Gold-Containing Indoles as Anticancer Agents That Potentiate the Cytotoxic Effects of Ionizing Radiation

Abstract

This report describes the design and application of several distinct gold-containing indoles as anti-cancer agents. When used individually, all gold-bearing compounds display cytostatic effects against leukemia and adherent cancer cell lines. However, two gold-bearing indoles show unique behavior by increasing the cytotoxic effects of clinically relevant levels of ionizing radiation. Quantifying the amount of DNA damage demonstrates that each gold-indole enhances apoptosis by inhibiting DNA repair. Both Au(I)-indoles were tested for inhibitory effects against various cellular targets including thioredoxin reductase, a known target of several gold compounds, and various ATP-dependent kinases. While neither compound significantly inhibits the activity of thioreoxin reductase, both showed inhibitory effects against several kinases associated with cancer initiation and progression. The inhibition of these kinases provides a possible mechanism for the ability of these Au(I)-indoles potentiate the cytotoxic effects of ionizing radiation. Clinical applications of combining Au(I)-indoles with ionizing radiation are discussed as a new strategy to achieve chemosensitization of cancer cells.

Spectroscopic (FT-IR, FT-Raman, and UV–visible) and quantum chemical studies on molecular geometry, Frontier molecular orbitals, NBO, NLO and thermodynamic properties of 1-acetylindole

“…Sumatriptan [11], Ondansetron [12] and Indomethacin [13] are some important drugs which contain indole nucleus, for treatment of migraine, suppression of nausea and vomiting caused by cancer chemotherapy and radiotherapy, and for the treatment of rheumatoid arthritis respectively. Recently it has been established that gold-containing indoles, act as anticancer agents that potentiate the cytotoxic effects of ionizing radiation [14]. Indole derivatives also possess antimicrobial [15], antifungal [16], and antidepressant [17] activities.…”

Arylgold(I) Complexes from Base-Assisted Transmetalation: Structures, NMR Properties, and Density-Functional Theory Calculations

“…This result, alongside the isolation of 9, is notable in that indole is a privileged structure in biology. 56 Recent work 38 shows that gold(I) complexes of N-protected indoles are broadly cytotoxic to malignant cell lines. At least some such compounds potentiate the cell-killing action of ionizing radiation.…”

Indoles as anticancer agents

“…Consequently, it is a potential anti-cancer product derived from its strong tumor growth inhibition and positive pharmacologic properties. It also increases the manufacture of reactive oxygen species (ROS) and triggers DNA damage [126][127][128] . Cyclohepta [b] indole and benzo [6,7] cyclohepta [1,2-b] indole ( Figure 17) were subsequently screened for cytotoxic activity against human nasopharyngeal carcinoma (HOME-1) and gastric adenocarcinoma (NUGC-3) cell lines, where the product showed imperative cytotoxicity at a concentration of 4 µg [126] .…”

“…In 2014, it has been proved that an indole and its derivatives NC001-8 could be novel therapeutic agents for spinocerebellar ataxias (SCA17). The development of indole- based compounds offers a promising strategy for the treatment of polyglutamine (polyQ) diseases via activation of haperone expression to reduce polyQ aggregation in SCA17 neuronal cell and slice culture models [127] . Sandra et al [129] , reported the relevance of goldcontaining indoles as anti-cancer agents.…”