(5R,6R)2,3-dicyano-5,6-dimethoxy-5,6-dimethyl-5,6-dihydro-1,4-dioxine | 263331-64-2

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: (5R,6R)2,3-dicyano-5,6-dimethoxy-5,6-dimethyl-5,6-dihydro-1,4-dioxine
• 英文别名: (2R,3R)-5,6-dimethoxy-5,6-dimethyl-1,4-diox-2-ene-2,3-dinitrile；(5R,6R)-2,3-dicyano-5,6-dimethoxy-5,6-dimethyl-1,4-diox-2-ene；38；(5R,6R)-5,6-dimethoxy-5,6-dimethyl-1,4-dioxine-2,3-dicarbonitrile
• CAS: 263331-64-2
• 化学式: C₁₀H₁₂N₂O₄
• 分子量: 224.216
• InChiKey: QXCTVMNTNRNWRK-NXEZZACHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.5
• 重原子数：
  16
• 可旋转键数：
  2
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  84.5
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (5R,6R)2,3-dicyano-5,6-dimethoxy-5,6-dimethyl-5,6-dihydro-1,4-dioxine 在 碘 、 magnesium 、 溶剂黄146 作用下， 以 正丁醇 为溶剂， 反应 14.17h， 生成 (21R,22R)-21,22-dimethoxy-21,22-dimethyl-4,5,9,10,14,15-hexapropyl-20,23-dioxa-2,7,12,17,25,26,27,28-octazahexacyclo[16.6.1.13,6.18,11.113,16.019,24]octacosa-1(24),2,4,6,8(27),9,11,13(26),14,16,18-undecaene
  参考文献：
  名称：

  卟啉嗪二醇：IVB族金属茂的合成，表征和络合。

  摘要：

  由（L）-（+）-酒石酸二甲酯通过转化为相应的排料或由2,3-二甲氧基-2,3-丁二基保护的2,3-二羟基马来腈，Linstead大环化，反金属化和脱保护。它们的稳定性非常依赖于卟啉腔中金属离子的性质。这些卟啉嗪二醇与茂金属二氯化物的反应产生了新的单卟啉卟啉12，而DDQ氧化然后用二氨基马来腈捕获则得到了新的卟啉嗪二腈14。

  DOI：

  10.1021/jo9916840
• 作为产物：
  描述：

  (2R,3R,5R,6R)-5,6-dimethoxy-5,6-dimethyl[1,4]dioxane-2,3-dicarboxylic acid dimethyl ester 在 吡啶 、 2,2,6,6-tetramethylpiperidinyl-lithium 、 氨 、 碘 、 三氟乙酸酐 作用下， 以 四氢呋喃 、 甲醇 、 正己烷 为溶剂， 反应 98.0h， 生成 (5R,6R)2,3-dicyano-5,6-dimethoxy-5,6-dimethyl-5,6-dihydro-1,4-dioxine
  参考文献：
  名称：

  卟啉嗪二醇：IVB族金属茂的合成，表征和络合。

  摘要：

  由（L）-（+）-酒石酸二甲酯通过转化为相应的排料或由2,3-二甲氧基-2,3-丁二基保护的2,3-二羟基马来腈，Linstead大环化，反金属化和脱保护。它们的稳定性非常依赖于卟啉腔中金属离子的性质。这些卟啉嗪二醇与茂金属二氯化物的反应产生了新的单卟啉卟啉12，而DDQ氧化然后用二氨基马来腈捕获则得到了新的卟啉嗪二腈14。

  DOI：

  10.1021/jo9916840

文献信息

• Chiral porphyrazine near-IR optical imaging agent exhibiting preferential tumor accumulation
  作者：Evan R. Trivedi、Allison S. Harney、Mary B. Olive、Izabela Podgorski、Kamiar Moin、Bonnie F. Sloane、Anthony G.M. Barrett、Thomas J. Meade、Brian M. Hoffman

  DOI：10.1073/pnas.0912811107

  日期：2010.1.26

  A chiral porphyrazine (pz), H ₂ [pz( trans - A ₂ B ₂ )] (247), has been prepared that exhibits preferential in vivo accumulation in the cells of tumors. Pz 247 exhibits near-infrared (NIR) emission with λ  > 700 nm in the required wavelength range for maximum tissue penetration. When MDA-MB-231 breast tumor cells are treated with 247, the agent shows strong intracellular fluorescence with an emission maximum, 704 nm, which indicates that it localizes within a hydrophobic microenvironment. Pz 247 is shown to associate with the lipophilic core of LDL and undergo cellular entry primarily through receptor-mediated endocytosis accumulating in lysosomes. Preliminary in vivo studies show that 247 exhibits preferential accumulation and retention in the cells of MDA-MB-231 tumors subcutaneously implanted in mice, thereby enabling NIR optical imaging with excellent contrast between tumor and surrounding tissue. The intensity of fluorescence from 247 within the tumor increases over time up to 48 h after injection presumably due to the sequestration of circulating 247/LDL complex by the tumor tissue. As the need for cholesterol, and thus LDL, is elevated in highly proliferative tumor cells over nontumorigenic cells, 247 has potential application for all such tumors.

  已制备出手性卟啉（pz）H2[pz（trans-A2B2）]（247），在体内表现出对肿瘤细胞的优先积累。Pz 247表现出近红外（NIR）发射，波长范围在要求的700 nm以上，以达到最大组织穿透深度。当MDA-MB-231乳腺肿瘤细胞接受247处理时，该剂量显示出强烈的胞内荧光，发射峰值为704 nm，表明它定位于一个疏水微环境内。研究表明，Pz 247与LDL的疏水性核心相结合，并主要通过受体介导的内吞作用进入细胞，积累在溶酶体内。初步的体内研究表明，247在小鼠皮下植入的MDA-MB-231肿瘤细胞中表现出优先积累和保留，从而实现了NIR光学成像，肿瘤和周围组织之间的对比度极佳。肿瘤内247的荧光强度随时间增加，48小时后注射，可能是由于肿瘤组织通过固定循环的247 / LDL复合物而产生。由于高度增殖性的肿瘤细胞需要胆固醇和LDL，因此247具有潜在的应用价值。
• Porphyrazine-chemotherapeutic agents conjugates
  申请人：Hoffman/Barrett, L.L.C.

  公开号：EP2599497A2

  公开（公告）日：2013-06-05

  Conjugates of Porphyrazines capable of localizing in a tumor of a mammal are disclosed. The porphyrazines are used in methods of imaging a tumor and in methods of treating tumors, in combination with a chemotherapeutic agent and/or radiation.

  本发明公开了能够在哺乳动物肿瘤中定位的卟吩嗪类共轭物。卟嗪类化合物与化疗药物和/或放射线结合使用，可用于肿瘤成像方法和肿瘤治疗方法。
• Multi-gram synthesis of a porphyrazine platform for cellular translocation, conjugation to Doxorubicin, and cellular uptake
  作者：Evan R. Trivedi、Carl M. Blumenfeld、Todd Wielgos、Sharon Pokropinski、Prasad Dande、Ton T. Hai、Anthony G.M. Barrett、Brian M. Hoffman

  DOI：10.1016/j.tetlet.2012.07.087

  日期：2012.10

  We report the synthesis of the near infrared (NIR) fluorescent porphyrazine (Pz) 285, with pendant hydroxyl groups, as a non-toxic platform for delivery of conjugated chemotherapeutic agents to tumor cells. Conjugation of Pz 285 to Doxorubicin via an acid labile linker and initial biological studies are reported. (C) 2012 Elsevier Ltd. All rights reserved.
• Chiral<i>bis</i>-Acetal Porphyrazines as Near-infrared Optical Agents for Detection and Treatment of Cancer
  作者：Evan R. Trivedi、Benjamin J. Vesper、Hana Weitman、Benjamin Ehrenberg、Anthony G.M. Barrett、James A. Radosevich、Brian M. Hoffman

  DOI：10.1111/j.1751-1097.2009.00681.x

  日期：2010.3

  AbstractWe report the preparation of chiral oxygen atom‐appended porphyrazines (pzs) as biomedical optical agents that absorb and emit in the near‐IR wavelength range. These pzs take the form M[pz(A4‐nBn)], where “A” and “B” represent moieties appended to the pz’s pyrrole entities, A = (2R,3R) 2,3‐dimethyl‐2,3‐dimethoxy‐1,4‐diox‐2‐ene, B = β,β′‐di‐isopropoxybenzo, M is the incorporated metal ion (M = H2, Zn), and n = 0, 1, 2 (‐cis/‐trans) and 3 (Scheme 1). When dissolved in polar media, H2[pz(trans‐A2B2)] 5a does not fluoresce and has a negligible quantum yield for singlet oxygen generation (ФΔ = 0.074 ± 0.001, methanol), as measured by the photo‐oxidation of DMA. However, when sequestered in the nonpolar environment of a liposome, it displays strong NIR emission (λmax = 705 nm, Фf = 0.087) and an extremely high singlet oxygen quantum yield (ФΔ→1). Of this series, H2[pz(trans‐A2B2)] 5a is attractive as a potential optical probe, showing strongly fluorescent uptake by cells in culture, while 3‐[4,5‐dimethylthiazol‐2‐yl]‐2,5‐diphenyltetrazolium bromide measurements of cell viability show no evidence of dark toxicity. This agent does show significant photoinduced toxicity suggesting that pzs such as 5a have promise as “theranostic” optical agents that can be visualized with fluorescence imaging while acting as a sensitizer for photodynamic therapy. Synthesis of Porphyrazines 3a–7a, 3b–7b.image
• Discovery of the Antitumor Effects of a Porphyrazine Diol (Pz 285) in MDA-MB-231 Breast Tumor Xenograft Models in Mice
  作者：Irawati K. Kandela、Katherine J. McAuliffe、Lauren E. Cochran、Anthony G. M. Barrett、Brian M. Hoffman、Andrew P. Mazar、Evan R. Trivedi

  DOI：10.1021/acsmedchemlett.7b00063

  日期：2017.7.13

  A series of porphyrazines (Pzs) with chiral bis-acetal moieties in the beta-pyrrole positions ((2R,3R)-2,3-dimethyl-2,3dimethoxy-1,4-diox-2-ene) have been synthesized and screened as antitumor agents in MDA-MB-231 breast tumor cells in vitro. The lead Pz 285 was further tested in a mouse tumor xenograft model with Td-tomato-luc2 fluorescent breast tumor cells (MDA-MB-231 LM24 Her2+) that are highly metastatic to the lungs. Pz 285 shows marked antitumor effects in vivo, with treated mice exhibiting longer median survival that we attribute to smaller primary tumor regrowth after resection and less occurrence of metastasis when compared to vehicle control groups. Pz 285 is further compared to the clinically approved chemotherapeutic doxorubicin (Dox). This report lays the groundwork for development of an understudied class of compounds for classical chemotherapy.