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

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.