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1.
Chemistry ; 26(68): 15922-15930, 2020 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-32585059

RESUMO

Lapatinib (LAP) is an anticancer drug, which is metabolized to the N- and O-dealkylated products (N-LAP and O-LAP, respectively). In view of the photosensitizing potential of related drugs, a complete experimental and theoretical study has been performed on LAP, N-LAP and O-LAP, both in solution and upon complexation with human serum albumin (HSA). In organic solvents, coplanar locally excited (LE) emissive states are generated; they rapidly evolve towards twisted intramolecular charge-transfer (ICT) states. By contrast, within HSA only LE states are detected. Accordingly, femtosecond transient absorption reveals a very fast switching (ca. 2 ps) from LE (λmax =550 nm) to ICT states (λmax =480 nm) in solution, whereas within HSA the LE species become stabilized and live much longer (up to the ns scale). Interestingly, molecular dynamics simulation studies confirm that the coplanar orientation is preferred for LAP (or to a lesser extent N-LAP) within HSA, explaining the experimental results.


Assuntos
Antineoplásicos , Lapatinib , Antineoplásicos/química , Humanos , Lapatinib/química , Simulação de Dinâmica Molecular , Albumina Sérica Humana/química , Análise Espectral
2.
Free Radic Biol Med ; 67: 417-25, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24316197

RESUMO

The mechanism responsible for the remarkable photomutagenicity of fluoroquinolone (FQ) antibiotics remains unknown. For this reason, it was considered worthwhile to study in detail the interactions between DNA and a dihalogenated FQ such as lomefloxacin (LFX; one of the most photomutagenic FQs) and its N-acetyl derivative ALFX. Studies of photosensitized DNA damage by (A)LFX, such as formation of DNA single-strand breaks (SSBs), together with pulse radiolysis, laser flash photolysis, and absorption and fluorescence measurements, have shown the important effects of the cationic character of the piperazinyl ring on the affinity of this type of drug for DNA. Hence, the formation of SSBs was detected for LFX, whereas ALFX and ciprofloxacin (a monofluorated FQ) needed a considerably larger dose of light to produce some damage. In this context, it was determined that the association constant (Ka) for the binding of LFX to DNA is ca. 2×10(3)M(-1), whereas in the case of ALFX it is only ca. 0.5×10(3)M(-1). This important difference is attributed to an association between the cationic peripheral ring of LFX and the phosphate moieties of DNA and justifies the DNA SSB results. The analysis of the transient species detected and the photomixtures has allowed us to establish the intermolecular processes involved in the photolysis of FQ in the presence of DNA and 2'-deoxyguanosine (dGuo). Interestingly, although a covalent binding of the dihalogenated FQ to dGuo occurs, the photodegradation of FQ…DNA complexes did not reveal any significant covalent attachment. Another remarkable outcome of this study was that (A)LFX radical anions, intermediates required for the onset of DNA damage, were detected by pulse radiolysis but not by laser flash photolysis.


Assuntos
Ciprofloxacina/química , DNA/química , Fluoroquinolonas/química , Mutagênicos/química , Acetilação , Animais , Bovinos , Quebras de DNA de Cadeia Simples/efeitos dos fármacos , Quebras de DNA de Cadeia Simples/efeitos da radiação , Desoxiguanosina/química , Cinética , Lasers de Estado Sólido , Fotólise , Radiólise de Impulso , Soluções , Relação Estrutura-Atividade
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