Cobaltabis(dicarbollide) anion ([o-COSAN] À ) is a well-known metallacarborane with multiple applications in a variety of fields. In aqueous solution, the cisoid rotamer is the most stable disposition in the ground state. The present work provides theoretical evidence on the possibility to photoinduce the rotation from the cisoid to the transoid rotamer, a conversion that can be reverted when the ground state is repopulated. The non-radiative decay mechanisms proposed in this work are coherent with the lack of fluorescence observed in 3D fluorescence mapping experiments performed on [o-COSAN] À and its derivatives. This phenomenon induced by light has the potential to destruct the vesicles and micelles cisoid [o-COSAN] À typically forms in aqueous solution, which could lead to promising applications, particularly in the field of nanomedicine.

DNA damage is ubiquitous in nature and is at the basis of emergent treatments such as photodynamic therapy, which is based on the activation of highly oxidative reactive oxygen species by photosensitizing O 2 . However, hypoxia observed in solid tumors imposes the necessity to devise oxygen-independent modes of action able to induce DNA damage under a low oxygen concentration. The complexity of these DNA damage mechanisms in realistic environments grows exponentially when taking into account light absorption and subsequent excited-state population, photochemical and (photo)-redox reactions, the multiple species involved in different electronic states, noncovalent interactions, multiple reaction steps, and the large number of DNA reactive sites. This work tackles all the intricate reactivity of a photosensitizer based on a nitroimidazole derivative reacting toward DNA in solution under UV light exposition. This is performed through a combination of ground- and excited-state quantum chemistry, classical molecular dynamics, and hybrid QM/MM simulations to rationalize in detail the formation of DNA interstrand cross-links (ICLs) exerted by the noncanonical noncovalent photosensitizer. Unprecedented spatial and temporal resolution of these phenomena is achieved, revealing that the ICL is sequence-specific and that the fastest reactions take place at AT, GC, and GT steps involving either the opposite nucleobases or adjacent Watson–Crick base pairs. The N7 and O6 positions of guanine, the N7 and N3 sites of adenine, the N4 position of cytosine, and the O2 atom of thymine are deemed as the most nucleophile sites and are positively identified to participate in the ICL productions. This work provides a multiscale computational protocol to study DNA reactivity with noncovalent photosensitizers, and contributes to the understanding of therapies based on photoinduced DNA damage at molecular and electronic levels. In addition, we believe the depth understanding of these processes should assist the design of new photosensitizers considering their molecular size, electronic properties, and the observed regioselectivity toward nucleic acids.

Cobaltabis(dicarbollide) anion ([o-COSAN] À ) is a well-known metallacarborane with multiple applications in a variety of fields. In aqueous solution, the cisoid rotamer is the most stable disposition in the ground state. The present work provides theoretical evidence on the possibility to photoinduce the rotation from the cisoid to the transoid rotamer, a conversion that can be reverted when the ground state is repopulated. The non-radiative decay mechanisms proposed in this work are coherent with the lack of fluorescence observed in 3D fluorescence mapping experiments performed on [o-COSAN] À and its derivatives. This phenomenon induced by light has the potential to destruct the vesicles and micelles cisoid [o-COSAN] À typically forms in aqueous solution, which could lead to promising applications, particularly in the field of nanomedicine.