trans-α-acetoxytamoxifen | 205924-32-9

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 二苯乙烯类
• 英文名称: trans-α-acetoxytamoxifen
• 英文别名: (E)-α-acetoxytamoxifen；α-acetoxytamoxifen；(E)-1-[4-[2-(dimethylamino)ethoxy]phenyl]-1,2-diphenyl-1-buten-3-yl acetate；alpha-Acetoxytamoxifen；[(E)-4-[4-[2-(dimethylamino)ethoxy]phenyl]-3,4-diphenylbut-3-en-2-yl] acetate
• CAS: 205924-32-9
• 化学式: C₂₈H₃₁NO₃
• 分子量: 429.559
• InChiKey: WPNNUCSYTLOQFN-DQSJHHFOSA-N

物化性质

• 沸点：
  565.1±50.0 °C(Predicted)
• 密度：
  1.092±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  6.4
• 重原子数：
  32
• 可旋转键数：
  10
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  38.8
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  trans-α-acetoxytamoxifen 以 水 为溶剂， 生成 tamoxifen cation
  参考文献：
  名称：

  Reaction of the tamoxifen cation and the bis-(4-methoxyphenyl)methyl cation in aqueous solutions containing 2'-deoxyguanosine

  摘要：

  2'-脱氧鸟苷（dG）与水之间的竞争已经定量评估了从他莫昔芬衍生的烯丙基碳离子和稳定的二芳基甲基阳离子（双（4-甲氧基苯基）甲基）中。这两个系统都通过竞争动力学方法进行了研究，在其中，在含有核苷的水溶液中，对应的乙酸酯经S_N1溶解后，产物被定量分析。两个阳离子与dG的反应的主要产物是NH₂基团的加合物，这是离域化碳离子的特征。他莫昔芬阳离子也通过激光闪光光解法进行了研究，获得了与dG和水反应的绝对速率常数，并转化为速率常数比。这项研究的主要结果是，在这些阳离子与dG和其共轭碱的中性形式之间的反应性存在三个数量级的差异。在反应发生于中性dG的酸性条件下，鸟嘌呤-水选择性较低。即使在相对高浓度的dG下，大多数产物也是来自水反应的醇。相比之下，在pH 10到11之间，dG以阴离子的形式存在，这是高度竞争的。可以获得高达90％的加合物收率。反应性差异巨大的一个结果是，在中性pH下，阳离子与dG的大多数反应实际上是通过少量存在的共轭碱进行的。结果的另一个特征是，NH₂加合物是来自阴离子的主要稳定产物。为了解释形成该产物的反应速率常数高的原因，提出了一种机理，其中NH₂基团的一个质子在N1形成N2-阳离子键时被转移。关键词：鸟嘌呤，DNA加合物，碳离子，他莫昔芬。

  DOI：

  10.1139/v02-011

文献信息

• The tamoxifen cation reacts to give indene products
  作者：Cristina Sanchez、Robert A McClelland

  DOI：10.1139/v00-122

  日期：2000.9.1

  The tamoxifen carbocation (Ph(Ar)C=CPh-CH⁺-CH₃, Ar = 4-Me₂NCH₂CH₂OC₆H₄) is generated from acetate and sulfate precursors by S_N1 ionization in water. The cation exists in (E) and (Z) forms which equilibrate before reaction. The major products are the α-hydroxytamoxifens Ph(Ar)C=CPh-CHOH-CH₃, both (E) 64% and (Z) 29%, with the ratio independent of the configuration of the starting ester. Two minor products with a total yield of 7% account for the rest of the products. These have been characterized as indenes derived from intramolecular cyclization, a 4.5% yield of the indene derived from cyclization into the Ar ring with 2.5% due to cyclization into the phenyl ring. Experiments in acid solutions (0.01-0.1 M HCl) starting with pure (E)- or (Z)-α-hydroxytamoxifen reveal that the two alcohols equilibrate. This occurs by H⁺-catalyzed formation of the carbocation followed by water capture. Occurring about 10-fold slower than this isomerization is an irreversible process resulting in the two indenes. This cyclization will result in the destruction of the α-hydroxytamoxifens upon exposure to acidic conditions and also makes the direct observation of the tamoxifen carbocation under super-acid conditions difficult, if not impossible. The indenes do form in low yield whenever the tamoxifen carbocation is generated from an S_N1 precursor. Thus these products could serve as markers for the formation of the tamoxifen carbocation in cellular systems or in in vivo experiments.Key words: carbocation, indene, allylic cation, isomerization.

  他莫昔芬卡阳离子（Ph（Ar）C=CPh-CH⁺-CH₃，Ar = 4-Me₂NCH₂CH₂OC₆H₄）是由乙酸盐和硫酸盐前体在水中通过S_N1电离生成的。这个阳离子存在（E）和（Z）形式，在反应前平衡。主要产物是α-羟基他莫昔芬Ph（Ar）C=CPh-CHOH-CH₃，分别为（E）64%和（Z）29%，比例与起始酯的构型无关。两种产物的总产率为7%，其余的产品为两种次要产物。这些次要产物已被确定为由分子内环化衍生的茚烯，其中4.5%的产率来自于环化成Ar环的茚烯，2.5%来自于环化成苯环的茚烯。在酸性溶液（0.01-0.1 M HCl）中进行的实验，从纯（E）或（Z）-α-羟基他莫昔芬开始，显示这两种醇会平衡。这是通过H⁺催化形成卡阳离子，然后被水捕获来实现的。比这种异构化慢大约10倍的是一个不可逆过程，导致两种茚烯的形成。这种环化将导致α-羟基他莫昔芬在酸性条件下暴露时被破坏，并且使在超酸条件下直接观察他莫昔芬卡阳离子变得困难，甚至不可能。每当他莫昔芬卡阳离子由S_N1前体生成时，茚烯都会以低产率形成。因此，这些产物可以作为细胞系统或体内实验中他莫昔芬卡阳离子形成的标志。关键词：卡阳离子，茚烯，烯丙基阳离子，异构化。
• Tamoxifen−DNA Adducts Formed by α-Acetoxytamoxifen <i>N</i>-Oxide
  作者：Atsushi Umemoto、Yasumasa Monden、Kansei Komaki、Masato Suwa、Yoshikazu Kanno、Masanobu Suzuki、Chun-Xing Lin、Yuji Ueyama、Md. Abdul Momen、Anisetti Ravindernath、Shinya Shibutani

  DOI：10.1021/tx990132+

  日期：1999.11.1

  DNA adduct formation is assumed to be a major carcinogenic event, leading to the development of endometrial cancer in breast cancer patients taking tamoxifen and healthy women enrolled in a tamoxifen chemopreventive trial. To determine whether DNA adducts were formed by tamoxifen, trans- and cis-alpha-acetoxytamoxifen N-oxides were synthesized as model-activated forms via major tamoxifen metabolites, tamoxifen N-oxide and alpha-hydroxytamoxifen N-oxide. When alpha-acetoxytamoxifen N-oxide was reacted with human DNA, at least three DNA adducts were detected by P-32-postlabeling coupled with HPLC. The total amount of DNA adducts formed by trans-alpha-hydroxytamoxifen N-oxide was 1.5-fold higher than that formed by the cis form. Both trans- and cis-alpha-acetoxytamoxifen N-oxide reacted with 2'-deoxyguanosine, resulting in the formation of three adducts (fr-1, fr-2-1, and fr-2-2). These products were studied using mass spectroscopy and proton magnetic resonance spectroscopy. fr-1 was identified as a mixture of the epimers of trans-alpha-(N-2-deoxyguanosinyl)tamoxifen N-oxide. fr-2-1 and fr-2-2 were determined to be epimers of cis-alpha-(N-2-deoxyguanosinyl)tamoxifen N-oxide.
• Reaction of the tamoxifen cation and the bis-(4-methoxyphenyl)methyl cation in aqueous solutions containing 2<i>'</i>-deoxyguanosine
  作者：Robert A McClelland、Cristina Sanchez、Effiette Sauer、Sinisa Vukovic

  DOI：10.1139/v02-011

  日期：2002.3.1

  The competition between 2'-deoxyguanosine (dG) and water has been quantitatively evaluated for the allylic carbocation derived from tamoxifen and for the stabilized diarylmethyl cation (bis-(4-methoxyphenyl)methyl). Both systems were examined by the competition kinetics method, in which the products were quantitatively analyzed after the S_N1 solvolysis of the corresponding acetate esters in aqueous solutions containing the nucleoside. The principal product of the reaction of both cations with dG is the adduct at the NH₂ group, a characteristic of delocalized carbocations. The tamoxifen cation was also examined by laser flash photolysis, with absolute rate constants for the reaction with dG and water being obtained and converted into rate constant ratios. The principal result of this study is that there is a three orders of magnitude difference in the reactivity of these cations towards the neutral form of dG and its conjugate base. Under acidic conditions where the reaction occurs with neutral dG, the guanine–water selectivity is low. Even at relatively high concentrations of dG, the majority of the product is alcohol derived from the water reaction. At pH 10 to 11, in contrast, dG is present as the anion and this is highly competitive. Yields of adduct as high as 90% can be attained. A consequence of the large difference in reactivities is that at neutral pH the majority of the reaction of the cation with dG is actually occurring via the small amount of conjugate base present. A further feature of the results is that the NH₂ adduct is the predominant stable product from the anion. To explain the high rate constant for the reaction forming this product, a mechanism is proposed whereby one of the protons of the NH₂ group is transferred to N1 as the N2-cation bond is forming.Key words: guanine, DNA adduct, carbocation, tamoxifen.

  2'-脱氧鸟苷（dG）与水之间的竞争已经定量评估了从他莫昔芬衍生的烯丙基碳离子和稳定的二芳基甲基阳离子（双（4-甲氧基苯基）甲基）中。这两个系统都通过竞争动力学方法进行了研究，在其中，在含有核苷的水溶液中，对应的乙酸酯经S_N1溶解后，产物被定量分析。两个阳离子与dG的反应的主要产物是NH₂基团的加合物，这是离域化碳离子的特征。他莫昔芬阳离子也通过激光闪光光解法进行了研究，获得了与dG和水反应的绝对速率常数，并转化为速率常数比。这项研究的主要结果是，在这些阳离子与dG和其共轭碱的中性形式之间的反应性存在三个数量级的差异。在反应发生于中性dG的酸性条件下，鸟嘌呤-水选择性较低。即使在相对高浓度的dG下，大多数产物也是来自水反应的醇。相比之下，在pH 10到11之间，dG以阴离子的形式存在，这是高度竞争的。可以获得高达90％的加合物收率。反应性差异巨大的一个结果是，在中性pH下，阳离子与dG的大多数反应实际上是通过少量存在的共轭碱进行的。结果的另一个特征是，NH₂加合物是来自阴离子的主要稳定产物。为了解释形成该产物的反应速率常数高的原因，提出了一种机理，其中NH₂基团的一个质子在N1形成N2-阳离子键时被转移。关键词：鸟嘌呤，DNA加合物，碳离子，他莫昔芬。