Copper complexes of bis(thiosemicarbazones): from chemotherapeutics to diagnostic and therapeutic radiopharmaceuticals

Abstract

The molecules known as bis(thiosemicarbazones) derived from 1,2-diones can act as tetradentate ligands for Cu(II), forming stable, neutral complexes. As a family, these complexes possess fascinating biological activity. This critical review presents an historical perspective of their progression from potential chemotherapeutics through to more recent applications in nuclear medicine. Methods of synthesis are presented followed by studies focusing on their potential application as anti-cancer agents and more recent investigations into their potential as therapeutics for Alzheimer's disease. The Cu(II) complexes are of sufficient stability to be used to coordinate copper radioisotopes for application in diagnostic and therapeutic radiopharmaceuticals. Detailed understanding of the coordination chemistry has allowed careful manipulation of the metal based properties to engineer specific biological activities. Perhaps the most promising complex radiolabelled with copper radioisotopes to date is Cu(II)(atsm), which has progressed to clinical trials in humans (162 references).

Positron emission tomography to assess hypoxia and perfusion in lung cancer

“…This tracer shows favorable kinetics with rapid uptake in hypoxic tissue and fast clearance from normoxic tissues, enabling imaging within 30 min after injection [66,67] . However, the exact uptake mechanism of [Cu]ATSM is still under debate [63,68,69] and several preclinical studies have shown that [Cu]ATSM uptake depends on tumor type and other characteristics than hypoxia alone [70][71][72][73][74][75][76] .…”

“…[Cu]ATSM is a therapeutic agent which, by replacing the Cu atom with a suitable radioactive Cu isotope, can be used for hypoxia PET imaging [63] . In nuclear medicine, Cu is of particular interest for its favorable radiochemical properties.…”

An impaired mitochondrial electron transport chain increases retention of the hypoxia imaging agent diacetylbis(4-methylthiosemicarbazonato)copper II

“…These qualities have led to the use of bis (thiosemicarbazones) as delivery vehicles for radioactive copper isotopes in the development of unique radiopharmaceuticals (1)(2)(3)(4). A particular focus is on the use of radiolabeled diacetylbis ð4-methylthiosemicarbazonatoÞcopper II [Cu II ðatsmÞ] (Fig.…”

Synthesis and Characterization of Novel Cu(II), Pd(II) and Pt(II) Complexes with 8-Ethyl-2-hydroxytricyclo(7.3.1.02,7)tridecan-13-one-thiosemicarbazone: Antimicrobial and in Vitro Antiproliferative Activity

“…The cytotoxicity of these ligands is enhanced by coordination to metal ions such as copper, zinc, platinum and palladium. This activity is explained not only by the metals' ability to influence lipophilicity but also the mechanism of action within the cell [18][19][20][21][22][23][24][25][26]. Substitution on the C 2 position can also affect the coordination and biological properties.…”