The Photochemistry of Flutamide and its Inclusion Complex with β-Cyclodextrin. Dramatic Effect of the Microenvironment on the Nature and on the Efficiency of the Photodegradation Pathways¶

Sortino, Salvatore; Giuffrida, Salvatore; Guidi, Guido De; Chillemi, Rosa; Petralia, Salvatore; Marconi, Giancarlo; Condorelli, G.; Sciuto, Sebastiano

doi:10.1562/0031-8655(2001)073<0006:tpofai>2.0.co;2

Cited by 62 publications

(47 citation statements)

References 36 publications

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“…These results account for a highly selective shutdown These dramatic changes of the photochemical outcome observed in the phospholipid vesicles cannot be roughly rationalized on the basis of the presence of the abstractable H-atoms of the bilayer or its low polarity. Actually, as observed in our previous work, the irradiation of FM performed in solvents characterized by good Hdonating properties and polarity similar to the vesicles interior did not activate the photonitroreductive pathway [20]. On the contrary, it was recently proposed that a plausible explanation to account for the inhibition of 1 and the photogeneration of 2 might be consistent with structural changes of FM occurring upon its self-compartmentalization in the bilayer structure [23].…”

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confidence: 66%

“…In fact, the −out of plane× geometry makes the p-orbital of the O-atom constructively overlap with the adjacent p-orbital of the aromatic ring in the ground state (see Scheme 1). As a result of this molecular structure, the lowest excited triplet state is characterized by low biradical character and, as a consequence, by considerable inefficiency towards H-abstraction even in H-donating solvents [20] contrary to what was commonly observed for nitro aromatic compounds in which the NO 2 group is conjugated with the aromatic plane [26] [27]. The optimized structures (MM ) of the two relevant conformations are displayed in Fig.…”

mentioning

confidence: 95%

“…In our previous study, we have reported on the FM photochemistry in homogeneous solvents and in the b-cyclodextrin cavity [20]. This latter medium was chosen to model the influence of nonaqueous biological environments on the drug photoreactivity.…”

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confidence: 99%

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Photobinding of Flutamide to Phospholipid Vesicles: Additional Evidence for Photoprocesses Unexpectedly Triggered by Conformational Changes in the Bilayer

Sortino

Marconi

Petralia

et al. 2002

HCA

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It is demonstrated that irradiation of the anticancer drug flutamide (FM) in the presence of unilamellar phospholipid bilayer vesicles, chosen as a model for cell membranes, leads to an efficient photobinding process. This pathway is triggered by an unexpected hydrogen-abstraction reaction of the excited drug by the lipid chain and provides additional evidence that the overall photochemical scenario observed in the vesicles is unusually triggered by conformational change of the drug×s molecular structure upon incarceration in the −close-packed× bilayer. The present investigation, beyond contributing to the general picture concerning fundamental aspects of the light-induced processes in self-organized assemblies, may also provide important insights for a more satisfactory understanding of the recently reported adverse photoallergic and phototoxic phenomena displayed by this anticancer drug.

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confidence: 95%

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Photobinding of Flutamide to Phospholipid Vesicles: Additional Evidence for Photoprocesses Unexpectedly Triggered by Conformational Changes in the Bilayer

Sortino

Marconi

Petralia

et al. 2002

HCA

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“…NMR correlation data along with the published data ( 1 H-NMR) were used to characterize the compound as 4-nitro-3-(trifluoromethyl)analine. 2,13) The light yellow solid 3 (15 mg, 3.1%) gave a molecular ion peak at m/z 247.1123 [MϪH] ϩ in its HR-ESI-MS corresponding to the elemental formula, C 11 H 13 F 3 N 2 O. The 1 H-NMR data showed close resemblance to those of 1 except for the presence of a two proton singlet due to an amino group at d 5.30.…”

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“…Flutamide, a nonsteroidal antiandrogen is a commonly used drug to treat advanced prostate cancer, 2) which is one of the leading causes of death in men in the United States. 3) It is absorbed rapidly from the gastrointestinal track of humans and rats after oral administration and undergoes extensive metabolism in the liver [3][4][5] through hydrolysis, hydroxylation, N-acetylation and nitroreduction to yield several metabolites.…”

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Microbial Metabolism. Part 11. Metabolites of Flutamide

Herath

Khan

2010

CHEMICAL & PHARMACEUTICAL BULLETIN

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Flutamide, a nonsteroidal antiandrogen is a commonly used drug to treat advanced prostate cancer, 2) which is one of the leading causes of death in men in the United States. 3) It is absorbed rapidly from the gastrointestinal track of humans and rats after oral administration and undergoes extensive metabolism in the liver [3][4][5] through hydrolysis, hydroxylation, N-acetylation and nitroreduction to yield several metabolites. 6) The major metabolites detected in plasma are 2-hydroxyflutamide (OH-FLU) and 4-nitro-3-(trifluoromethyl)phenylamine (FLU-1) 7) with concentrations higher than that of flutamide. 8) It is suggested that the antiandrogen activity of flutamide is largely associated with its main metabolite, 2-hydroxyflutamide. 6) Its activity is based on the ability to attach itself to the receptors of the cancer cells preventing the attachment of testosterone, the male hormone which is essential for the growth of the prostate cancer cells. Flutamide with the structure similar to that of testosterone 9) however, is a weak antiandrogen. 10) FLU-1, which is devoid of any antiandrogenic activity 7) is formed by carboxyesterase-catalysed hydrolysis. 6) It is a product of a clearance pathway. Thus, the main metabolite identified in urine is 2-amino-5-nitro-4-(trifluoromethyl)phenol (FLU-3). 3) However, urinary excretion is not a major pathway of flutamide elimination in humans. 7) The use of flutamide as therapeutic agent against prostrate cancers is eclipsed by rare incidences of idiosyncratic liver injury. 6) Although it is suggested that flutamide and its toxic metabolites could be responsible for such hepatic injury the mechanism of toxicity remains presently unknown. 6) It is observed that the serum concentration of FLU-1 is higher 3,7) and that of OH-flutamide is lower in patients with liver dysfunction than in those with normal liver function. 11) The formation of OH-flutamide from the parent compound is catalyzed by CYP1A2. Thus, a lower concentration of OH-flutamide is due to reduced activity of the enzyme. 11) Therefore, it is suggested that since CYP1A2 seems to be involved in the initiation of flutamide-induced liver injury, attention should be paid to patients with low CYP1A2 activity before administrating flutamide. 11) Genetic mutations and factors such as smoking, food and drugs are shown to influence the activity of the enzyme. 11) Smoking induces CYP1A2 activity and reduces the risk of liver toxicity due to flutamide. 3) In the present investigation we used microbial models retrospectively in an attempt to obtain mammalian metabolites of 1. No more than three metabolites were detected in the culture media of the forty microorganisms used. Among them the most prominent compound was FLU-1, detected in almost all the cultures used. Rhodotorula mucilaginosa culture which gave all three metabolites in good yields was selected for scale up studies. The structures of the metabolites (2-4) were elucidated by detailed study of their high resolution spectroscopic data. Results and DiscussionOf the for...

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Light-Controlled Nitric Oxide Generation from a Novel Self-Assembled Monolayer on a Gold Surface This work was supported by MURST “cofinanziamento di programmi di ricerca di rilevante interesse nazionale” (Project: Mechanisms of Photoinduced Processes in Organized Systems). We also thank Prof. S. Giuffrida for his critical reading of the manuscript, Prof. V. Amico for his useful suggestions, and the referees for constructive comments.

et al. 2002

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Increasing evidence demonstrates that nitric oxide (NO) plays important roles in numerous physiological processes. [1±8] For instance, it is involved in the bioregulation of functions such as vasodilatation, neurotransmission, and hormone secretion in living bodies. In addition to these effects, NO has also been reported to act as efficient anticancer agent that inhibits key metabolic pathways to block the growth of or to kill cells. [9±13] This has stimulated intense interest in com-Figure 6. Photolysis profile: the formation of colloidal silver at different illumination times (l % 410 nm) and the stability of [SiW 12 O 40 ] 4À photocatalyst (l 263 nm). Photolysis of a deaerated solution containing propan-2-ol (0.5 m), [SiW 12 O 40 ] 4À (0.035 mm), Ag (0.1 mm) at pH 5 (l > 320 nm). Experimental SectionK 4 [SiW 12 O 40 ] was synthesized according to literature methods. [18] The metal ions added to the photolysed solution were aqueous solutions of AgNO 3 , PdCl 2 , HAuCl 4 , or H 2 PtCl 6 .In photolysis experiments, an aqueous solution of SiW 12 O 40 4À 0.7 mm and propan-2-ol 0.5 m, at pH 5, was put into a spectrophotometer cell (1 cm path length) deaerated with Ar and covered with a cerum cap. Photolysis was performed with a 1000 W Xe arc lamp, the light intensity of which was mechanically reduced by approximately 40 %, while cut-off filters (up to 320 nm) were used to avoid direct photolysis of organic substrates. The absorption spectra of metal particles or catalyst were taken with a UV/Vis/ NIR Spectrometer (Perkin Elmer Lambda 19), and the degree of reduction of POM in photolyzed, deaerated solutions was calculated from the known extinction coefficient of reduced catalyst, SiW 12 O 40 5À , at 730 nm (0.21 Â 10 4 M À1 cm À1 ). TEM images were obtained using a Philips 200 kV microscope, and the samples were prepared by placing microdrops of colloid solution on a Formvar/carbon coated copper grid.

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The Photochemistry of Flutamide and its Inclusion Complex with β-Cyclodextrin. Dramatic Effect of the Microenvironment on the Nature and on the Efficiency of the Photodegradation Pathways¶

Cited by 62 publications

References 36 publications

Photobinding of Flutamide to Phospholipid Vesicles: Additional Evidence for Photoprocesses Unexpectedly Triggered by Conformational Changes in the Bilayer

Photobinding of Flutamide to Phospholipid Vesicles: Additional Evidence for Photoprocesses Unexpectedly Triggered by Conformational Changes in the Bilayer

Microbial Metabolism. Part 11. Metabolites of Flutamide

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