1,4-14C-succinic anhydride | 42415-11-2

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: 1,4-14C-succinic anhydride
• 英文别名: 1,4-<14>C-succinic anhydride；<1,4-¹⁴C>succinic anhydride；succinic anhydride (1,4-14C)；Bernsteinsaeureanhydrid-1,4-14C；(2,5-14C2)oxolane-2,5-dione
• CAS: 42415-11-2
• 化学式: C₄H₄O₃
• 分子量: 104.052
• InChiKey: RINCXYDBBGOEEQ-NUQCWPJISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.5
• 重原子数：
  7
• 可旋转键数：
  0
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  43.4
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  1,4-14C-succinic anhydride 、 10-deacetyl-2'-(tert-butyldimethylsilyl)-7-(triethylsilyl) paclitaxel 在 4-二甲氨基吡啶 作用下， 以 甲苯 为溶剂， 反应 20.0h， 以3.9 mg的产率得到4-[[(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-acetyloxy-15-[(2R,3S)-3-benzamido-2-[tert-butyl(dimethyl)silyl]oxy-3-phenylpropanoyl]oxy-2-benzoyloxy-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-9-triethylsilyloxy-6-oxatetracyclo[11.3.1.03,10.04,7]heptadec-13-en-12-yl]oxy]-4-oxo(1,4-14C2)butanoic acid
  参考文献：
  名称：

  Chemical Modification of Paclitaxel (Taxol) Reduces P-Glycoprotein Interactions and Increases Permeation across the Blood−Brain Barrier in Vitro and in Situ

  摘要：

  The purpose of this work was to introduce a chemical modification into the paclitaxel (Taxol) structure to reduce interactions with the product of the multidrug resistant type 1 (MDR1) gene, P-glycoprotein (Pgp), resulting in improved blood-brain barrier (BBB) permeability. Specifically, a taxane analogue, Tx-67, with a succinate group added at the C10 position of Taxol, was synthesized and identified as such a candidate. In comparison studies, Tx-67 had no apparent interactions with Pgp, as demonstrated by the lack of enhanced uptake of rhodamine 123 by brain microvessel endothelial cells (BMECs) in the presence of the agent. By contrast, Taxol exposure substantially enhanced rhodamine 123 uptake by BMECs through inhibition of Pgp. The transport across BMEC monolayers was polarized for both Tx-67 and Taxol with permeation in the apical to basolateral direction greater for Tx-67 and substantially reduced for Taxol relative to basolateral. to apical permeation. Taxol and cyclosporin A treatments also did not enhance Tx-67 permeation across BMEC monolayers. In an in situ rat brain perfusion study, Tx-67 was demonstrated to permeate across the BBB at a greater rate than Taxol. These results demonstrate that the Taxol analogue Tx-67 had a reduced interaction with Pgp and, as a consequence, enhanced permeation across the blood-brain barrier in vitro and in situ.

  DOI：

  10.1021/jm040114b

文献信息

• Synthesis of radiolabeled racemic and enantiomeric antiarrhythmic agents
  作者：Wayne T. Stolle、Lindsay S. Stelzer、Jackson B. Hester、Salvatore C. Perricone、Richard S. P. Hsi

  DOI：10.1002/jlcr.2580341006

  日期：1994.10

  Ibutilide fumarate, racemic N-[4-[4-(ethyl-n-heptylamino)-1-hydroxybutyl]phenyl]methanesulfonamide hemifumarate, and artilide, the R-(+)-enantiomer of N-[4-[4-(di-n-butylalmino)-1-hydroxybutyl]-phenyl]methanesulfonamide hemifumerate, are under clinical investigation as Class III antiarrhythmic agents. For conducting drug disposition studies, we synthesized carbon-14 labeled ibutilide, as well as its two enantiomeric forms. In addition, high specific activity tritium labeled ibutilide was also prepared to facilitate development of a radioimmunoassay and for studying receptor site characteristics of this agent. Results of metabolism studies with [14C]ibutilide led us to prepare tritium labeled artilide, which is more readily accessible than the C-14 labeled drug. The optical antipode of artilide was also labeled with tritium for comparative drug disposition investigations on the two enantiomers.

  富马酸伊布利特、外消旋 N-[4-[4-(乙基-正庚氨基)-1-羟基丁基]苯基]甲磺酰胺半富马酸盐和阿替利特，N-[4-[4-(二正丁基氨基)-1-羟基丁基]-苯基]甲磺酰胺半富马酸盐，作为 III 类抗心律失常药物正在进行临床研究。为了进行药物处置研究，我们合成了碳 14 标记的伊布利特及其两种对映体形式。此外，还制备了高比活性氚标记的伊布利特，以促进放射免疫测定的开发和研究该药物的受体位点特征。 [14C]伊布利特的代谢研究结果使我们制备了氚标记的阿替利特，它比 C-14 标记的药物更容易获得。阿替利特的光学对映体也用氚标记，用于两种对映体的比较药物分布研究。
• Anti-Cocaine Catalytic Antibodies:  A Synthetic Approach to Improved Antibody Diversity
  作者：G. Yang、J. Chun、H. Arakawa-Uramoto、X. Wang、M. A. Gawinowicz、K. Zhao、D. W. Landry

  DOI：10.1021/ja953077+

  日期：1996.1.1

  Catalytic antibodies are potential therapeutic agents for drug overdose and addiction, and we previously reported the first such artificial enzymes to degrade cocaine. However, as described herein, these catalytic monoclonal antibodies (Mab's) were found to have nearly identical complementarity-determining regions (CDR's). Such limited diversity among catalytic antibodies of similar specificity has been reported previously and poses a problem since the capacity of any single group of homologous catalytic antibodies to yield one of high activity, whether through repetitive screening of hybridomas or through antibody mutagenesis, is unpredictable. One strategy to increase the diversity of the immune response to an analog would be to vary the tether site of the immunogenic conjugate thereby exposing unique epitopes for immunorecognition. We now report the syntheses of three immunogenic conjugates of a transition-state analog (TSA) of cocaine benzoyl ester hydrolysis which have identical phosphonate monoester core structures but varying tether sites for attachment to carrier protein: TSA 1 at the methyl ester, TSA 2 at the 4'-phenyl position, and TSA 3 at the tropane nitrogen. Mixed phosphonate diester precursors were obtained from phosphonic dichlorides and ecgonine alkyl esters through our 1H-tetrazole catalysis method. We found that all three analogs provided catalytic antibodies that hydrolyze cocaine at the benzoyl ester; the most active catalytic antibody, Mab 15A10, displayed a rate acceleration (k(cat)/k(uncat) = 2.3 x 10(4)) sufficient to commence preclinical studies. On competitive ELISA, all nine catalytic antibodies, regardless of the eliciting antigen, bound TSA 1 with high affinity but four bound TSA 3 poorly and five failed to bind TSA 2 despite the inhibition of all antibodies by free TSA (TSA 4). A comparison of heavy and of light chain CDR's showed four discrete groups with TSA 1 and 3 each yielding two non-overlapping families of catalytic antibodies; TSA 2 yielded one antibody with CDR's nearly identical to those of the largest group of catalytic antibodies elicited by TSA 1. The failure of TSA 2 and TSA 3 to bind to catalytic antibodies derived from alternative immunogenic conjugates demonstrates that the tether sire does limit the catalytic antibodies produced and supports the general strategy of varying the attachment to carrier protein.
• SAUNDERS, D.;WARRINGTON, B. H., J. LABELLED COMPOUNDS AND RADIOPHARM., 1985, 22, N 9, 869-881
  作者：SAUNDERS, D.、WARRINGTON, B. H.

  DOI：——

  日期：——
• Chiccarelli; Eisner; Van Lear, Arzneimittel Forschung, 1980, vol. 30, # 4 a, p. 728 - 735
  作者：Chiccarelli、Eisner、Van Lear

  DOI：——

  日期：——
• Chemical Modification of Paclitaxel (Taxol) Reduces P-Glycoprotein Interactions and Increases Permeation across the Blood−Brain Barrier in Vitro and in Situ
  作者：Antonie Rice、Yanbin Liu、Mary Lou Michaelis、Richard H. Himes、Gunda I. Georg、Kenneth L. Audus

  DOI：10.1021/jm040114b

  日期：2005.2.1

  The purpose of this work was to introduce a chemical modification into the paclitaxel (Taxol) structure to reduce interactions with the product of the multidrug resistant type 1 (MDR1) gene, P-glycoprotein (Pgp), resulting in improved blood-brain barrier (BBB) permeability. Specifically, a taxane analogue, Tx-67, with a succinate group added at the C10 position of Taxol, was synthesized and identified as such a candidate. In comparison studies, Tx-67 had no apparent interactions with Pgp, as demonstrated by the lack of enhanced uptake of rhodamine 123 by brain microvessel endothelial cells (BMECs) in the presence of the agent. By contrast, Taxol exposure substantially enhanced rhodamine 123 uptake by BMECs through inhibition of Pgp. The transport across BMEC monolayers was polarized for both Tx-67 and Taxol with permeation in the apical to basolateral direction greater for Tx-67 and substantially reduced for Taxol relative to basolateral. to apical permeation. Taxol and cyclosporin A treatments also did not enhance Tx-67 permeation across BMEC monolayers. In an in situ rat brain perfusion study, Tx-67 was demonstrated to permeate across the BBB at a greater rate than Taxol. These results demonstrate that the Taxol analogue Tx-67 had a reduced interaction with Pgp and, as a consequence, enhanced permeation across the blood-brain barrier in vitro and in situ.