3-(3-吡啶基)-2-膦酰基丙酸的N-氧化物衍生物作为Rab香叶基香叶基化的潜在抑制剂
N-Oxide derivatives of 3-(3-pyridyl)-2-phosphonopropanoic acids as potential inhibitors of Rab geranylgeranylation.
作者信息
Zhou Xiang, Born Ella J, Allen Cheryl, Holstein Sarah A, Wiemer David F
机构信息
Department of Chemistry, University of Iowa, Iowa City, IA 52242-1294, USA.
Department of Internal Medicine, University of Iowa, Iowa City, IA 52242-1294, USA.
出版信息
Bioorg Med Chem Lett. 2015 Jun 1;25(11):2331-4. doi: 10.1016/j.bmcl.2015.04.021. Epub 2015 Apr 17.
Abstract
The N-oxide derivatives of [2-(3-pyridinyl)-1-hydroxyethylidene-1,1-phosphonocarboxylic acid (or PEHPC) and [2-(3-pyridinyl)-1-ethylidene-1,1-phosphonocarboxylic acid (or PEPC) have been prepared and evaluated for their activity against several enzymes which utilize isoprenoids. The parent pyridines are known inhibitors of GGTase II, but the N-oxide derivatives show no improvement in biological activity in assays with the isolated enzyme. However, the PEHPC N-oxide did induce significant accumulation of intracellular light chain in myeloma cells, consistent with inhibition of Rab geranylgeranylation.
摘要
已制备了[2-(3-吡啶基)-1-羟基亚乙基-1,1-膦酰基羧酸（或PEHPC）和[2-(3-吡啶基)-1-亚乙基-1,1-膦酰基羧酸（或PEPC）的N-氧化物衍生物，并对它们针对几种利用类异戊二烯的酶的活性进行了评估。母体吡啶是已知的γ-谷氨酰转移酶II抑制剂，但在与分离酶的测定中，N-氧化物衍生物的生物活性没有改善。然而，PEHPC N-氧化物确实在骨髓瘤细胞中诱导了细胞内轻链的显著积累，这与Rab香叶基香叶基化的抑制一致。
相似文献
1
N-Oxide derivatives of 3-(3-pyridyl)-2-phosphonopropanoic acids as potential inhibitors of Rab geranylgeranylation.
Bioorg Med Chem Lett. 2015 Jun 1;25(11):2331-4. doi: 10.1016/j.bmcl.2015.04.021. Epub 2015 Apr 17.
2
Selective inhibition of Rab prenylation by a phosphonocarboxylate analogue of risedronate induces apoptosis, but not S-phase arrest, in human myeloma cells.
Int J Cancer. 2006 Sep 15;119(6):1254-61. doi: 10.1002/ijc.21977.
3
Phosphonocarboxylate inhibitors of Rab geranylgeranyl transferase disrupt the prenylation and membrane localization of Rab proteins in osteoclasts in vitro and in vivo.
Bone. 2005 Sep;37(3):349-58. doi: 10.1016/j.bone.2005.04.021.
4
Synthesis and Biological Evaluation of Imidazole-Bearing α-Phosphonocarboxylates as Inhibitors of Rab Geranylgeranyl Transferase (RGGT).
ChemMedChem. 2018 Apr 23;13(8):842-851. doi: 10.1002/cmdc.201700791. Epub 2018 Mar 2.
5
Synthesis, chiral high performance liquid chromatographic resolution and enantiospecific activity of a potent new geranylgeranyl transferase inhibitor, 2-hydroxy-3-imidazo[1,2-a]pyridin-3-yl-2-phosphonopropionic acid.
J Med Chem. 2010 May 13;53(9):3454-64. doi: 10.1021/jm900232u.
6
Development of selective, potent RabGGTase inhibitors.
J Med Chem. 2012 Oct 11;55(19):8330-40. doi: 10.1021/jm300624s. Epub 2012 Oct 3.
7
Triazole-based inhibitors of geranylgeranyltransferase II.
Bioorg Med Chem Lett. 2013 Feb 1;23(3):764-6. doi: 10.1016/j.bmcl.2012.11.089. Epub 2012 Dec 1.
8
Characterization of the in vitro activity of AZD3409, a novel prenyl transferase inhibitor.
Cancer Chemother Pharmacol. 2011 Jan;67(1):137-45. doi: 10.1007/s00280-010-1300-6. Epub 2010 Mar 13.
9
Design, synthesis, and characterization of peptide-based rab geranylgeranyl transferase inhibitors.
J Med Chem. 2009 Dec 24;52(24):8025-37. doi: 10.1021/jm901117d.
10
Inhibition of geranylgeranylation mediates sensitivity to CHOP-induced cell death of DLBCL cell lines.
Exp Cell Res. 2011 May 1;317(8):1179-91. doi: 10.1016/j.yexcr.2011.02.006. Epub 2011 Feb 13.
引用本文的文献
1
Targeting the Isoprenoid Biosynthetic Pathway in Multiple Myeloma.
Int J Mol Sci. 2022 Dec 21;24(1):111. doi: 10.3390/ijms24010111.
2
Targeting prenylation inhibition through the mevalonate pathway.
RSC Med Chem. 2019 Dec 23;11(1):51-71. doi: 10.1039/c9md00442d. eCollection 2020 Jan 1.
3
Novel benzimidazole phosphonates as potential inhibitors of protein prenylation.
Bioorg Med Chem Lett. 2019 Dec 15;29(24):126757. doi: 10.1016/j.bmcl.2019.126757. Epub 2019 Oct 31.
4
P53- and mevalonate pathway-driven malignancies require Arf6 for metastasis and drug resistance.
J Cell Biol. 2016 Apr 11;213(1):81-95. doi: 10.1083/jcb.201510002. Epub 2016 Apr 4.
本文引用的文献
1
Updates on mechanism of action and clinical efficacy of risedronate in osteoporosis.
Clin Cases Miner Bone Metab. 2014 Sep;11(3):208-14.
2
Geranyl and neryl triazole bisphosphonates as inhibitors of geranylgeranyl diphosphate synthase.
Bioorg Med Chem. 2014 May 1;22(9):2791-8. doi: 10.1016/j.bmc.2014.03.014. Epub 2014 Mar 24.
3
Targeting HSP90 and monoclonal protein trafficking modulates the unfolded protein response, chaperone regulation and apoptosis in myeloma cells.
Blood Cancer J. 2013 Dec 6;3(12):e167. doi: 10.1038/bcj.2013.64.
4
Triazole-based inhibitors of geranylgeranyltransferase II.
Bioorg Med Chem Lett. 2013 Feb 1;23(3):764-6. doi: 10.1016/j.bmcl.2012.11.089. Epub 2012 Dec 1.
5
Development of selective, potent RabGGTase inhibitors.
J Med Chem. 2012 Oct 11;55(19):8330-40. doi: 10.1021/jm300624s. Epub 2012 Oct 3.
6
Psoromic acid is a selective and covalent Rab-prenylation inhibitor targeting autoinhibited RabGGTase.
J Am Chem Soc. 2012 May 2;134(17):7384-91. doi: 10.1021/ja211305j. Epub 2012 Apr 22.
7
Structure-guided development of selective RabGGTase inhibitors.
Angew Chem Int Ed Engl. 2011 May 16;50(21):4957-61. doi: 10.1002/anie.201101210. Epub 2011 Apr 21.
8
The relationship between the chemistry and biological activity of the bisphosphonates.
Bone. 2011 Jul;49(1):20-33. doi: 10.1016/j.bone.2011.03.774. Epub 2011 Apr 9.
9
Synthesis and biological evaluation of a series of aromatic bisphosphonates.
Bioorg Med Chem. 2010 Oct 15;18(20):7212-20. doi: 10.1016/j.bmc.2010.08.036. Epub 2010 Aug 19.
10
Isoprenoid biosynthetic pathway inhibition disrupts monoclonal protein secretion and induces the unfolded protein response pathway in multiple myeloma cells.
Leuk Res. 2011 Apr;35(4):551-9. doi: 10.1016/j.leukres.2010.08.008. Epub 2010 Sep 9.
Zotero 插件