Characterization of tautomeric forms of anti-cancer drug gemcitabine and their interconversion upon mechano-chemical treatment, using ATR-FTIR spectroscopy and complementary methods.
Characterization of tautomeric forms of anti-cancer drug gemcitabine and their interconversion upon mechano-chemical treatment, using ATR-FTIR spectroscopy and complementary methods.
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使用 ATR-FTIR 光谱和补充方法表征抗癌药物吉西他滨的互变异构形式及其在机械化学处理后的相互转化。
DOI：
10.1016/j.jpba.2023.115243
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发表时间：
2023
影响因子：
3.4
通讯作者：
Samokhvalov,Alexander
中科院分区：
文献类型：
--
作者：
Henry,Barrington;Samokhvalov,Alexander
吉西他滨是一种广泛使用的嘧啶结构的抗癌药物，其可以以游离碱分子形式存在于晶体中。互变异构体是分子的结构异构体，它们通过质子转移相互转化。机械力化学研究机械冲击下的固体反应。我们使用ATR-FTIR光谱分析，粉末XRD，光学显微镜和HPLC研究了吉西他滨游离碱中存在的特定分子互变异构体。氨基-酮互变异构体在3390 cm-1处具有氨基的特征红外（IR）峰。首次检测到吉西他滨游离碱的亚氨基-酮互变异构体。亚胺-酮互变异构体具有=N-H基团的特征红外吸收峰，其吸收峰与氨基-酮互变异构体的吸收峰相比发生了位移。这作为这些互变异构体的独特光谱“指纹”。ATR-FTIR光谱分析表明，吉西他滨游离碱可以富集氨基-酮或亚氨基-酮互变异构体。此外，我们研究了在液体辅助研磨（LAG）条件下，晶体中吉西他滨游离碱在其互变异构体之间的转化。亚氨基-酮互变异构体经历互变异构化为氨基-酮互变异构体，而氨基-酮互变异构体保持稳定。通过HPLC-UV分析证实，在LAG期间，吉西他滨游离碱分子（以互变异构体形式存在）未发生破坏。LAG是一种新型、直接、简便、快速的晶体互变异构体互变方法，ATR-FTIR光谱是研究药物互变异构反应的首选方法。所提出的方法是有前途的分析晶体的药物含有一个或一个以上的互变异构体，和知识驱动的设计的复合材料，其中包含特定的互变异构分子形式的嘧啶，嘌呤和其他生物活性杂环化合物。
Gemcitabine is a widely used anti-cancer drug of pyrimidine structure, which can exist as a free base molecular form in crystals. Tautomers are structural isomers of molecules, which interconvert via proton transfer.Mechano-chemistry studies reactions of solids under mechanical impact.We investigated gemcitabine free base for the presence of specific molecular tautomers, using ATR-FTIR spectroscopic analysis, powder XRD, optical microscopy and HPLC. The amino-keto tautomer has the characteristic infrared (IR) peak of the amino group at 3390 cm−1. For the first time, the imino-keto tautomer of gemcitabine free base was detected. The imino-keto tautomer has the characteristic IR peak of the =N–H group, and its peak due to the Cdouble bondO group in pyrimidine ring is shifted vs. that of the amino-keto tautomer. This serves as the unique spectroscopic “fingerprints” of these tautomers. The ATR-FTIR spectroscopic analysis shows that gemcitabine free base can be enriched with the amino-keto or the imino-keto tautomer. Further, we studied the transformation of gemcitabine free base in crystals between its tautomers under conditions of liquid-assisted grinding (LAG). The imino-keto tautomer undergoes tautomerization to the amino-keto tautomer, while the amino-keto tautomer remains stable. No destruction of molecules of gemcitabine free base, when present as either tautomer, occurs during LAG as was verified by the HPLC-UV analysis. LAG is a new, straightforward, facile and fast method to interconvert tautomers in crystals, and ATR-FTIR spectroscopy is a method of choice to study tautomerization reactions of pharmaceuticals. The presented approach is promising for analysis of crystals of drugs containing one or more than one tautomer, and the knowledge-driven design of composite materials, which contain specific tautomeric molecular forms of pyrimidines, purines and other biologically active heterocyclic compounds.
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DOI：
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