In vivo nucelophilic addition of thiolates to C12 and consequent opening of the core epoxide has been hypothesized to trigger Bergman cyclization in kedarcidin chromophore.
Nucleophilic activiation is thought to diminish the ring strain incurred by formation of the cycloaromatized product, and thus activate kedarcidin chromophore toward DNA scission.
In the isolation and structural characterization studies carried out by Leet et al.,
C12-sodium borohydride reduction of kedarcidin chromophore induced rapid cycloaromatization and so facilitated studies of the otherwise unstable natural product.
Consequently, C12-nucleophilic activation is proposed extensively in review literature as a possible means for triggering the cycloaromatization event in vivo.

Recent evidence suggests that spontaneous cycloaromatization of kedarcidin chromophore is competitive with nucleophilic bioactivation, if not the predominant mechanism in vivo.
While MM2 calculations show that the C1–C12 double bond in the bicyclic core imparts a considerable amount of ring strain (ca.
14 kcal·mol⁻¹) to the [6,5,5] tricycle formed upon Bergman cyclization–reduction, Hirama et al.
note that the 5,9-fused enediyne core is susceptible to cycloaromatization–reduction in the absence of both thiol "activating agents" and (non-solvent) hydrogen donors.
The kedarcidin chromophore aglycone similarly undergoes reductive cycloaromatization at comparable rates irrespective of the presence of β-mercaptoethanol, a common thiol reductant.
In a model system, it was found that the 5,9-bicyclic core of kedarcidin chromophore exists in equilibrium with the corresponding 5,5,6-tricyclic cycloaromatized biradical.
The rate of pseudo-first-order decay of this model enediyne is highly dependent on the solvent hydrogen-donor ability, indicating that the hydrogen abstraction step following biradical formation is kinetically significant in the cycloaromatization of the enediyne, as opposed to acyclic systems, where formation of the biradical itself is known to be the rate-limiting step.
It is noteworthy that of the solvents examined, tetrahydrofuran—structurally homologous with deoxyribose—led to comparatively fast decomposition of the 5,9-fused enediyne scaffold (t½ = 68 min); Zein et al.
independently remark that deoxyribose 4'-hydrogen abstraction is most likely operative in kedarcidin chromophore bioactivity.
In vivo nucelophilic addition of thiolates to C12 and consequent opening of the core epoxide has been hypothesized to trigger Bergman cyclization in kedarcidin chromophore. Nucleophilic activiation is thought to diminish the ring strain incurred by formation of the cycloaromatized product, and thus activate kedarcidin chromophore toward DNA scission. In the isolation and structural characterization studies carried out by Leet et al., C12-sodium borohydride reduction of kedarcidin chromophore induced rapid cycloaromatization and so facilitated studies of the otherwise unstable natural product. Consequently, C12-nucleophilic activation is proposed extensively in review literature as a possible means for triggering the cycloaromatization event in vivo.
Recent evidence suggests that spontaneous cycloaromatization of kedarcidin chromophore is competitive with nucleophilic bioactivation, if not the predominant mechanism in vivo. While MM2 calculations show that the C1–C12 double bond in the bicyclic core imparts a considerable amount of ring strain (ca. 14 kcal·mol⁻¹) to the [6,5,5] tricycle formed upon Bergman cyclization–reduction, Hirama et al. note that the 5,9-fused enediyne core is susceptible to cycloaromatization–reduction in the absence of both thiol "activating agents" and (non-solvent) hydrogen donors. The kedarcidin chromophore aglycone similarly undergoes reductive cycloaromatization at comparable rates irrespective of the presence of β-mercaptoethanol, a common thiol reductant. In a model system, it was found that the 5,9-bicyclic core of kedarcidin chromophore exists in equilibrium with the corresponding 5,5,6-tricyclic cycloaromatized biradical. The rate of pseudo-first-order decay of this model enediyne is highly dependent on the solvent hydrogen-donor ability, indicating that the hydrogen abstraction step following biradical formation is kinetically significant in the cycloaromatization of the enediyne, as opposed to acyclic systems, where formation of the biradical itself is known to be the rate-limiting step. It is noteworthy that of the solvents examined, tetrahydrofuran—structurally homologous with deoxyribose—led to comparatively fast decomposition of the 5,9-fused enediyne scaffold (t½ = 68 min); Zein et al. independently remark that deoxyribose 4'-hydrogen abstraction is most likely operative in kedarcidin chromophore bioactivity.
Kedarcidin