Phosphatidylcholine-Specific Phospholipase C As a Promising Drug Target

Overview

Journal Molecules

Publisher MDPI

Specialty Biology

Date 2023 Aug 12

PMID 37570610

Authors

Chatchakorn Eurtivong

Euphemia Leung

Nabangshu Sharma

Ivanhoe K H Leung

Johannes Reynisson

Affiliations

Soon will be listed here.

Abstract

Phosphatidylcholine-specific phospholipase C (PC-PLC) is an enzyme that catalyzes the formation of the important secondary messengers phosphocholine and diacylglycerol (DAG) from phosphatidylcholine. Although PC-PLC has been linked to the progression of many pathological conditions, including cancer, atherosclerosis, inflammation and neuronal cell death, studies of PC-PLC on the protein level have been somewhat neglected with relatively scarce data. To date, the human gene expressing PC-PLC has not yet been found, and the only protein structure of PC-PLC that has been solved was from (PC-PLC). Nonetheless, there is evidence for PC-PLC activity as a human functional equivalent of its prokaryotic counterpart. Additionally, inhibitors of PC-PLC have been developed as potential therapeutic agents. The most notable classes include 2-aminohydroxamic acids, xanthates, ,'-hydroxyureas, phospholipid analogues, 1,4-oxazepines, pyrido[3,4-]indoles, morpholinobenzoic acids and univalent ions. However, many medicinal chemistry studies lack evidence for their cellular and in vivo effects, which hampers the progression of the inhibitors towards the clinic. This review outlines the pathological implications of PC-PLC and highlights current progress and future challenges in the development of PC-PLC inhibitors from the literature.

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References

Gonzalez-Bulnes P, Gonzalez-Roura A, Canals D, Delgado A, Casas J, Llebaria A . 2-aminohydroxamic acid derivatives as inhibitors of Bacillus cereus phosphatidylcholine preferred phospholipase C PC-PLC(Bc). Bioorg Med Chem. 2010; 18(24):8549-55. DOI: 10.1016/j.bmc.2010.10.031. View

Rees S, Leung E, Reynisson J, Barker D, Pilkington L . Development of 2-Morpholino-N-hydroxybenzamides as anti-proliferative PC-PLC inhibitors. Bioorg Chem. 2021; 114:105152. DOI: 10.1016/j.bioorg.2021.105152. View

Gonzalez-Roura A, Casas J, Llebaria A . Synthesis and phospholipase C inhibitory activity of D609 diastereomers. Lipids. 2002; 37(4):401-6. DOI: 10.1007/s1145-002-0908-0. View

Schutze S, Berkovic D, Tomsing O, Unger C, Kronke M . Tumor necrosis factor induces rapid production of 1'2'diacylglycerol by a phosphatidylcholine-specific phospholipase C. J Exp Med. 1991; 174(5):975-88. PMC: 2118987. DOI: 10.1084/jem.174.5.975. View

Bagnoli M, Granata A, Nicoletti R, Krishnamachary B, Bhujwalla Z, Canese R . Choline Metabolism Alteration: A Focus on Ovarian Cancer. Front Oncol. 2016; 6:153. PMC: 4916225. DOI: 10.3389/fonc.2016.00153. View

Zhu D, Tan Y, Yang X, Qiao J, Yu C, Wang L . Phospholipase C gamma 1 is a potential prognostic biomarker for patients with locally advanced and resectable oral squamous cell carcinoma. Int J Oral Maxillofac Surg. 2014; 43(12):1418-26. DOI: 10.1016/j.ijom.2014.07.001. View

Patil S, Addo J, Deokar H, Sun S, Wang J, Li W . Synthesis, Biological Evaluation and Modeling Studies of New Pyrido[3,4-]indole Derivatives as Broad-Spectrum Potent Anticancer Agents. Drug Des. 2018; 6(1). PMC: 5771418. DOI: 10.4172/2169-0138.1000143. View

Powis G, Seewald M, Gratas C, Melder D, Riebow J, MODEST E . Selective inhibition of phosphatidylinositol phospholipase C by cytotoxic ether lipid analogues. Cancer Res. 1992; 52(10):2835-40. View

Schutze S, Potthoff K, Machleidt T, Berkovic D, Wiegmann K, Kronke M . TNF activates NF-kappa B by phosphatidylcholine-specific phospholipase C-induced "acidic" sphingomyelin breakdown. Cell. 1992; 71(5):765-76. DOI: 10.1016/0092-8674(92)90553-o. View

10.

Reynisson J, Jaiswal J, Barker D, DMello S, Denny W, Baguley B . Evidence that phospholipase C is involved in the antitumour action of NSC768313, a new thieno[2,3-b]pyridine derivative. Cancer Cell Int. 2016; 16:18. PMC: 4785615. DOI: 10.1186/s12935-016-0293-6. View

11.

Saxena A, Jain P, Anand N . Agents acting on the central nervous system. 15. 2-Substituted 1,2,3,4,6,7,12,12a-octahydropyrazino(2',1':6,1)pyrido(3,4-b)indoles. A new class of central nervous system depressants. J Med Chem. 1973; 16(5):560-4. DOI: 10.1021/jm00263a036. View

12.

Meisamy S, Bolan P, Baker E, Bliss R, Gulbahce E, Everson L . Neoadjuvant chemotherapy of locally advanced breast cancer: predicting response with in vivo (1)H MR spectroscopy--a pilot study at 4 T. Radiology. 2004; 233(2):424-31. DOI: 10.1148/radiol.2332031285. View

13.

Rosoff P, Savage N, Dinarello C . Interleukin-1 stimulates diacylglycerol production in T lymphocytes by a novel mechanism. Cell. 1988; 54(1):73-81. DOI: 10.1016/0092-8674(88)90181-x. View

14.

Wilson J, Kurukulasuriya R, Sinz C, Lombardo M, Bender K, Parker D . Discovery and development of benzo-[1,2,4]-triazolo-[1,4]-oxazepine GPR142 agonists for the treatment of diabetes. Bioorg Med Chem Lett. 2016; 26(12):2947-2951. DOI: 10.1016/j.bmcl.2016.04.018. View

15.

Zhao Y, Su L, Li K, Zhao B . Discovery of novel PC-PLC activity inhibitors. Chem Biol Drug Des. 2019; 95(3):380-387. DOI: 10.1111/cbdd.13606. View

16.

Tamiz A, Whittemore E, Woodward R, Upasani R, Keana J . Structure-activity relationship for a series of 2-substituted 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indoles: potent subtype-selective inhibitors of N-methyl-D-aspartate (NMDA) receptors. Bioorg Med Chem Lett. 1999; 9(11):1619-24. DOI: 10.1016/s0960-894x(99)00248-6. View

17.

Xie W, Peng H, Kim D, Kunkel M, Powis G, Zalkow L . Structure-activity relationship of aza-steroids as PI-PLC inhibitors. Bioorg Med Chem. 2001; 9(5):1073-83. DOI: 10.1016/s0968-0896(00)00302-3. View

18.

Clark M, Shorr R, Bomalaski J . Antibodies prepared to Bacillus cereus phospholipase C crossreact with a phosphatidylcholine preferring phospholipase C in mammalian cells. Biochem Biophys Res Commun. 1986; 140(1):114-9. DOI: 10.1016/0006-291x(86)91065-x. View

19.

Pisanu M, Ricci A, Paris L, Surrentino E, Liliac L, Bagnoli M . Monitoring response to cytostatic cisplatin in a HER2(+) ovary cancer model by MRI and in vitro and in vivo MR spectroscopy. Br J Cancer. 2013; 110(3):625-35. PMC: 3915124. DOI: 10.1038/bjc.2013.758. View

20.

VOGLER W, Berdel W, Geller R, Brochstein J, Beveridge R, Dalton W . A phase II trial of autologous bone marrow transplantation (ABMT) in acute leukemia with edelfosine purged bone marrow. Adv Exp Med Biol. 1996; 416:389-96. DOI: 10.1007/978-1-4899-0179-8_62. View