二氧化錳氧化頭孢子類抗生素結構與反應性之研究

Abstract

頭孢子類抗生素為國內外廣泛使用之藥物，已有研究顯示當其進入環境地表水體中會受到自然淨化影響，而氧化作用於其自然淨化過程中扮演重要之降解機制。本研究以五種頭孢子抗生素cefotaxime (CTX)、cephalexin (CFX)、cephradine (CFD)、cephapirin (CFP)和 cefazolin (CFZ)為目標化合物探討其在環境中之宿命。錳氧化物為普遍存在於土壤、岩層和底泥中的氧化劑，其在自然環境中具有氧化眾多有機物之能力。本研究使用合成的δ-MnO2作為氧化劑以批次實驗進行其氧化機制之探討。 研究結果顯示，CFX經由二氧化錳的氧化降解主要發生於其核心部位的降解 (7-Aminodesacetoxycephalosporanic acid, 7-ADCA)。因此CFX被選為建構氧化機制模型的代表物。CFX於不同濃度(100 ppb - 2 ppm)皆符合基於吸附行為與電子傳遞機制而建構的Langmuir反應模型。本研究亦針對五種目標抗生素之二氧化錳氧化反應位置(核心或副結構)進行探討，副產物之辨識輔助證明了氧化降解之位置。結果顯示，頭孢子抗生素的核心結構 (7-ADCA部位)為二氧化錳氧化降解的結構之一，且氧化後生成比核心分子量小的產物碎片 (就CFX與CFZ的碎片而言)。此外，連結於頭孢子環3號碳位置的基團會影響核心部位的反應性 (如CFZ和7-aminocephalosporanic acid (7-ACA))，而7號位置的基團則不影響核心結構之反應性。 比較各頭孢子抗生素以二氧化錳氧化之反應部位，顯示CFX的降解主要發生於其核心結構，而CTX、CFD和CFP的降解則主要發生於其核心環7號碳位置的取代基 (分別為2-Amino-α-(methoxyimino)-4-thiazoleacetyl取代基 (2-AMTA)、dienylglycylamino取代基(DGA)和2-pyridin-4-ylsulfanylacetyl取代基(2-PSA))。研究進一步發現CFP取代基(2-PSA)的降解是透過其與核心環連接處的醯胺鍵斷鍵而形成的降解。而CFZ之1-methyltetrazole (1-M)部位非二氧化錳氧化的部位。五種頭孢子類藥物子結構之活性大小比較顯示：2-AMTA > 2-PSA > DGA > 7-ADCA > phenylglycylamino group ≈ 1-M (不與二氧化錳反應)。 五種頭孢子類藥物於二氧化錳降解前後總有機碳維持不變，表示氧化過程中無礦化現象，即僅有機物結構轉變，且其產物不易再被二氧化錳降解。反應後的產物在Microtox毒性測試中無顯著毒性反應。 此外，太陽光為自然淨化中另一重要因子，並可能影響二氧化錳的氧化機制，因此在本研究中也被探討。CFX、CFD和CTX在結合照光之二氧化錳氧化反應中，主要由氧化主導總降解反應，而CFZ之降解則由直接光解主導。雖然照光於本實驗條件下並未顯著加速CFX、CFD、CFZ和CTX之氧化，然而由CFP之實驗結果顯示照光顯著使二氧化錳之初始溶解速率提升近八倍。

Oxidative transformation could be an important degradation pathway for cephalosporin antibiotics in natural surface water environments. Five cephalosporin antibiotics, cefotaxime (CTX), cephalexin (CFX), cephradine (CFD), cephapirin (CFP), and cefazolin (CFZ), were selected as target compounds to study their environmental fates. Synthetic δ-MnO2 was used in this study, and all reactions were conducted in batch experiments. Oxidation on the core structure (7-aminodesacetoxycephalosporanic acid, 7-ADCA) by MnO2 was the main degradation pathway for CFX; therefore, CFX was chosen as a representative compound for further reaction mechanism study. The results showed that the oxidation of CFX (at concentrations of 100 ppb to 2 ppm) fits the Langmuir-type equilibrium and reaction model, which was proposed based on the adsorption and electron transfer steps. The oxidation on the core and substructures by MnO2 was investigated, and the formed byproducts from oxidation were examined to elucidate the reactivities of the five target compounds and to identify the positions where oxidation occurs. The results indicated that the core structure (7-ADCA moiety) of cephalosporin is one oxidation site for MnO2 oxidation, and the oxidation on the core structure resulted in smaller fragments (shown in the case of CFX and CFZ). The substituent in the C-3 position of the cephem ring could change the reactivity of the core structure (i.e., 7-ADCA and CFZ); however, the substituent in the C-7 position does not change the reactivity of the core structure. The oxidation position of CFX mainly occurs in the core structure, while CTX, CFD, and CFP oxidation mainly occur in the substructures attached to the C-7 position of the cephem ring (2-amino-α-(methoxyimino)-4-thiazolylacetyl group (2-AMTA), dienylglycylamino group (DGA), 2-pyridin-4-ylsulfanylacetyl group (2-PSA), respectively). In CFP, bond breaking likely occurs at the amide bond of the C-7 substituent. In CFZ, the 1-M moiety is not the oxidation site of degradation. Furthermore, the reactivities of the substructures decrease as follows: 2-AMTA > 2-PSA > DGA > 7-ADCA > phenylglycylamino group ≈ 1-methyltetrazole (inert to oxidation). The total organic carbon content remained constant throughout the MnO2 reaction, indicating that no mineralization occurred and that the reaction was merely a transformation process. Although the resultant byproducts showed no Microtox toxicity, they were more resistant to further MnO2 oxidation. Sunlight, another important environmental factor that may affect the oxidation mechanisms of MnO2, was also studied in this work. For CFX, CFD, and CTX, photo-assisted oxidative degradation was predominated by MnO2 oxidation. However, for CFZ, the overall degradation was predominated by direct photolysis. Although enhanced CFX, CFD, CFZ, and CTX oxidation was not obvious under the current experimental conditions, sunlight significantly increased the initial dissolution rate of MnO2 (by a factor of eight).