Caffeine-Based Gold(I) N-Heterocyclic Carbenes as Possible Anticancer Agents: Synthesis and Biological Properties

Abstract

A new series of gold(I) N-heterocyclic carbene (NHC) complexes based on xanthine ligands have been synthesized and characterized by mass spectrometry, NMR, and X-ray diffraction. The compounds have been tested for their antiproliferative properties in human cancer cells and nontumorigenic cells in vitro, as well as for their toxicity in healthy tissues ex vivo. The bis-carbene complex [Au(caffein-2-ylidene)2][BF4] (complex 4) appeared to be selective for human ovarian cancer cell lines and poorly toxic in healthy organs. To gain preliminary insights into their actual mechanism of action, two biologically relevant in cellulo targets were studied, namely, DNA (more precisely a higher-order DNA structure termed G-quadruplex DNA that plays key roles in oncogenetic regulation) and a pivotal enzyme of the DNA damage response (DDR) machinery (poly-(adenosine diphosphate (ADP)-ribose) polymerase 1 (PARP-1), strongly involved in the cancer resistance mechanism). Our results indicate that complex 4 acts as an efficient and selective G-quadruplex ligand while being a modest PARP-1 inhibitor (i.e., poor DDR impairing agent) and thus provide preliminary insights into the molecular mechanism that underlies its antiproliferative behavior.

On the binding modes of metal NHC complexes with DNA secondary structures: implications for therapy and imaging

“…The bulky ligand brakes the planarity of the organometallic compound and results in an orthogonal arrangement of the xanthine ligands. 78 This derivative was equally potent, but less selective for telomeric G4 over duplex DNA compared to the methyl-derivative and suggests that it may interact with telomeric G4 in a different manner. Compound 22 and analogues were evaluated for their toxicity in an ex vivo model that uses tissue slices.…”

“…Compound 22 and analogues were evaluated for their toxicity in an ex vivo model that uses tissue slices. 78 Notably, the xanthine-derived compounds were not toxic in healthy tissues, at variance with the benzimidazole-derived analogues.…”

“…75,77 Recently, a bis-NHC gold(I) complex -[Au(9-methylcaffein-8-ylidene)2] + (22, Figure 9) -bearing the natural product caffeine as carbene ligand, has been demonstrated by DNA FRET melting assays to selectively targeting telomeric G4 structures with respect to duplex DNA, while showing selective antiproliferative effects on tumorigenic over healthy cells. 78 The G4…”

Metal Complexes of Biologically Important Ligands, Part CLXXVIII. Addition of the Pentacarbonylrhenium Cation [(OC)5Re]+ to the Xanthine Alkaloids Caffeine, Theophylline, and Theobromine

“…[20] Of high interest are the caffeine derived (N9-protonated or alkylated) N-heterocyclic carbene (NHC) complexes of ruthenium, [21,22] rhodium, [22] palladium(II), [23] platinum, [24] gold, [25] and mercury, [20] which also exhibit cytotoxicity. [22,24,25] The first NHC complexes have been discovered by Öfele [26] and Wanzlick. [27] The use of NHC complexes in catalysis has been successfully and widely studied by Herrmann and his group and is still a most active field of research.…”

Fitalimid Fonksiyonel Grup İçeren Yeni Bir Benzimidazol Tuzunun Sentezlenmesi, Yapısal Özelliklerinin Spektroskopik ve Hesapsal Yöntemlerle İncelenmesi

“…doğal bileşiklerin modifiye edilmesiyle de karben tuzları sentezlemiş ve bunların başta Ag(I) olmak üzere komplekslerini elde etmişlerdir (Şekil 3). Bu amaçla kullanılan doğal bileşikler arasında kafein, urokanik asid ve teofilin gibi yapılarında halkalı karben grubu bulunduran bileşikler yer alır [11]. …”