Photoinstability of Some Tyrphostin Drugs: Chemical Consequences of Crystallinity
Photoinstability of Some Tyrphostin Drugs: Chemical Consequences of Crystallinity
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某些酪氨酸磷酸酶药物的光不稳定性：结晶度的化学后果
DOI：
10.1023/a:1016213721861
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发表时间：
1995
影响因子：
3.7
通讯作者：
H. Ammon
中科院分区：
文献类型：
--
作者：
Narendra Kumar;V. Windisch;H. Ammon
目的.本工作的目的是研究抗增殖酪氨酸磷酸化抑制剂药物化合物RG 13022（I）和RG 14620（II）的光稳定性，作为处方前计划的一部分。将化合物在溶液和固态中暴露于冷白色荧光灯下，并通过HPLC进行分析。通过色谱法分离降解产物，并通过光谱法测定其结构。 对上述化合物及其固态降解产物进行了X射线晶体学分析，以了解其光降解机理。发现这些化合物在溶液中以及在固态下经历有效的光化学转化。溶液中的降解是由于光异构化成其E-异构体（III和IV）。固态光降解产物为[2 + 2]-环加成产物（V和VI）。光环化加成产物的立体化学是其单体前体的晶体堆积的指示。RG 13022的光环加成产物具有头-尾键，与晶体中RG 13022分子头-尾堆积的预期一致。然而，发现RG 14620的光环加成产物涉及头对头连接，与RG 14620的头对头晶体堆积一致。含开链烯属双键的药物化合物在晶体中的两个双键之间的距离接近4.2°A时，在固态下对温和的光条件敏感，并且它们具有合适的紫外吸收特性。氯原子间的吸引作用对氯代芳香族化合物的晶体堆积有重要影响。
Purpose. The purpose of this work was to study the photostability of the antiproliferative tyrphostin drug compounds RG 13022(I) and RG 14620(II) as a part of preformulation program.Methods. The compounds were exposed to cool white fluorescent light in solution as well as in the solid state and analyzed by HPLC. The degradation products were isolated chromatographically and their structures determined by spectroscopic methods. X-ray crystallographic analyses of the above compounds and their solid state degradation products were carried out to understand the mechanism of photodegradation.Results. The compounds were found to undergo efficient photochemical transformations in solution as well as in the solid state. The degradation in the solution was due to the photoisomerization into their E-isomers (III and IV). The solid state photodegradation products were [2 + 2]-cycloaddition products (V and VI). The stereochemistry of the photocycloaddition products was indicative of the crystal packing of their monomeric precursors. The photocycloaddition product of RG 13022 possesses the head-to-tail linkage as expected from the head-to-tail packing of RG 13022 molecules in the crystal. The photocycloaddition product of RG 14620, however, was found to involve head-to-head linkage in agreement with the head-to-head crystal packing of RG 14620.Conclusions. Drug compounds containing open chain olefmic double bonds could be sensitive to mild condition of light in the solid state if the distance between the two double bonds in the crystal approaches 4.2°A and they have suitable UV absorption characteristics. Attractive interactions between chlorine atoms have significant influence in controlling the crystal packing of chlorinated aromatic compounds.