Transfer of Phenanthrene and Its Hydroxylated Metabolites to Milk, Urine and Faeces

Abstract

Single oral ingestion of phenanthrene was administered in lactating goats with the aim of characterizing its behavior and its biotransformation in milk and other excretion products. Detection and identification of the analytes (phenanthrene, 1-, 2-, 3-, 4-, 9-hydroxyphenanthrene and 9,10-dihydroxyphenanthrene) were achieved using GC-MS procedure. The blood kinetics revealed the presence of phenanthrene and its hydroxylated forms quite soon (3-7 h) after the oral administration. The high concentration of metabolites in blood (3-300 ng/mL) suggests a very fast biotransformation process of phenanthrene. A direct link between the lipophily and the presence of the molecule in milk or urine was established. Indeed, 94% and 99.6% of the excreted phenanthrene were recovered under metabolite forms in milk and urine respectively. The non-metabolized phenanthrene was principally found in faeces. The more the solubility increased, the more the compound was transferred through milk and urine; as a consequence, the 99 9,10-diOHphenanthrene appeared mainly in urine whereas phenanthrene was practically not detectable. These results provide original information on the ability of the dairy ruminant to metabolize and to transfer phenanthrene. The extremely low rate transfer of phenanthrene and its metabolites to the milk (0.25%) should not, therefore, be considered as a major health concern.

Directed Metalation–Suzuki–Miyaura Cross-Coupling Strategies: Regioselective Synthesis of Hydroxylated 1-Methyl-phenanthrenes

“…37 The 1 H NMR-spectra of all biphenyls indicated the presence of rotamers, more pronounced in the more crowded biphenyls. 38 The cross-coupling reactions of the 4-OMe boronic acid benzamide and bromobenzamides series proved to be unexceptional providing modest to good yields of biaryl products 3f and 3g (entries [11][12][13][14][15][16]. While the 3-OMe benzamide 2-boronic acid 1d was prepared by DoM chemistry using the less hindered B(OMe) 3 reagent, the corresponding halogenated products 1e, 1f and 1h were obtained via metalation and quench with Br 2 or I 2 .…”

“…After standard workup, the residue was purified via column chromatography using heptane/ ethyl acetate (1:1) to afford the title compound as a colorless solid (2.56 g, 94%). mp 102−103 °C (cyclohexane); 1 H NMR (400 MHz, CDCl 3 ) δ 6.85−7.24 (m, 6H), 3.85 (s, 3H), 3.72 (br s, 1H), 2.50−3.20 (m, 3H), 2.28 (s, 3H), 2.08 (br s, 3H), 0.50−1.05 (m, 6H); 13 C NMR (100 MHz, CDCl 3 ) δ 11.7, 13.7, 17.1, 20.6, 37.9, 42.4, 55.4, 114.2, 128.9, 136.8, 158.6, 169.9; MS (EI, DIP) m/z 311 (M + , 5), 282 (1), 239 (55), 238 (100), 224 (10), 211 (13), 196 (14), 181 (11), 165 (11), 152 (13); FTIR (KBr, cm −1 ): 3059, 2971, 2929, 1627, 1479, 1461, 1292, 1230, 1077, 1042; HRMS (EI-TOF) m/z [M − H] + for C 20 H 24 NO 2 : calcd, 310.1807; found, 310.1800.…”

“…The title compound was isolated as a colorless solid (79 mg, 70%). mp 87 °C (cyclohexane); 1 H NMR (400 MHz, DMSO-d 6 , 70 °C) δ 7.39−7.55 (m, 2H), 7.08− 7.32 (m, 5H), 3.44 (sext, J = 6.6 Hz, 1H), 2.75−3.33 (m, 3H), 2.12 (s, 3H), 0.96 (br s, 3H), 0.64 (t, J = 6.9 Hz, 3 H); 13 C NMR (100 MHz, DMSO-d 6 , 70 °C) δ 11.9, 13.8, 20.3, 37.6, 42.4, 125.4, 128.4, 128.7, 129.4, 129.8, 130.3, 136.5, 165.7; MS (EI, DIP) m/z 301 (M + , 3), 264 (41), 229 (32), 219 (100), 165 (48), 131 (79), 114 (14), 100 (25), 69 (99); FTIR (KBr, cm −1 ) 2977, 2929, 2870, 1634, 1464, 1283; HRMS (EI-TOF) m/z [M] + for C 18 H 20 ClNO: calcd, 301.1233; found, 301.1253.…”

“…9 Unfortunately phenanthrenes, as most classes of PAHs, are also persistent pollutants in the environment, 10,11 e.g., annelids on tidal flats concentrate phenanthrene in their excrements, 12 phenanthrene-based synthetic musk fragrances have been found in shrimps, 13 and metabolites of phenanthrenes have been detected in goat's milk. 14 Among the many fractions of PAHs in oil sources currently under study, 11,15 alkylated PAHs have been established to cause general detrimental environmental effects 10,16 and in particular are toxic to marine life. 17,18 In the substantial body of literature on the construction of phenanthrenes, 19 the dominant classical Pschorr 20 and the more recent Mallory photo-21 and oxidative cyclizations 22 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 heteroaromatic synthesis, 27,28 we have devised combined metalation-cross-coupling strategies, 29 which have had particular relevance to the construction of phenanthrene derivatives.…”

“…9 Unfortunately, phenanthrenes, as is the case for most classes of PAHs, are also persistent pollutants in the environment, 10,11 e.g., annelids on tidal flats concentrate phenanthrene in their excrements, 12 phenanthrene-based synthetic musk fragrances have been found in shrimps, 13 and metabolites of phenanthrenes have been detected in goat's milk. 14 Among the many fractions of PAHs in oil sources currently under study, 11,15 alkylated PAHs have been established to cause general detrimental environmental effects 10,16 and, in particular, are toxic to marine life. 17,18 In the substantial body of literature on the construction of phenanthrenes, 19 the dominant classical Pschorr 20 and the more recent Mallory photo-21 and oxidative cyclizations 22 have been augmented by an evolving number of transition metal-catalyzed methods, 6,16,23 including the popular Suzuki−Miyaura crosscoupling reaction.…”