Oxysterols from free radical chain oxidation of 7-dehydrocholesterol: product and mechanistic studies.
Oxysterols from free radical chain oxidation of 7-dehydrocholesterol: product and mechanistic studies.
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DOI：
10.1021/ja9080265
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发表时间：
2010-02-24
影响因子：
15
通讯作者：
Porter, Ned A.
中科院分区：
文献类型：
--
作者：
Xu, Libin;Korade, Zeljka;Porter, Ned A.
以2，2′-azobis(4-methoxy-2，4-dimethylvaleronitrile)为引发剂，在37℃苯溶液中进行了高氧化7-脱氢胆固醇的自由基链氧化反应。从7-DHC中分离得到15个氧化甾醇，并用一维和二维核磁共振波谱和质谱学进行了表征。提出了一个涉及C-9和/或C-14上的氢原子抽象的机理来解释所有氧甾醇的形成和反应进程。在H-9或H-14机理中，H-9或H-14被过氧基抽提后形成戊二烯自由基中间体。在这一步之后，在多不饱和脂肪酸的过氧化反应中观察到了很好的先例转化，如氧加成、过氧基5-外环化和石碳基对过氧化键的攻击。7-DHC的过氧化机制也解释了从真菌物种、海洋海绵和仙人掌物种中分离出来的大量氧固醇天然产物的形成。在细胞活力测试中，7-DHC过氧化生成的氧固醇混合物在微摩尔浓度范围内对Neuro2a神经母细胞瘤细胞具有细胞毒性。我们认为，7-DHC的高反应性及其过氧化生成的氧固醇可能在Smith-Lemli-Opitz综合征(SLOS)、X连锁显性点状软骨发育不良(CDPX2)和脑腱黄瘤病(CTX)的发病机制中起重要作用，所有这些都是7-DHC水平升高的代谢紊乱。
Free radical chain oxidation of highly oxidizable 7-dehydrocholesterol (7-DHC) initiated by 2,2′-azobis(4-methoxy-2,4-dimethylvaleronitrile) was carried out at 37°C in benzene for 24 hours. Fifteen oxysterols derived from 7-DHC were isolated and characterized with 1D- and 2D-NMR spectroscopy and mass spectrometry. A mechanism that involves abstraction of hydrogen atoms at C-9 and/or C-14 is proposed to account for the formation of all of the oxysterols and the reaction progress profile. In either the H-9 or H-14 mechanism, a pentadienyl radical intermediate is formed after abstraction of H-9 or H-14 by a peroxyl radical. This step is followed by the well-precedented transformations observed in peroxidation reactions of polyunsaturated fatty acids such as oxygen addition, peroxyl radical 5-exo cyclization, and SHi carbon radical attack on the peroxide bond. The mechanism for peroxidation of 7-DHC also accounts for the formation of numerous oxysterol natural products isolated from fungal species, marine sponges, and cactaceous species. In a cell viability test, the oxysterol mixture from 7-DHC peroxidation was found to be cytotoxic to Neuro2a neuroblastoma cells in the micromolar concentration range. We propose that the high reactivity of 7-DHC and the oxysterols generated from its peroxidation may play important roles in the pathogenesis of Smith-Lemli-Opitz syndrome (SLOS), X-linked dominant chondrodysplasia punctata (CDPX2), and cerebrotendinous xanthomatosis (CTX), all of these being metabolic disorders having an elevated level of 7-DHC.
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影响因子：
1.9
作者：
GARDNER, HW;WEISLEDER, D;KLEIMAN, R
通讯作者：
KLEIMAN, R
影响因子：
4.2
作者：
Honda, M;Tint, GS;Tanaka, N
通讯作者：
Tanaka, N
DOI：
10.1016/0006-291x(77)91674-6
发表时间：
1977-01-01
影响因子：
3.1
作者：
HOLICK, MF;FROMMER, JE;POTTS, JT
通讯作者：
POTTS, JT
影响因子：
4.1
作者：
Berliner, Judith A.;Zimman, Alejandro
通讯作者：
Zimman, Alejandro
影响因子：
2.7
作者：
AIELLO, A;FATTORUSSO, E;MENNA, M
通讯作者：
MENNA, M