分析光不安定性藥物在光解過程中和維生素C的相互作用:新化合物之純化，結構鑑定與化學反應機轉之確立

Studies on the Interactions between Photo-sensitive Dihydropyridine Drugs and Vitamin C : Characterization of the New Compounds and Mechanism of the Interactions

楊凱勝(Yang Kai-Sheng)

指導教授 ： 程中玉

國立中正大學/理學院/化學暨生物化學系/碩士(2013年)

摘要

本研究主要以液相層析技術 (HPLC) 及電噴灑質譜儀 (ESI-MS) 來分析確定 Dihydropyridine (1,4-DHP) 類降血壓藥物與 Vitamin C 在光照射環境下進行的光解化學反應機轉，並進行新化合物純化及結構確定。
第一部份研究目前醫院中常被用來作為降血壓的鈣離子通道阻斷劑 Nifedipine (NF)，此藥物具有光不安定性而在紫外光及白晝光刺激情況下會產生結構變化，甚至有光毒性之疑慮；在它的光解產物方面，目前大部分研究報告只在有限的研究中指出其藥物曝露於光環境下亦會光解形成產物為 -nitro (-NO2) 或 -nitroso (-NO) 衍生物。由於 1,4-DHP 藥物對光刺激非常敏感，我們發現高血壓患者在未避光環境下誤食此藥物可能導致與人體內血清和肝組織中的 Vitamin C 作用，因此本研究第一階段主要針對在 Vitamin C 環境中與 1,4-DHP 降血壓藥物之間的相互作用進行實驗;其中我們發現到 NF 在光解的過程中可與 Vitamin C 進行化學反應，這變化在 UV-Vis 光譜上的 280 nm 與 310 nm 波長最為明顯；而控制組結果表示這變化是來自於 Vitamin C。這個未知反應可以是 NF 與 Vitamin C 在光照進行中形成兩者的複合物或是一個具新結構化合物的生成，非常具有深入探討化學與藥學上的價值。因此我們將對於這新反應分析和確定其化學反應機轉；同時也對新生成的化合物進行純化與結構鑑定。
第二部份中我們也進行分析與 NF 同屬 1,4-DHP 結構苯環鄰位硝基 (-NO2) 取代的藥物 Nisoldipine (NS) 與 Vitamin C 產生此種反應的可能性，另外也將以一個結構為苯環間位硝基 (-NO2) 取代的藥物 Nimodipine (NM) 作為本實驗對照組進行比較，且探討 Vitamin C 在這些藥物光照反應實驗中扮演的主要角色，值得分析這些新化合物和三種鈣離子阻斷劑藥物在活性上的改變。由於 NF 對動脈粥樣化之影響現在已經知道，但在光解過程中與 Vitamin C 產生的新化合物對動脈粥樣化之影響則仍未知，因此這些新化合物在成為改善 atherosclerosis 上可能是新潛力的藥物。

關鍵詞: nifedipine, nisoldipine, nimodipine, 1,4-DHP, vitamin C, ESI-MS, UV-Vis

並列摘要

This study used high performance liquid chromatography (HPLC) and electrospray ionization mass spectrometry (ESI-MS) to analyze the interactions between dihydropyridine (1,4-DHP) drug after photodegradation and vitamin C (VitC), and to purify and characterize the after formed new compounds.
In the first part, a study on a calcium channel blocker Nifedipine (NF), currently used as an antihypertensive drug, is conducted. This photo-sensitive drug undergoes conformational changes and may even become photo-toxic after UV light and sunlight exposure. In terms of photodegradation products, only limited studies indicated that NF under light exposure would transform into -nitro (-NO2) or -nitroso (-NO) derivatives. Considering the some 1,4-DHP drug is very photo-sensitive, if patients with hypertension took this medication without protection from light exposure will lead an interaction between photodegraded 1,4-DHP and VitC in human serum and liver tissues. Therefore, the first part of the study aimed to investigate the interactions between VitC and 1,4-DHP antihypertensive drug under light or UV exposure. We found that during photodegradation of NF, a specific reaction with VitC occurred and was most prominent changes at 280 and 310 nm wavelengths of UV-Vis spectrum were observed. The results of control group revealed that the spectral changes originated in precence of VitC. This unknown reaction could come from a compound photosynthesized by NF and VitC, or a brand new synthesis, which is very valuable for farther chemical and pharmaceutical research. Hence we will analyze this new reaction and ascertain its chemical mechanism, as well as purity and identify the newly synthesized compound.
In the second part, we investigated the possibility of proceeding the interaction to VitC by replacing another photosensitive 1,4-DHP medicine, Nisoldipine (NS), with an ortho-nitro (-NO2) base. An analog, Nimodipine (NM), a 1,4-DHP with meta-nitro (-NO2) group, was used as a control. Moreover, for safety concerns, an examination on the changes of activity levels of the new compound to other calcium channel blockers will be performed. Since the effects of NF on atherosclerosis were known, it is also valuable to see the influences of the new compounds on atherosclerosis. These new compounds may become a potential new medicine with effectiveness on hypertension or atherosclerosis.

Keywords: nifedipine, nisoldipine, nimodipine, 1,4-DHP, vitamin C, ESI-MS, UV-Vis

並列關鍵字

vitamin C ； 1,4-DHP ； nimodipine ； nisoldipine ； nifedipine ； ESI-MS ； UV-Vis

參考文獻

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