γ-丁内酯衍生物 MSA-2 的是 STING 前药。
γ-Butyrolactone Derivatives of MSA-2 are STING Prodrugs.
机构信息
Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge St, CPZN 5206, Boston, MA-02114.
Department of Systems Biology, Harvard Medical School, 200 Longwood Ave, Boston, MA-02115.
出版信息
ChemMedChem. 2024 Oct 1;19(19):e202400416. doi: 10.1002/cmdc.202400416. Epub 2024 Aug 5.
Abstract
STING agonists are potent enhancers of a pro-inflammatory response and, thus, potentially useful therapeutics. Unfortunately, many agonists developed to date require complex drug delivery formulations and often have poor water solubility, limiting their use for systemic administration. Here, we report the discovery and chemical characterization of lactones of MSA-2 as new STING prodrugs with enhanced properties. We show that these prodrugs form efficient inclusion complexes with tumor myeloid cell targeting cyclodextrin nanoparticles and propose a new mechanism of formation and hydrolysis.
摘要
STING 激动剂是一种强烈的促炎反应增强剂，因此具有潜在的治疗作用。不幸的是，迄今为止开发的许多激动剂需要复杂的药物传递配方，并且通常水溶性差，限制了它们用于全身给药。在这里，我们报告了 MSA-2 的内酯作为新型 STING 前药的发现和化学表征，这些前药具有增强的特性。我们表明，这些前药与肿瘤髓样细胞靶向环糊精纳米粒形成有效的包合复合物，并提出了一种新的形成和水解机制。
相似文献
1
γ-Butyrolactone Derivatives of MSA-2 are STING Prodrugs.γ-丁内酯衍生物 MSA-2 的是 STING 前药。
ChemMedChem. 2024 Oct 1;19(19):e202400416. doi: 10.1002/cmdc.202400416. Epub 2024 Aug 5.
2
Protolichesterinic acid derivatives: α-methylene-γ-lactones as potent dual activators of PPARγ and Nrf2 transcriptional factors.原利舍斯的酸衍生物：α-亚甲基-γ-内酯作为PPARγ和Nrf2转录因子的强效双重激活剂。
Bioorg Med Chem Lett. 2014 Aug 15;24(16):3819-22. doi: 10.1016/j.bmcl.2014.06.062. Epub 2014 Jun 27.
3
Symbiotic prodrugs (SymProDs) dual targeting of NFkappaB and CDK.共生前药（SymProDs）双重靶向 NFkappaB 和 CDK。
Chem Biol Drug Des. 2020 Aug;96(2):773-784. doi: 10.1111/cbdd.13684. Epub 2020 Apr 22.
4
NMR spectroscopic study of cyclodextrin inclusion complexes with A-007 prodrugs.环糊精与A - 007前药包合物的核磁共振光谱研究
Carbohydr Res. 2008 May 19;343(7):1180-90. doi: 10.1016/j.carres.2008.03.014. Epub 2008 Mar 14.
5
Sulfonamido, azidosulfonyl and N-acetylsulfonamido analogues of rofecoxib: 4-[4-(N-acetylsulfonamido)phenyl]-3-(4-methanesulfonylphenyl)-2(5H)furanone is a potent and selective cyclooxygenase-2 inhibitor.罗非昔布的磺酰胺、叠氮磺酰基和N - 乙酰磺酰胺类似物：4 - [4 - (N - 乙酰磺酰胺基)苯基] - 3 - (4 - 甲磺酰基苯基) - 2(5H) - 呋喃酮是一种强效且选择性的环氧化酶 - 2抑制剂。
Bioorg Med Chem Lett. 2004 Apr 19;14(8):1957-60. doi: 10.1016/j.bmcl.2004.01.076.
6
Synthesis and biological properties of new alpha-methylene-gamma-butyrolactones and alpha,beta-unsaturated delta-lactones.新型α-亚甲基-γ-丁内酯和α,β-不饱和δ-内酯的合成及生物学性质
Eur J Med Chem. 2006 Feb;41(2):192-200. doi: 10.1016/j.ejmech.2005.10.009. Epub 2005 Dec 20.
7
Novel approach to pro-drugs of lactones: water soluble imidate and ortho-ester derivatives of a furanone-based COX-2 selective inhibitor.内酯前药的新方法：基于呋喃酮的COX-2选择性抑制剂的水溶性亚氨酸酯和原酸酯衍生物
Bioorg Med Chem Lett. 2005 May 2;15(9):2259-63. doi: 10.1016/j.bmcl.2005.03.009.
8
Synthesis and radioprotective properties of pulvinic acid derivatives.新型戊酸衍生物的合成及其辐射防护性能。
ChemMedChem. 2011 Mar 7;6(3):561-9. doi: 10.1002/cmdc.201000391. Epub 2011 Jan 18.
9
The telescoped intramolecular michael/olefination (TIMO) approach to alpha-alkylidene-gamma-butyrolactones: synthesis of (+)-paeonilactone B.用于合成α-亚烷基-γ-丁内酯的分子内迈克尔/烯烃化缩合（TIMO）方法：（+）-芍药内酯B的合成
Angew Chem Int Ed Engl. 2008;47(10):1935-7. doi: 10.1002/anie.200705329.
10
Diastereoselective, vinylogous mukaiyama aldol additions of silyloxy furans to cyclic ketones: annulation of butenolides and gamma-lactones.硅氧基呋喃与环状酮的非对映选择性、乙烯基化向山羟醛加成反应：丁烯内酯和γ-内酯的环化反应
Org Lett. 2006 Jul 6;8(14):2909-12. doi: 10.1021/ol060534q.
引用本文的文献
1
Studies on the Reactions of Lactone Intermediates Derived from Levulinic Acid: Telescoped Routes to Higher Levulinate Ester Biofuels.乙酰丙酸衍生的内酯中间体的反应研究：通往高级乙酰丙酸酯生物燃料的串联路线。
ACS Omega. 2025 Apr 3;10(14):13898-13905. doi: 10.1021/acsomega.4c08315. eCollection 2025 Apr 15.
本文引用的文献
1
Pharmacological Polarization of Tumor-Associated Macrophages Toward a CXCL9 Antitumor Phenotype.肿瘤相关巨噬细胞向 CXCL9 抗肿瘤表型的药理学极化。
Adv Sci (Weinh). 2024 Apr;11(15):e2309026. doi: 10.1002/advs.202309026. Epub 2024 Feb 11.
2
Antitumor Effect of Platinum-Modified STING Agonist MSA-2.铂修饰的STING激动剂MSA-2的抗肿瘤作用
ACS Omega. 2024 Jan 3;9(2):2650-2656. doi: 10.1021/acsomega.3c07498. eCollection 2024 Jan 16.
3
Highly Active Myeloid Therapy for Cancer.高活性骨髓治疗癌症。
ACS Nano. 2023 Oct 24;17(20):20666-20679. doi: 10.1021/acsnano.3c08034. Epub 2023 Oct 12.
4
Chemically programmed STING-activating nano-liposomal vesicles improve anticancer immunity.化学编程的 STING 激活纳米脂质体囊泡改善抗肿瘤免疫。
Nat Commun. 2023 Jul 31;14(1):4584. doi: 10.1038/s41467-023-40312-y.
5
Photochemically controlled activation of STING by CAIX-targeting photocaged agonists to suppress tumor cell growth.通过靶向碳酸酐酶IX（CAIX）的光笼式激动剂对干扰素基因刺激蛋白（STING）进行光化学控制激活以抑制肿瘤细胞生长。
Chem Sci. 2023 May 15;14(22):5956-5964. doi: 10.1039/d3sc01896b. eCollection 2023 Jun 7.
6
Discovery of a photoactivatable dimerized STING agonist based on the benzo[]selenophene scaffold.基于苯并[]硒吩支架的光活化二聚化STING激动剂的发现。
Chem Sci. 2023 Mar 13;14(15):4174-4182. doi: 10.1039/d2sc06860e. eCollection 2023 Apr 12.
7
The cGAS-STING pathway and cancer.cGAS-STING 通路与癌症。
Nat Cancer. 2022 Dec;3(12):1452-1463. doi: 10.1038/s43018-022-00468-w. Epub 2022 Dec 12.
8
Dual Immunostimulatory Pathway Agonism through a Synthetic Nanocarrier Triggers Robust Anti-Tumor Immunity in Murine Glioblastoma.通过合成纳米载体的双重免疫刺激途径激动剂在小鼠脑胶质瘤中引发强大的抗肿瘤免疫。
Adv Mater. 2023 Feb;35(7):e2208782. doi: 10.1002/adma.202208782. Epub 2022 Dec 18.
9
Discovery of Selenium-Containing STING Agonists as Orally Available Antitumor Agents.发现含硒的STING激动剂作为口服可用的抗肿瘤药物
J Med Chem. 2022 Nov 24;65(22):15048-15065. doi: 10.1021/acs.jmedchem.2c00634. Epub 2022 Sep 7.
10
Structure-Activity relationship study of benzothiophene oxobutanoic acid analogues leading to novel stimulator of interferon gene (STING) agonists.苯并噻吩氧丁酸类似物的结构-活性关系研究，导致新型干扰素基因（STING）激动剂。
Eur J Med Chem. 2022 Nov 5;241:114627. doi: 10.1016/j.ejmech.2022.114627. Epub 2022 Aug 7.
Zotero 插件