（+）-石房蛤毒素天然衍生物（包括 11-石房蛤毒素乙醇酸）的发散合成。
Divergent Synthesis of Natural Derivatives of (+)-Saxitoxin Including 11-Saxitoxinethanoic Acid.
机构信息
SAFC, Inc., 645 Science Dr., Madison, WI, 53711, USA.
Gilead Sciences, 333 Lakeside Dr., Foster City, CA, 94404, USA.
出版信息
Angew Chem Int Ed Engl. 2019 Feb 4;58(6):1689-1693. doi: 10.1002/anie.201811717. Epub 2019 Jan 2.
Abstract
The bis-guanidinium toxins are a collection of natural products that display nanomolar potency against select isoforms of eukaryotic voltage-gated Na ion channels. We describe a synthetic strategy that enables access to four of these poisons, namely 11-saxitoxinethanoic acid, C13-acetoxy saxitoxin, decarbamoyl saxitoxin, and saxitoxin. Highlights of this work include an unusual Mislow-Evans rearrangement and a late-stage Stille ketene acetal coupling. The IC value of 11-saxitoxinethanoic acid was measured against rat Na 1.4, and found to be 17.0 nm, similar to those of the sulfated toxins gonyautoxin II and III.
摘要
双胍毒素是一组天然产物，对真核电压门控 Na 离子通道的某些同工型具有纳摩尔效力。我们描述了一种合成策略，可获得其中的四种毒素，即 11-石房蛤毒素乙醇酸、C13-乙酰氧基石房蛤毒素、脱氨甲酰石房蛤毒素和石房蛤毒素。这项工作的重点包括不寻常的 Mislow-Evans 重排和晚期的 Stille 酮烯醇缩合。11-石房蛤毒素乙醇酸对大鼠 Na 1.4 的 IC 值进行了测量，发现为 17.0nm，与硫酸化毒素 GTX2 和 GTX3 的相似。
相似文献
1
Divergent Synthesis of Natural Derivatives of (+)-Saxitoxin Including 11-Saxitoxinethanoic Acid.（+）-石房蛤毒素天然衍生物（包括 11-石房蛤毒素乙醇酸）的发散合成。
Angew Chem Int Ed Engl. 2019 Feb 4;58(6):1689-1693. doi: 10.1002/anie.201811717. Epub 2019 Jan 2.
2
A Direct C11 Alkylation Strategy on the Saxitoxin Core: A Synthesis of (+)-11-Saxitoxinethanoic Acid.在石房蛤毒素核心上的直接 C11 烷基化策略：（+）-11-石房蛤毒素乙醇酸的合成。
Org Lett. 2019 Oct 4;21(19):7999-8002. doi: 10.1021/acs.orglett.9b02986. Epub 2019 Sep 25.
3
Synthesis of the Paralytic Shellfish Poisons (+)-Gonyautoxin 2, (+)-Gonyautoxin 3, and (+)-11,11-Dihydroxysaxitoxin.麻痹性贝类毒素 (+)-GTX2、(+)-GTX3 和 (+)-11,11-二羟基石房蛤毒素的合成。
J Am Chem Soc. 2016 May 11;138(18):5994-6001. doi: 10.1021/jacs.6b02343. Epub 2016 May 3.
4
Saxitoxin.石房蛤毒素。
Angew Chem Int Ed Engl. 2014 Jun 2;53(23):5760-84. doi: 10.1002/anie.201308235. Epub 2014 Apr 25.
5
Synthetic Approaches to Zetekitoxin AB, a Potent Voltage-Gated Sodium Channel Inhibitor.泽替毒素 AB 的合成方法，一种有效的电压门控钠离子通道抑制剂。
Mar Drugs. 2019 Dec 26;18(1):24. doi: 10.3390/md18010024.
6
Total Synthesis of 11-Saxitoxinethanoic Acid and Evaluation of its Inhibitory Activity on Voltage-Gated Sodium Channels.11-脱磺基石房蛤毒素乙醇酸的全合成及其对电压门控钠离子通道抑制活性的评价。
Angew Chem Int Ed Engl. 2016 Sep 12;55(38):11600-3. doi: 10.1002/anie.201604155. Epub 2016 Aug 11.
7
Synthesis of saxitoxin derivatives bearing guanidine and urea groups at C13 and evaluation of their inhibitory activity on voltage-gated sodium channels.合成在 C13 位带有胍基和脲基的石房蛤毒素衍生物，并评估它们对电压门控钠离子通道的抑制活性。
Org Biomol Chem. 2013 Oct 14;11(38):6642-9. doi: 10.1039/c3ob41398e. Epub 2013 Aug 30.
8
Total synthesis of (+)-decarbamoylsaxitoxin and (+)-gonyautoxin 3.(+)-去氨甲酰基石房蛤毒素和 (+)-GTX3 的全合成。
Org Lett. 2010 May 7;12(9):2150-3. doi: 10.1021/ol1006696.
9
Silylpyrrole Oxidation En Route to Saxitoxin Congeners Including 11-Saxitoxinethanoic Acid.硅基吡咯氧化反应生成沙克毒素类似物，包括 11-沙克毒素乙醇酸。
J Org Chem. 2021 Dec 17;86(24):17790-17803. doi: 10.1021/acs.joc.1c02116. Epub 2021 Dec 7.
10
A synthesis of (+)-saxitoxin.（+）-石房蛤毒素的合成。
J Am Chem Soc. 2006 Mar 29;128(12):3926-7. doi: 10.1021/ja0608545.
引用本文的文献
1
Dearomative Mislow-Braverman-Evans Rearrangement of Aryl Sulfoxides.芳基亚砜的去芳构化米斯洛-布雷弗曼-埃文斯重排反应
JACS Au. 2025 Feb 5;5(2):998-1006. doi: 10.1021/jacsau.4c01238. eCollection 2025 Feb 24.
2
Synthesis of Saxitoxin Biosynthetic Intermediates: Reveal the Mechanism for Formation of its Tricyclic Skeleton in Biosynthesis.石房蛤毒素生物合成中间体的合成：揭示其生物合成中三环骨架形成的机制。
Chem Asian J. 2024 Dec 16;19(24):e202400834. doi: 10.1002/asia.202400834. Epub 2024 Oct 31.
3
Base-Induced Sulfoxide-Sulfenate Rearrangement of 2-Sulfinyl Dienes for the Regio- and Stereoselective Synthesis of Enantioenriched Dienyl Diols.基于碱基诱导的 2-亚磺酰二烯的亚砜-亚磺酸盐重排反应，用于区域和立体选择性合成对映富集的二烯基二醇。
J Org Chem. 2023 Mar 17;88(6):3697-3713. doi: 10.1021/acs.joc.2c02931. Epub 2023 Mar 3.
4
Discovery of Selective Inhibitors of Na1.7 Templated on Saxitoxin as Therapeutics for Pain.以石房蛤毒素为模板发现选择性Na1.7抑制剂作为疼痛治疗药物
ACS Med Chem Lett. 2022 Oct 18;13(11):1763-1768. doi: 10.1021/acsmedchemlett.2c00378. eCollection 2022 Nov 10.
5
Silylpyrrole Oxidation En Route to Saxitoxin Congeners Including 11-Saxitoxinethanoic Acid.硅基吡咯氧化反应生成沙克毒素类似物，包括 11-沙克毒素乙醇酸。
J Org Chem. 2021 Dec 17;86(24):17790-17803. doi: 10.1021/acs.joc.1c02116. Epub 2021 Dec 7.
6
Salinity Affects Saxitoxins (STXs) Toxicity in the Dinoflagellate , with Low Transcription of SXT-Biosynthesis Genes and .盐度影响甲藻中的麻痹性贝类毒素（STXs）毒性，导致 SXT 生物合成基因和 的转录水平降低。
Toxins (Basel). 2021 Oct 18;13(10):733. doi: 10.3390/toxins13100733.
7
Discovery of a selective, state-independent inhibitor of Na1.7 by modification of guanidinium toxins.通过胍毒素修饰发现一种对钠离子通道 Na1.7 具有选择性和状态独立性的抑制剂。
Sci Rep. 2020 Sep 9;10(1):14791. doi: 10.1038/s41598-020-71135-2.
8
Identification of promoter elements in the Dolichospermum circinale AWQC131C saxitoxin gene cluster and the experimental analysis of their use for heterologous expression.鉴定螺旋鱼腥藻 AWQC131C 石房蛤毒素基因簇中的启动子元件及其用于异源表达的实验分析。
BMC Microbiol. 2020 Feb 17;20(1):35. doi: 10.1186/s12866-020-1720-3.
9
Biosynthesis of Saxitoxin in Marine Dinoflagellates: An Omics Perspective.海洋甲藻中石房蛤毒素的生物合成：组学视角。
Mar Drugs. 2020 Feb 5;18(2):103. doi: 10.3390/md18020103.
10
Synthetic Approaches to Zetekitoxin AB, a Potent Voltage-Gated Sodium Channel Inhibitor.泽替毒素 AB 的合成方法，一种有效的电压门控钠离子通道抑制剂。
Mar Drugs. 2019 Dec 26;18(1):24. doi: 10.3390/md18010024.
本文引用的文献
1
A Synthetic Strategy for Saxitoxin Skeleton by a Cascade Bromocyclization: Total Synthesis of (+)-Decarbamoyl-α-saxitoxinol.通过级联溴环化反应构建石房蛤毒素骨架的合成策略：（+）-去甲氨甲酰基-α-石房蛤毒素醇的全合成。
Org Lett. 2016 Dec 16;18(24):6368-6371. doi: 10.1021/acs.orglett.6b03262. Epub 2016 Dec 5.
2
Total Synthesis of 11-Saxitoxinethanoic Acid and Evaluation of its Inhibitory Activity on Voltage-Gated Sodium Channels.11-脱磺基石房蛤毒素乙醇酸的全合成及其对电压门控钠离子通道抑制活性的评价。
Angew Chem Int Ed Engl. 2016 Sep 12;55(38):11600-3. doi: 10.1002/anie.201604155. Epub 2016 Aug 11.
3
Mutant cycle analysis with modified saxitoxins reveals specific interactions critical to attaining high-affinity inhibition of hNaV1.7.使用修饰后的石房蛤毒素进行突变循环分析揭示了对实现hNaV1.7的高亲和力抑制至关重要的特定相互作用。
Proc Natl Acad Sci U S A. 2016 May 24;113(21):5856-61. doi: 10.1073/pnas.1603486113. Epub 2016 May 9.
4
Synthesis of the Paralytic Shellfish Poisons (+)-Gonyautoxin 2, (+)-Gonyautoxin 3, and (+)-11,11-Dihydroxysaxitoxin.麻痹性贝类毒素 (+)-GTX2、(+)-GTX3 和 (+)-11,11-二羟基石房蛤毒素的合成。
J Am Chem Soc. 2016 May 11;138(18):5994-6001. doi: 10.1021/jacs.6b02343. Epub 2016 May 3.
5
Saxitoxin.石房蛤毒素。
Angew Chem Int Ed Engl. 2014 Jun 2;53(23):5760-84. doi: 10.1002/anie.201308235. Epub 2014 Apr 25.
6
Modular Synthesis of the Pentacyclic Core of Batrachotoxin and Select Batrachotoxin Analogue Designs.蟾毒素五环核心的模块化合成及选定的蟾毒素类似物设计
Chem Sci. 2013 Mar 1;4(3):1059-1063. doi: 10.1039/C2SC21723F.
7
A stereocontrolled synthesis of (+)-saxitoxin.（+）-石房蛤毒素的立体控制合成。
J Am Chem Soc. 2011 Dec 21;133(50):20172-4. doi: 10.1021/ja2098063. Epub 2011 Nov 23.
8
Diastereoselective total synthesis of (±)-schindilactone A.（±）-schindilactone A的非对映选择性全合成。
Angew Chem Int Ed Engl. 2011 Aug 1;50(32):7373-7. doi: 10.1002/anie.201103088. Epub 2011 Jul 7.
9
Neurotoxic alkaloids: saxitoxin and its analogs.神经毒素生物碱：石房蛤毒素及其类似物。
Mar Drugs. 2010 Jul 20;8(7):2185-211. doi: 10.3390/md8072185.
10
Total synthesis of (+)-decarbamoylsaxitoxin and (+)-gonyautoxin 3.(+)-去氨甲酰基石房蛤毒素和 (+)-GTX3 的全合成。
Org Lett. 2010 May 7;12(9):2150-3. doi: 10.1021/ol1006696.
Zotero 插件