Transfer hydrogenation catalysis in cells as a new approach to anticancer drug design

Abstract

Organometallic complexes are effective hydrogenation catalysts for organic reactions. For example, Noyori-type ruthenium complexes catalyse reduction of ketones by transfer of hydride from formate. Here we show that such catalytic reactions can be achieved in cancer cells, offering a new strategy for the design of safe metal-based anticancer drugs. The activity of ruthenium(II) sulfonamido ethyleneamine complexes towards human ovarian cancer cells is enhanced by up to 50 × in the presence of low non-toxic doses of formate. The extent of conversion of coenzyme NAD+ to NADH in cells is dependent on formate concentration. This novel reductive stress mechanism of cell death does not involve apoptosis or perturbation of mitochondrial membrane potentials. In contrast, iridium cyclopentadienyl catalysts cause cancer cell death by oxidative stress. Organometallic complexes therefore have an extraordinary ability to modulate the redox status of cancer cells.

Comparative solution equilibrium studies on pentamethylcyclopentadienyl rhodium complexes of 2,2ʹ-bipyridine and ethylenediamine and their interaction with human serum albumin

“…It has been recently reported that the catalytic activity of the [Ru(II)( 6 -p-cymene)] complexes of sulfonamido ethyleneamine ligands can be transferred in cancer cells, which has influence on the extent of intracellular conversion of NAD + to NADH. This exciting finding offers a novel drug design concept [7]. In all, these results strongly motivate the development of novel metallodrugs with antitumor activity.…”

Bioorthogonal Catalytic Activation of Platinum and Ruthenium Anticancer Complexes by FAD and Flavoproteins

“…MES was selected as an electron donor to follow up our previous work on riboflavin11 while NADH was chosen for its relevance as a biological cofactor in numerous reactions catalyzed by flavoenzymes 19. Moreover, metal‐based catalytic drugs have been recently shown to kill cancer cells by interfering with cellular NAD + /NADH homeostasis 20, 21, 22…”

Selective cytotoxicity of arene tricarbonylchromium towards tumour cell lines

“…The complexes of Fe [20][21][22][23], Ru [24][25][26], Os [27,28] and Ag [29] have been found to be very active against cancer cells. Arene tricarbonylchromium group, for which the oxidation state of chromium is zero, has been attached to biological substances such as β-estradiol molecule to produce complexes that have been mainly studied for their capacity to act as a probe for the detection of biological substances by infrared spectroscopy [30].…”