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1
Polar 3-alkylidene-5-pivaloyloxymethyl-5'-hydroxymethyl-gamma-lactones as protein kinase C ligands and antitumor agents.作为蛋白激酶 C 配体和抗肿瘤剂的 Polar 3-烷基-5-新戊酰氧甲基-5'-羟甲基-γ-内酰胺。
Bioorg Med Chem Lett. 2010 Feb 1;20(3):1008-12. doi: 10.1016/j.bmcl.2009.12.058. Epub 2009 Dec 21.
2
Conformationally constrained analogues of diacylglycerol (DAG). 16. How much structural complexity is necessary for recognition and high binding affinity to protein kinase C?二酰基甘油（DAG）的构象受限类似物。16. 对于蛋白激酶C的识别和高结合亲和力而言，需要多少结构复杂性？
J Med Chem. 2000 Mar 9;43(5):921-44. doi: 10.1021/jm9904607.
3
Conformationally constrained analogues of diacylglycerol. 10. Ultrapotent protein kinase C ligands based on a racemic 5-disubstituted tetrahydro-2-furanone template.二酰基甘油的构象受限类似物。10. 基于外消旋5-二取代四氢-2-呋喃酮模板的超高效蛋白激酶C配体。
J Med Chem. 1996 Jan 5;39(1):19-28. doi: 10.1021/jm950276v.
4
Design and synthesis of bioisosteres of ultrapotent protein kinase C (PKC) ligand, 5-acetoxymethyl-5-hydroxymethyl-3-alkylidene tetrahydro-2-furanone.超高效蛋白激酶C（PKC）配体5-乙酰氧甲基-5-羟甲基-3-亚烷基四氢-2-呋喃酮的生物电子等排体的设计与合成
Arch Pharm Res. 1998 Aug;21(4):452-7. doi: 10.1007/BF02974642.
5
Conformationally constrained analogues of diacylglycerol. 12. Ultrapotent protein kinase C ligands based on a chiral 4,4-disubstituted heptono-1,4-lactone template.二酰基甘油的构象受限类似物。12. 基于手性4,4-二取代庚糖-1,4-内酯模板的超高效蛋白激酶C配体。
J Med Chem. 1996 Jan 5;39(1):36-45. doi: 10.1021/jm950278f.
6
Conformationally constrained analogues of diacylglycerol. 11. Ultrapotent protein kinase C ligands based on a chiral 5-disubstituted tetrahydro-2-furanone template.二酰基甘油的构象受限类似物。11. 基于手性5-二取代四氢-2-呋喃酮模板的超高效蛋白激酶C配体。
J Med Chem. 1996 Jan 5;39(1):29-35. doi: 10.1021/jm950277n.
7
Elucidating the interaction of γ-hydroxymethyl-γ-butyrolactone substituents with model membranes and protein kinase C-C1 domains.阐明γ-羟甲基-γ-丁内酯取代基与模型膜及蛋白激酶C-C1结构域的相互作用。
Mol Biosyst. 2015 May;11(5):1389-99. doi: 10.1039/c5mb00100e.
8
Conformationally constrained analogues of diacylglycerol (DAG). 17. Contrast between sn-1 and sn-2 DAG lactones in binding to protein kinase C.二酰基甘油（DAG）的构象受限类似物。17. 1-位和2-位DAG内酯与蛋白激酶C结合的对比
J Med Chem. 2000 Aug 24;43(17):3209-17. doi: 10.1021/jm990613q.
9
Novel synthesis, cytotoxic evaluation, and structure-activity relationship studies of a series of alpha-alkylidene-gamma-lactones and lactams.一系列α-亚烷基-γ-内酯和内酰胺的新型合成、细胞毒性评估及构效关系研究
J Med Chem. 2005 May 19;48(10):3516-21. doi: 10.1021/jm048970a.
10
Macrocyclic diacylglycerol-bis-lactones as conformationally constrained analogues of diacylglycerol-lactones. Interactions with protein kinase C.大环二酰甘油双内酯作为二酰甘油内酯的构象受限类似物。与蛋白激酶C的相互作用。
J Med Chem. 2004 Jul 29;47(16):4000-7. doi: 10.1021/jm0497747.

引用本文的文献

1
Natural and Synthetic Lactones Possessing Antitumor Activities.具有抗肿瘤活性的天然和合成内酯。
Int J Mol Sci. 2021 Jan 21;22(3):1052. doi: 10.3390/ijms22031052.

本文引用的文献

1
Conformationally constrained analogues of diacylglycerol. 29. Cells sort diacylglycerol-lactone chemical zip codes to produce diverse and selective biological activities.二酰基甘油的构象受限类似物。29. 细胞对二酰基甘油内酯化学邮政编码进行分类以产生多样且具选择性的生物活性。
J Med Chem. 2008 Sep 11;51(17):5198-220. doi: 10.1021/jm8001907. Epub 2008 Aug 13.
2
Wealth of opportunity - the C1 domain as a target for drug development.机遇无限——C1结构域作为药物开发靶点
Curr Drug Targets. 2008 Aug;9(8):641-52. doi: 10.2174/138945008785132376.
3
Practical synthesis of prostratin, DPP, and their analogs, adjuvant leads against latent HIV.前体素、二肽基肽酶（DPP）及其类似物的实用合成，针对潜伏性HIV的辅助先导化合物。
Science. 2008 May 2;320(5876):649-52. doi: 10.1126/science.1154690.
4
The anti-tumor agent, ingenol-3-angelate (PEP005), promotes the recruitment of cytotoxic neutrophils by activation of vascular endothelial cells in a PKC-delta dependent manner.抗肿瘤药物ingenol-3-当归酸酯（PEP005）通过以蛋白激酶C-δ依赖性方式激活血管内皮细胞来促进细胞毒性中性粒细胞的募集。
Cancer Immunol Immunother. 2008 Aug;57(8):1241-51. doi: 10.1007/s00262-008-0458-9. Epub 2008 Feb 12.
5
Bryostatin-1: a novel PKC inhibitor in clinical development.苔藓抑素-1：一种处于临床开发阶段的新型蛋白激酶C抑制剂。
Cancer Invest. 2003;21(6):924-36. doi: 10.1081/cnv-120025095.
6
Synthetic diacylglycerols (DAG) and DAG-lactones as activators of protein kinase C (PK-C).合成二酰基甘油（DAG）和二酰基甘油内酯作为蛋白激酶C（PK-C）的激活剂。
Acc Chem Res. 2003 Jun;36(6):434-43. doi: 10.1021/ar020124b.
7
Protein kinase C: structural and spatial regulation by phosphorylation, cofactors, and macromolecular interactions.蛋白激酶C：通过磷酸化、辅因子和大分子相互作用进行的结构和空间调节
Chem Rev. 2001 Aug;101(8):2353-64. doi: 10.1021/cr0002801.
8
Pharmacology of the receptors for the phorbol ester tumor promoters: multiple receptors with different biochemical properties.佛波酯肿瘤促进剂受体的药理学：具有不同生化特性的多种受体
Biochem Pharmacol. 2000 Nov 15;60(10):1417-24. doi: 10.1016/s0006-2952(00)00470-6.
9
Conformationally constrained analogues of diacylglycerol (DAG). 16. How much structural complexity is necessary for recognition and high binding affinity to protein kinase C?二酰基甘油（DAG）的构象受限类似物。16. 对于蛋白激酶C的识别和高结合亲和力而言，需要多少结构复杂性？
J Med Chem. 2000 Mar 9;43(5):921-44. doi: 10.1021/jm9904607.
10
Mechanism of antitumor action of PKC activator, gnidimacrin.蛋白激酶C激活剂gnidimacrin的抗肿瘤作用机制
Int J Cancer. 1998 Jul 17;77(2):243-50. doi: 10.1002/(sici)1097-0215(19980717)77:2<243::aid-ijc13>3.0.co;2-c.

作为蛋白激酶 C 配体和抗肿瘤剂的 Polar 3-烷基-5-新戊酰氧甲基-5'-羟甲基-γ-内酰胺。

Polar 3-alkylidene-5-pivaloyloxymethyl-5'-hydroxymethyl-gamma-lactones as protein kinase C ligands and antitumor agents.

机构信息

Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Shinlim-Dong, Kwanak-Ku, Seoul 151-742, Republic of Korea.

出版信息

Bioorg Med Chem Lett. 2010 Feb 1;20(3):1008-12. doi: 10.1016/j.bmcl.2009.12.058. Epub 2009 Dec 21.

DOI:10.1016/j.bmcl.2009.12.058
PMID:20045644
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3725291/
Abstract

A series of DAG-lactones with polar 3-alkylidene substituents have been investigated as PKC-alpha ligands and antitumor agents. Extensive analysis of structure-activity relationships for the 3-alkylidene chain revealed that polar groups such as ether, hydroxyl, aldehyde, ester, acyloxy, and amido were tolerated with similar binding affinities and reduced lipophilicities compared to the corresponding unsubstituted alkylidene chain. Among the derivatives, compounds 5, 6 and 8 with an ether type of side chain showed high binding affinities in range of K(i)= 3-5 nM and excellent antitumor profiles, particularly against the colo205 colon cancer and the K562 leukemia cell lines.

摘要

一系列带有极性 3-亚烷基取代基的 DAG-内酯被研究作为 PKC-α配体和抗肿瘤剂。对 3-亚烷基链的结构-活性关系进行了广泛分析，结果表明，与相应的未取代的亚烷基链相比，极性基团如醚、羟基、醛基、酯基、酰氧基和酰胺基具有相似的结合亲和力和降低的亲脂性。在这些衍生物中，具有醚类型侧链的化合物 5、6 和 8 具有高的结合亲和力范围为 K(i)=3-5 nM 和优异的抗肿瘤特性，特别是对colo205 结肠癌和 K562 白血病细胞系。