Novel Meta-iodobenzylguanidine-Based Copper Thiosemicarbazide-1-guanidinomethylbenzyl Anticancer Compounds Targeting Norepinephrine Transporter in Neuroblastoma

Haiyuan Zhang; Fang Xie; Muhua Cheng; Fangyu Peng

doi:10.1021/acs.jmedchem.9b00386

Novel Meta-iodobenzylguanidine-Based Copper Thiosemicarbazide-1-guanidinomethylbenzyl Anticancer Compounds Targeting Norepinephrine Transporter in Neuroblastoma

Haiyuan Zhang, Fang Xie, Muhua Cheng, Fangyu Peng

Research output: Contribution to journal › Article › peer-review

20 Scopus citations

Abstract

Meta-iodobenzylguanidine (MIBG) is a ligand with high affinity against norepinephrine transporter (NET) that has been used for diagnostic imaging and radionuclide therapy of NET-expressing tumors, such as neuroblastoma. We hypothesize that MIBG can be used as a ligand for development of new anticancer drugs targeting NET-expressing neuroblastoma (NB). To test our hypothesis, we synthesized two MIBG-based anticancer copper complexes [Cu(m-TSBG)₂ and Cu(p-TSBG)₂] by conjugation of a thiosemicarbazone copper group onto MIBG ligand. Both Cu(m-TSBG)₂ and Cu(p-TSBG)₂ compounds showed potent anticancer activity against NB cells (BE2C and SK-N-DZ cells). The NB-specific anticancer activity of Cu(m-TSBG)₂ and Cu(p-TSBG)₂ was further demonstrated by the reduced anticancer activities when nonconjugated MIBG ligand was used to competitively block binding of Cu(m-TSBG)₂ or Cu(p-TSBG)₂ onto NET-expressing NB cells. Both Cu(m-TSBG)₂ or Cu(p-TSBG)₂ compounds hold potential as promising new drugs for targeted therapy of neuroblastoma and other NET-expressing tumors.

Original language	English (US)
Pages (from-to)	6985-6991
Number of pages	7
Journal	Journal of Medicinal Chemistry
Volume	62
Issue number	15
DOIs	https://doi.org/10.1021/acs.jmedchem.9b00386
State	Published - Aug 8 2019

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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title = "Novel Meta-iodobenzylguanidine-Based Copper Thiosemicarbazide-1-guanidinomethylbenzyl Anticancer Compounds Targeting Norepinephrine Transporter in Neuroblastoma",

abstract = "Meta-iodobenzylguanidine (MIBG) is a ligand with high affinity against norepinephrine transporter (NET) that has been used for diagnostic imaging and radionuclide therapy of NET-expressing tumors, such as neuroblastoma. We hypothesize that MIBG can be used as a ligand for development of new anticancer drugs targeting NET-expressing neuroblastoma (NB). To test our hypothesis, we synthesized two MIBG-based anticancer copper complexes [Cu(m-TSBG)2 and Cu(p-TSBG)2] by conjugation of a thiosemicarbazone copper group onto MIBG ligand. Both Cu(m-TSBG)2 and Cu(p-TSBG)2 compounds showed potent anticancer activity against NB cells (BE2C and SK-N-DZ cells). The NB-specific anticancer activity of Cu(m-TSBG)2 and Cu(p-TSBG)2 was further demonstrated by the reduced anticancer activities when nonconjugated MIBG ligand was used to competitively block binding of Cu(m-TSBG)2 or Cu(p-TSBG)2 onto NET-expressing NB cells. Both Cu(m-TSBG)2 or Cu(p-TSBG)2 compounds hold potential as promising new drugs for targeted therapy of neuroblastoma and other NET-expressing tumors.",

author = "Haiyuan Zhang and Fang Xie and Muhua Cheng and Fangyu Peng",

note = "Funding Information: This study was partly funded by a faculty research development fund awarded to F.P. by Carman & Ann Adams Department of Pediatrics, School of Medicine, Wayne State University, Detroit, MI, U.S.A., and a faculty research development fund awarded to F.P. by Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, U.S.A. Publisher Copyright: {\textcopyright} 2019 American Chemical Society.",

year = "2019",

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doi = "10.1021/acs.jmedchem.9b00386",

language = "English (US)",

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T1 - Novel Meta-iodobenzylguanidine-Based Copper Thiosemicarbazide-1-guanidinomethylbenzyl Anticancer Compounds Targeting Norepinephrine Transporter in Neuroblastoma

AU - Zhang, Haiyuan

AU - Xie, Fang

AU - Cheng, Muhua

AU - Peng, Fangyu

N1 - Funding Information: This study was partly funded by a faculty research development fund awarded to F.P. by Carman & Ann Adams Department of Pediatrics, School of Medicine, Wayne State University, Detroit, MI, U.S.A., and a faculty research development fund awarded to F.P. by Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, U.S.A. Publisher Copyright: © 2019 American Chemical Society.

PY - 2019/8/8

Y1 - 2019/8/8

N2 - Meta-iodobenzylguanidine (MIBG) is a ligand with high affinity against norepinephrine transporter (NET) that has been used for diagnostic imaging and radionuclide therapy of NET-expressing tumors, such as neuroblastoma. We hypothesize that MIBG can be used as a ligand for development of new anticancer drugs targeting NET-expressing neuroblastoma (NB). To test our hypothesis, we synthesized two MIBG-based anticancer copper complexes [Cu(m-TSBG)2 and Cu(p-TSBG)2] by conjugation of a thiosemicarbazone copper group onto MIBG ligand. Both Cu(m-TSBG)2 and Cu(p-TSBG)2 compounds showed potent anticancer activity against NB cells (BE2C and SK-N-DZ cells). The NB-specific anticancer activity of Cu(m-TSBG)2 and Cu(p-TSBG)2 was further demonstrated by the reduced anticancer activities when nonconjugated MIBG ligand was used to competitively block binding of Cu(m-TSBG)2 or Cu(p-TSBG)2 onto NET-expressing NB cells. Both Cu(m-TSBG)2 or Cu(p-TSBG)2 compounds hold potential as promising new drugs for targeted therapy of neuroblastoma and other NET-expressing tumors.

AB - Meta-iodobenzylguanidine (MIBG) is a ligand with high affinity against norepinephrine transporter (NET) that has been used for diagnostic imaging and radionuclide therapy of NET-expressing tumors, such as neuroblastoma. We hypothesize that MIBG can be used as a ligand for development of new anticancer drugs targeting NET-expressing neuroblastoma (NB). To test our hypothesis, we synthesized two MIBG-based anticancer copper complexes [Cu(m-TSBG)2 and Cu(p-TSBG)2] by conjugation of a thiosemicarbazone copper group onto MIBG ligand. Both Cu(m-TSBG)2 and Cu(p-TSBG)2 compounds showed potent anticancer activity against NB cells (BE2C and SK-N-DZ cells). The NB-specific anticancer activity of Cu(m-TSBG)2 and Cu(p-TSBG)2 was further demonstrated by the reduced anticancer activities when nonconjugated MIBG ligand was used to competitively block binding of Cu(m-TSBG)2 or Cu(p-TSBG)2 onto NET-expressing NB cells. Both Cu(m-TSBG)2 or Cu(p-TSBG)2 compounds hold potential as promising new drugs for targeted therapy of neuroblastoma and other NET-expressing tumors.

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ER -

Novel Meta-iodobenzylguanidine-Based Copper Thiosemicarbazide-1-guanidinomethylbenzyl Anticancer Compounds Targeting Norepinephrine Transporter in Neuroblastoma

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