β-内酰胺类抗生素及其杂质的质谱裂解规律研究和毒性预测与评价
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摘要
药品的质量安全问题不仅是各国药品监管机构和制药企业重点关注的领域,也是公众普遍关心的民生热点问题。药品的质量直接关系到临床使用时药品的不良反应,对药品中杂质的控制是保证药品质量安全的重要环节。进入新世纪以后,研究者提出了杂质谱控制的理念。杂质谱控制的理念是对药品中所有的杂质的总的描述,强调根据杂质的生理活性逐一制定质量控制限度。实现杂质谱控制的三个关键技术问题可概括为：复杂体系的分离分析、微量杂质的结构分析和杂质的毒性评价。本论文以临床上广泛应用的β-内酰胺类抗生素为研究对象,就杂质的结构分析和毒性预测与评价两方面展开研究。
利用HPLC-MS分析药品中微量不稳定杂质是主流的研究方法,根据杂质的来源,分析主成分和杂质的质谱裂解规律,可较快地推断出杂质可能的结构。因此,开展杂质谱研究前,首先需深刻认识p-内酰胺类抗生素及其杂质的质谱裂解规律,寻找主成分与杂质在质谱裂解规律上的共同点和不同点。针对与主成分互为同分异构体的杂质,本论文探索用质谱、光谱学、计算化学等多种技术手段来研究它们的质谱裂解行为。杂质毒性预测与评价方面,本论文针对模式动物斑马鱼胚胎毒性评价平台提出的毒性功能基团理念,通过计算p-内酰胺类抗生素在水溶液中的最稳定构象,分析毒性功能基团的空间结构；通过计算药物分子的极性大小,预测药物分子被斑马鱼胚胎吸收的情况；进而预测药物在斑马鱼胚胎毒性实验中的毒性作用。本论文研究内容主要包括以下四个部分：
1.以培南类抗生素为例,应用多级质谱和计算化学手段,研究质谱正离子模式下,p-内酰胺类抗生素共同的内酰胺环裂解机理。系统研究了培南类在质谱正离子条件下的质子化位点和离子结构,提出了四种不同的内酰胺环裂解途径。用理论计算的方法对不同裂解途径做了化学热力学研究,探讨了6个培南类化合物热力学上最有利的裂解途径。研究发现培南类抗生素7位羰基氧原子的质子亲和能决定了培南类内酰胺环裂解反应的最有利途径。
2.以头孢菌素△-3异构体为例,研究正离子和负离子模式下,头孢菌素与△-3异构体杂质裂解行为的差异。研究发现,由于双键位置的差异,头孢菌素和△-3异构体杂质可通过特征性碎片离子区分开来。综合质谱、红外多光子解离光谱、计算化学的手段,重点研究了特征性碎片离子的结构和产生机理,对质谱裂解行为的差异给出了合理的解释。
3.以头孢菌素反式异构体为例,研究质谱正离子模式下,头孢菌素和反式异构体杂质裂解行为的差异。对部分7位侧链含(刁-亚胺结构的头孢菌素和它们的反式异构体的质谱裂解行为的研究发现,顺反异构体的裂解行为受3位侧链的影响。当3位侧链首先发生裂解时,反式异构体更易于脱去亚胺上取代基,产生特征性碎片离子；当3位侧链不发生裂解时,顺反异构体的裂解行为基本相同。
4.用理论计算的方法研究头孢菌素和部分杂质在水溶液中的空间构象和极性大小,并用斑马鱼胚胎毒性实验评价和验证毒性作用大小。结果表明,头孢菌素的母核结构毒性较小,3位侧链和7位侧链取代基是主要的毒性功能基团。侧链取代基的空间构象不仅决定了毒性功能基团的毒性大小,还影响了分子极性大小,并影响了头孢菌素被动吸收的过程。极性越小,分子越易透过胚胎生物膜,使胚胎内药物浓度升高,增加毒性反应的强度。
The drug quality and safety are not only the tremendous issues for drug regulation administrations and pharmaceutical companies, but also the main concerns for public. The drug quality is closely related to the adverse drug reactions found in the clinics, and the drug impurity analysis is the key process ensuring the drug quality. Therefore, the concept of impurity profiling is proposed, the definition of impurity profiling is "A description of the identified and unidentified impurities, present in a new drug substance", with the aim of detecting, identifying or elucidating the structure and quantitatively determining all the impurities in bulk drugs and pharmaceutical dosage forms. Impurity profiling is focused on the limit determination according to the biological activity of impurities. To achieve the profiling of drug impurities, three key technical issues should be considered:separation of the complex sample, structural elucidation of unknown impurities in trace amount, and toxicity evaluation of impurities. In this dissertation, the widely prescribed P-lactam antibiotics in clinics are chosen, the studies are mainly about the structural elucidation and toxicity evaluation.
HPLC-MS is one of the most important tools in the drug quality control, the possible structures could be rapidly determined based on the knowledge of impurity source and fragmentation pathways in mass spectrometry. Thus, a deep understanding of the fragmentation behavior in mass spectrometry is desperately required for impurity profiling, the different fragmentation patterns in mass spectrometry, as well as the universal pathways are very useful information for structural elucidation. The differentiation of stereoisomeric impurities using mass spectrometry, infrared multiple photon dissociation (IRMPD) spectroscopy and computational chemistry is also highlighted. For toxicity prediction and evaluation, theoretical calculations were used to study the molecular conformations in aqueous solution and to confirm the concept of toxic functional groups of the C-3and C-7side chains. Molecular polarities were calculated to predict the passive absorption in Zebrafish embryo toxicity testing. The following four parts are included in this study:
1. The universal fragmentation behaviors of the cleavage of P-lactam ring in Penems were studied by collision-induced dissociation mass spectrometry and computational chemistry in the positive ion mode. The protonation sites and structures of several Penams were explored in the gas-phase, four β-lactam ring cleavage mechanisms were proposed, the thermodynamic characteristics of these pathways were also investigated, the most favorable pathway for each compound was located. The study indicated that the protonation sites have crucial impacts on the cleavage.
2. The differentiation of some cephalosporins and their A-3isomers were comprehensively investigated by mass spectrometry in both the positive and negative ion mode. The characteristic product ions enabled distinguish of these positional isomers. IRMPD spectroscopy and computational chemistry were applied for structural determination and fragmentation mechanism study.
3. In the positive ion mode, cephalosporins with (Z)-imine configuration of the C-7side chain, together with their (E)-isomers were studied by electrospray tandem mass spectrometry and computational chemistry. The results suggested that the fragmentation behavior of (Z)-and (E)-isomers are significantly influence by the nature of their C-3side chain. The (Z)-and (E)-isomers could only be distinct when the cleavage of C-3side chain occurred, the (E)-isomers were more likely to lose the substituents of the imine moieties, leading to the characteristic ions for differentiation. If the C-3side chain kept intact under collision-induced dissociation, the (Z)-and (E)-isomers would have the same fragmentation pattern.
4. The computational chemistry was applied to study the conformations and polarities of cephalosporins and their impurities in the aqueous solution, also, Zebrafish embryo toxicity testing was used to evaluate and validate the toxic effects. The results indicated that the basic structure of the cephalosporin was almost nontoxic, while the C-3and C-7side chains were the main toxic functional groups. The conformations of the side chain in the aqueous solution affected the potency of the toxic effect, moreover, they determined the polarity of the molecules. Consequently, the conformations would influence the ability of passive absorption through the embryo membrane. The decreased polarity would increase the membrane permeability and finally gave rise to more potent toxic activity.
利用HPLC-MS分析药品中微量不稳定杂质是主流的研究方法,根据杂质的来源,分析主成分和杂质的质谱裂解规律,可较快地推断出杂质可能的结构。因此,开展杂质谱研究前,首先需深刻认识p-内酰胺类抗生素及其杂质的质谱裂解规律,寻找主成分与杂质在质谱裂解规律上的共同点和不同点。针对与主成分互为同分异构体的杂质,本论文探索用质谱、光谱学、计算化学等多种技术手段来研究它们的质谱裂解行为。杂质毒性预测与评价方面,本论文针对模式动物斑马鱼胚胎毒性评价平台提出的毒性功能基团理念,通过计算p-内酰胺类抗生素在水溶液中的最稳定构象,分析毒性功能基团的空间结构；通过计算药物分子的极性大小,预测药物分子被斑马鱼胚胎吸收的情况；进而预测药物在斑马鱼胚胎毒性实验中的毒性作用。本论文研究内容主要包括以下四个部分：
1.以培南类抗生素为例,应用多级质谱和计算化学手段,研究质谱正离子模式下,p-内酰胺类抗生素共同的内酰胺环裂解机理。系统研究了培南类在质谱正离子条件下的质子化位点和离子结构,提出了四种不同的内酰胺环裂解途径。用理论计算的方法对不同裂解途径做了化学热力学研究,探讨了6个培南类化合物热力学上最有利的裂解途径。研究发现培南类抗生素7位羰基氧原子的质子亲和能决定了培南类内酰胺环裂解反应的最有利途径。
2.以头孢菌素△-3异构体为例,研究正离子和负离子模式下,头孢菌素与△-3异构体杂质裂解行为的差异。研究发现,由于双键位置的差异,头孢菌素和△-3异构体杂质可通过特征性碎片离子区分开来。综合质谱、红外多光子解离光谱、计算化学的手段,重点研究了特征性碎片离子的结构和产生机理,对质谱裂解行为的差异给出了合理的解释。
3.以头孢菌素反式异构体为例,研究质谱正离子模式下,头孢菌素和反式异构体杂质裂解行为的差异。对部分7位侧链含(刁-亚胺结构的头孢菌素和它们的反式异构体的质谱裂解行为的研究发现,顺反异构体的裂解行为受3位侧链的影响。当3位侧链首先发生裂解时,反式异构体更易于脱去亚胺上取代基,产生特征性碎片离子；当3位侧链不发生裂解时,顺反异构体的裂解行为基本相同。
4.用理论计算的方法研究头孢菌素和部分杂质在水溶液中的空间构象和极性大小,并用斑马鱼胚胎毒性实验评价和验证毒性作用大小。结果表明,头孢菌素的母核结构毒性较小,3位侧链和7位侧链取代基是主要的毒性功能基团。侧链取代基的空间构象不仅决定了毒性功能基团的毒性大小,还影响了分子极性大小,并影响了头孢菌素被动吸收的过程。极性越小,分子越易透过胚胎生物膜,使胚胎内药物浓度升高,增加毒性反应的强度。
The drug quality and safety are not only the tremendous issues for drug regulation administrations and pharmaceutical companies, but also the main concerns for public. The drug quality is closely related to the adverse drug reactions found in the clinics, and the drug impurity analysis is the key process ensuring the drug quality. Therefore, the concept of impurity profiling is proposed, the definition of impurity profiling is "A description of the identified and unidentified impurities, present in a new drug substance", with the aim of detecting, identifying or elucidating the structure and quantitatively determining all the impurities in bulk drugs and pharmaceutical dosage forms. Impurity profiling is focused on the limit determination according to the biological activity of impurities. To achieve the profiling of drug impurities, three key technical issues should be considered:separation of the complex sample, structural elucidation of unknown impurities in trace amount, and toxicity evaluation of impurities. In this dissertation, the widely prescribed P-lactam antibiotics in clinics are chosen, the studies are mainly about the structural elucidation and toxicity evaluation.
HPLC-MS is one of the most important tools in the drug quality control, the possible structures could be rapidly determined based on the knowledge of impurity source and fragmentation pathways in mass spectrometry. Thus, a deep understanding of the fragmentation behavior in mass spectrometry is desperately required for impurity profiling, the different fragmentation patterns in mass spectrometry, as well as the universal pathways are very useful information for structural elucidation. The differentiation of stereoisomeric impurities using mass spectrometry, infrared multiple photon dissociation (IRMPD) spectroscopy and computational chemistry is also highlighted. For toxicity prediction and evaluation, theoretical calculations were used to study the molecular conformations in aqueous solution and to confirm the concept of toxic functional groups of the C-3and C-7side chains. Molecular polarities were calculated to predict the passive absorption in Zebrafish embryo toxicity testing. The following four parts are included in this study:
1. The universal fragmentation behaviors of the cleavage of P-lactam ring in Penems were studied by collision-induced dissociation mass spectrometry and computational chemistry in the positive ion mode. The protonation sites and structures of several Penams were explored in the gas-phase, four β-lactam ring cleavage mechanisms were proposed, the thermodynamic characteristics of these pathways were also investigated, the most favorable pathway for each compound was located. The study indicated that the protonation sites have crucial impacts on the cleavage.
2. The differentiation of some cephalosporins and their A-3isomers were comprehensively investigated by mass spectrometry in both the positive and negative ion mode. The characteristic product ions enabled distinguish of these positional isomers. IRMPD spectroscopy and computational chemistry were applied for structural determination and fragmentation mechanism study.
3. In the positive ion mode, cephalosporins with (Z)-imine configuration of the C-7side chain, together with their (E)-isomers were studied by electrospray tandem mass spectrometry and computational chemistry. The results suggested that the fragmentation behavior of (Z)-and (E)-isomers are significantly influence by the nature of their C-3side chain. The (Z)-and (E)-isomers could only be distinct when the cleavage of C-3side chain occurred, the (E)-isomers were more likely to lose the substituents of the imine moieties, leading to the characteristic ions for differentiation. If the C-3side chain kept intact under collision-induced dissociation, the (Z)-and (E)-isomers would have the same fragmentation pattern.
4. The computational chemistry was applied to study the conformations and polarities of cephalosporins and their impurities in the aqueous solution, also, Zebrafish embryo toxicity testing was used to evaluate and validate the toxic effects. The results indicated that the basic structure of the cephalosporin was almost nontoxic, while the C-3and C-7side chains were the main toxic functional groups. The conformations of the side chain in the aqueous solution affected the potency of the toxic effect, moreover, they determined the polarity of the molecules. Consequently, the conformations would influence the ability of passive absorption through the embryo membrane. The decreased polarity would increase the membrane permeability and finally gave rise to more potent toxic activity.
引文
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