₂ to the ketone. This ruled out the cleavage via the Maxam−Gilbert mechanism as the major pathway.

Scheme 95. Photodeprotection and the mechanism of DNA cleavage of enediyne containing heteroatom “N”. Lane 1: DNA; lane 2: DNA + 5.082 (10 μM) (24 h) + hν (365 nm); lane 3: DNA + 5.082 (10 μM) (24 h).