Computational Study on the Mechanism of the Photouncaging Reaction of Vemurafenib: Toward an Enhanced Photoprotection Approach for Photosensitive Drugs

The photochemical behavior of the photosensitive first-line anticancer drug vemurafenib (VFB) is of great interest due to the impact of such behavior on its pharmacological activity. In this work, we computationally elucidated the mechanism of the photoinduced release of VFB from the 4,5-dimethoxy-2-nitrobenzene (DMNB) photoprotecting group by employing various density functional theory (DFT)/time-dependent DFT (TD-DFT) approaches. The computational investigations included a comparative assessment of the influence of the position of the photoprotecting group as a substituent on the thermodynamics and kinetics of the photouncaging reactions of two VFB-DMNB prodrugs, namely pyrrole (NP) and sulfonamide (NS). With the aid of the DFT calculations concerning the activation energy barrier (∆G‡), the obtained results suggest that the step of the photoinduced intramolecular proton transfer of the DMNB moiety is not detrimental concerning the overall reaction profile of the photouncaging reaction of both prodrugs. However, the obtained results suggested that the position of the substitution position of the DMNB photoprotecting group within the prodrug structure has a substantial impact on the photouncaging reaction. In particular, the DMNB-Ns-VFB prodrug exhibited a notable increase in ∆G‡ for the key step of ring opining within the DMNB moiety indicative of potentially hindered kinetics of the photouncaging process compared with DMNB-Np-VFB. Such an increase in ∆G‡ may be attributed to the electronic influence of the NP fragment of the prodrug. The results reported herein elaborate on the mechanism of the photoinduced release of an important anticancer drug from photoprotecting groups with the aim of enhancing our understanding of the photochemical behavior of such photosensitive pharmaceutical materials at the molecular level.

Cymantrene Derivatives Containing Imino Groups: Spectral and Photochemical Properties

The investigation of a photochemical behavior of imino derivatives of cymantrene reveals a possibility of formation of four-membered hemilabile chelate complexes. In the presence of external ligands, such as CO, MeCN, or PPh3, the ligand exchange between imino groups at the Mn atom in dicarbolyl chelates and the external ligand is observed. It is shown that MeCN or PPh3 can be substituted for CO under dark conditions, resulting in intermolecular photochromic systems between tricarbonyl complexes and dicarbonyl derivatives with MeCN and PPh3 ligand, respectively.

Chemical and photochemical behavior of ruthenium nitrosyl complexes with terpyridine ligands in aqueous media

The synthesis and behavior in water of a set of various cis(Cl,Cl)-[R-tpyRuCl2(NO)](PF6) and trans(Cl,Cl)-[R-tpyRuCl2(NO)](PF6) (R = fluorenyl, phenyl, thiophenyl; tpy = 2,2′:6′,2′′-terpyridine) complexes are presented.

Photochemical Deracemization of Chiral Sulfoxides Catalyzed by a Hydrogen-Bonding Xanthone Sensitizer

Several chiral sulfoxides with a lactam hydrogen-bonding site were prepared and their photochemical behavior was studied in the presence of xanthone and thioxanthone sensitizers. While acyclic sulfoxides showed only decomposition, chiral benzothiazinone-1-oxides with a stereogenic sulfur atom underwent a stereomutation upon irradiation at λ = 366 nm in the presence of catalytic quantities of a xanthone sensitizer. A chiral xanthone with a 1,5,7-trimethyl-3-azabicyclo-[3.3.1]nonan-2-one backbone was employed in catalytic quantities (5 mol%) to achieve a deracemization reaction of racemic benzothiazinone-1-oxides in acetonitrile solution. Five substrates could be successfully deracemized in good yields and with up to 55% ee.