Details der Publikation - SAR study of niclosamide derivatives in the human glioblastoma U-87 MG cells

SAR study of niclosamide derivatives in the human glioblastoma U-87 MG cells

Abstract Glioblastoma is a lethal malignant brain tumor, and the development of efficient chemotherapeutic agents remains an urgent need. Niclosamide, an anthelmintic drug, which has been used to treat tapeworm infections more than 50 years, has recently attracted renewed attention due to its evident anticancer activities. It has been shown that niclosamide induces cytotoxicity in human glioblastoma U-87 MG cells corresponding with increased protein ubiquitination, ER stress, and autophagy. Furthermore, niclosamide showed down regulation of multiple pro-survival signaling pathways including Wnt/β-catenin, PI3K/AKT, MAPK/ERK, and STAT3, which further caused reduction of U87-MG cell viability. However, the molecular mechanisms of niclosimide and its derivatives in cancer are not fully understood. In the present article, 12 niclosamide derivatives were synthesized by the replacement of substituents for the structure-activity relationship (SAR) study of the protein ubiquitination and related signaling pathways. Our approach is to identify which substituents of niclosamide play important roles in inducing cell apoptosis, inhibition of cell growth, and down regulation of cell survival signaling pathways. Our results indicate that phenol OH of niclosamide plays a significant role in the anti-glioblastoma activity, while missing Cl (5- or 2′-Cl) showed almost no such effect. 4′-$ N_{3} $ or $ CF_{3} $ has the similar activity to niclosamide (4′-$ NO_{2} $) whereas $ NH_{2} $ significantly decreased the cytotoxicity in U87 cells. These modified compounds can be tested to determine which are most effective on cancer treatment. These findings are important in the development of multi-functionalized niclosamide and drug design therapy in the future. Graphical abstract.

Medienart:	E-Artikel

Erscheinungsjahr:	2022
Erschienen:	2022

Enthalten in:	Zur Gesamtaufnahme - volume:31
Enthalten in:	Medicinal chemistry research - 31(2022), 8 vom: 26. Mai, Seite 1313-1322

Sprache:	Englisch

Beteiligte Personen:	Mito, Shizue [VerfasserIn] Cheng, Benxu [VerfasserIn] Garcia, Benjamin A. [VerfasserIn] Gonzalez, Daniela [VerfasserIn] Ooi, Xin Yee [VerfasserIn] Ruiz, Tess C. [VerfasserIn] Elisarraras, Francisco X. [VerfasserIn] Tsin, Andrew [VerfasserIn] Chew, Sue Anne [VerfasserIn] Arriaga, Marco A. [VerfasserIn]

Links:	Volltext [lizenzpflichtig]

Themen:	Glioblastoma Mechanism of action Niclosamide Protein ubiquitination Salicylicanilide

Anmerkungen:	© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022

doi:	10.1007/s00044-022-02907-w

funding:
Förderinstitution / Projekttitel:

PPN (Katalog-ID):	OLC2131173016

Internformat


LEADER	01000naa a22002652 4500
001	OLC2131173016
003	DE-627
005	20230506034323.0
007	cr uuu---uuuuu
008	230506s2022 xx \|\|\|\|\|o 00\| \|\|eng c
024	7		\|a 10.1007/s00044-022-02907-w \|2 doi
035			\|a (DE-627)OLC2131173016
035			\|a (DE-He213)s00044-022-02907-w-e
040			\|a DE-627 \|b ger \|c DE-627 \|e rakwb
041			\|a eng
082	0	4	\|a 540 \|a 610 \|q VZ
084			\|a PHARM \|q DE-84 \|2 fid
100	1		\|a Mito, Shizue \|e verfasserin \|0 (orcid)0000-0001-7954-7460 \|4 aut
245	1	0	\|a SAR study of niclosamide derivatives in the human glioblastoma U-87 MG cells
264		1	\|c 2022
336			\|a Text \|b txt \|2 rdacontent
337			\|a Computermedien \|b c \|2 rdamedia
338			\|a Online-Ressource \|b cr \|2 rdacarrier
500			\|a © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022
520			\|a Abstract Glioblastoma is a lethal malignant brain tumor, and the development of efficient chemotherapeutic agents remains an urgent need. Niclosamide, an anthelmintic drug, which has been used to treat tapeworm infections more than 50 years, has recently attracted renewed attention due to its evident anticancer activities. It has been shown that niclosamide induces cytotoxicity in human glioblastoma U-87 MG cells corresponding with increased protein ubiquitination, ER stress, and autophagy. Furthermore, niclosamide showed down regulation of multiple pro-survival signaling pathways including Wnt/β-catenin, PI3K/AKT, MAPK/ERK, and STAT3, which further caused reduction of U87-MG cell viability. However, the molecular mechanisms of niclosimide and its derivatives in cancer are not fully understood. In the present article, 12 niclosamide derivatives were synthesized by the replacement of substituents for the structure-activity relationship (SAR) study of the protein ubiquitination and related signaling pathways. Our approach is to identify which substituents of niclosamide play important roles in inducing cell apoptosis, inhibition of cell growth, and down regulation of cell survival signaling pathways. Our results indicate that phenol OH of niclosamide plays a significant role in the anti-glioblastoma activity, while missing Cl (5- or 2′-Cl) showed almost no such effect. 4′-$ N_{3} $ or $ CF_{3} $ has the similar activity to niclosamide (4′-$ NO_{2} $) whereas $ NH_{2} $ significantly decreased the cytotoxicity in U87 cells. These modified compounds can be tested to determine which are most effective on cancer treatment. These findings are important in the development of multi-functionalized niclosamide and drug design therapy in the future. Graphical abstract
650		4	\|a Niclosamide
650		4	\|a Glioblastoma
650		4	\|a Protein ubiquitination
650		4	\|a Salicylicanilide
650		4	\|a Mechanism of action
700	1		\|a Cheng, Benxu \|4 aut
700	1		\|a Garcia, Benjamin A. \|4 aut
700	1		\|a Gonzalez, Daniela \|4 aut
700	1		\|a Ooi, Xin Yee \|4 aut
700	1		\|a Ruiz, Tess C. \|4 aut
700	1		\|a Elisarraras, Francisco X. \|4 aut
700	1		\|a Tsin, Andrew \|4 aut
700	1		\|a Chew, Sue Anne \|4 aut
700	1		\|a Arriaga, Marco A. \|4 aut
773	0	8	\|i Enthalten in \|t Medicinal chemistry research \|d Springer US, 1991 \|g 31(2022), 8 vom: 26. Mai, Seite 1313-1322 \|h Online-Ressource \|w (DE-627)490223427 \|w (DE-600)2191978-1 \|w (DE-576)262493225 \|x 1554-8120 \|7 nnns
773	1	8	\|g volume:31 \|g year:2022 \|g number:8 \|g day:26 \|g month:05 \|g pages:1313-1322
856	4	0	\|u https://dx.doi.org/10.1007/s00044-022-02907-w \|z lizenzpflichtig \|3 Volltext
912			\|a GBV_USEFLAG_A
912			\|a SYSFLAG_A
912			\|a GBV_OLC
912			\|a FID-PHARM
912			\|a SSG-OPC-PHA
912			\|a GBV_ILN_11
912			\|a GBV_ILN_20
912			\|a GBV_ILN_22
912			\|a GBV_ILN_23
912			\|a GBV_ILN_24
912			\|a GBV_ILN_31
912			\|a GBV_ILN_32
912			\|a GBV_ILN_39
912			\|a GBV_ILN_40
912			\|a GBV_ILN_60
912			\|a GBV_ILN_62
912			\|a GBV_ILN_63
912			\|a GBV_ILN_65
912			\|a GBV_ILN_69
912			\|a GBV_ILN_70
912			\|a GBV_ILN_73
912			\|a GBV_ILN_74
912			\|a GBV_ILN_90
912			\|a GBV_ILN_95
912			\|a GBV_ILN_100
912			\|a GBV_ILN_101
912			\|a GBV_ILN_105
912			\|a GBV_ILN_110
912			\|a GBV_ILN_120
912			\|a GBV_ILN_138
912			\|a GBV_ILN_150
912			\|a GBV_ILN_151
912			\|a GBV_ILN_152
912			\|a GBV_ILN_161
912			\|a GBV_ILN_170
912			\|a GBV_ILN_171
912			\|a GBV_ILN_187
912			\|a GBV_ILN_213
912			\|a GBV_ILN_224
912			\|a GBV_ILN_230
912			\|a GBV_ILN_250
912			\|a GBV_ILN_281
912			\|a GBV_ILN_285
912			\|a GBV_ILN_293
912			\|a GBV_ILN_370
912			\|a GBV_ILN_602
912			\|a GBV_ILN_636
912			\|a GBV_ILN_702
912			\|a GBV_ILN_2001
912			\|a GBV_ILN_2003
912			\|a GBV_ILN_2004
912			\|a GBV_ILN_2005
912			\|a GBV_ILN_2006
912			\|a GBV_ILN_2007
912			\|a GBV_ILN_2008
912			\|a GBV_ILN_2009
912			\|a GBV_ILN_2010
912			\|a GBV_ILN_2011
912			\|a GBV_ILN_2014
912			\|a GBV_ILN_2015
912			\|a GBV_ILN_2020
912			\|a GBV_ILN_2021
912			\|a GBV_ILN_2025
912			\|a GBV_ILN_2026
912			\|a GBV_ILN_2027
912			\|a GBV_ILN_2031
912			\|a GBV_ILN_2034
912			\|a GBV_ILN_2037
912			\|a GBV_ILN_2038
912			\|a GBV_ILN_2039
912			\|a GBV_ILN_2044
912			\|a GBV_ILN_2048
912			\|a GBV_ILN_2049
912			\|a GBV_ILN_2055
912			\|a GBV_ILN_2057
912			\|a GBV_ILN_2059
912			\|a GBV_ILN_2061
912			\|a GBV_ILN_2064
912			\|a GBV_ILN_2065
912			\|a GBV_ILN_2068
912			\|a GBV_ILN_2088
912			\|a GBV_ILN_2093
912			\|a GBV_ILN_2106
912			\|a GBV_ILN_2107
912			\|a GBV_ILN_2108
912			\|a GBV_ILN_2110
912			\|a GBV_ILN_2111
912			\|a GBV_ILN_2112
912			\|a GBV_ILN_2113
912			\|a GBV_ILN_2118
912			\|a GBV_ILN_2129
912			\|a GBV_ILN_2131
912			\|a GBV_ILN_2143
912			\|a GBV_ILN_2144
912			\|a GBV_ILN_2147
912			\|a GBV_ILN_2148
912			\|a GBV_ILN_2152
912			\|a GBV_ILN_2153
912			\|a GBV_ILN_2188
912			\|a GBV_ILN_2190
912			\|a GBV_ILN_2232
912			\|a GBV_ILN_2336
912			\|a GBV_ILN_2446
912			\|a GBV_ILN_2470
912			\|a GBV_ILN_2474
912			\|a GBV_ILN_2507
912			\|a GBV_ILN_2522
912			\|a GBV_ILN_2548
912			\|a GBV_ILN_4035
912			\|a GBV_ILN_4037
912			\|a GBV_ILN_4046
912			\|a GBV_ILN_4112
912			\|a GBV_ILN_4125
912			\|a GBV_ILN_4126
912			\|a GBV_ILN_4242
912			\|a GBV_ILN_4246
912			\|a GBV_ILN_4249
912			\|a GBV_ILN_4251
912			\|a GBV_ILN_4305
912			\|a GBV_ILN_4306
912			\|a GBV_ILN_4307
912			\|a GBV_ILN_4313
912			\|a GBV_ILN_4322
912			\|a GBV_ILN_4323
912			\|a GBV_ILN_4324
912			\|a GBV_ILN_4325
912			\|a GBV_ILN_4326
912			\|a GBV_ILN_4328
912			\|a GBV_ILN_4333
912			\|a GBV_ILN_4334
912			\|a GBV_ILN_4335
912			\|a GBV_ILN_4336
912			\|a GBV_ILN_4338
912			\|a GBV_ILN_4393
912			\|a GBV_ILN_4700
951			\|a AR
952			\|d 31 \|j 2022 \|e 8 \|b 26 \|c 05 \|h 1313-1322

SAR study of niclosamide derivatives in the human glioblastoma U-87 MG cells

Zugang & Verfügbarkeit

Zugehörige Publikationen/Bände