Synthetic Metal–Organic Molecular Knots Potential New Anti-Cancer Category

The biological activity of five new, metal-organic hybrid knotted molecules, termed metal-organic trefoil knots (M-TKs), has been developed and studied by researchers from NYU Abu Dhabi (NYUAD). These molecules can effectively deliver metals to cancer cells, demonstrating the potential to act as a new category of anti-cancer agents.

These nanoscale, water-soluble M-TKs showed high potency in vitro against six cancer cell lines and in vivo in zebrafish embryos.

Zebrafish-related studies were performed by NYUAD Postdoctoral Associate Anjana Ramdas Nair from the Sadler Lab. NYUAD Research Scientists Farah Benyettou and Thirumurugan Prakasam from the Trabolsi Research Group, led by NYUAD Associate Professor of Chemistry Ali Trabolsi, are co-authors of the study.

Metal-organic Trefoil Knots

The metal-organic trefoil knots, generated by metal-templated self-assembly of a simple pair of chelating ligands, were well tolerated in vitro by non-cancer cells but were significantly more potent than cisplatin, a common chemotherapy medication, in both human cancer cells – including those that were cisplatin-resistant – and in zebrafish embryos. In cultured cells, M-TKs introduce reactive oxygen species (ROS) that damage the mitochondria of cancer cells, but not the nuclear DNA or the plasma membrane.

“The cytotoxicity and wide scope for structural variation of M-TKs indicate the potential of synthetic metal-organic knots as a new field of chemical space for pharmaceutical design and development. There is significant promise for developing new cancer therapies that can complement the existing chemotherapy options that are currently used to treat nearly half of all cancer patients undergoing chemotherapy,”

said Trabolsi.

Medicinal Inorganic Chemistry

The M-TKs synthesised by NYUAD Research Scientist Thirumurugan Prakasam from the Trabolsi Research Group were found, in many cases, to have greater potency than has been previously reported in cisplatin and other metal complexes, explains NYUAD Research Scientist Farah Benyettou. The main delivery routes were macropinocytosis and both caveolin- and clathrin-mediated endocytosis, which are all more active in cancer cells than in normal cells.

Cisplatin and other small molecules penetrate cells by diffusion, which is less cancer-selective in vitro. The researchers hypothesize that the molecules they have developed are less toxic to healthy cells because they are internalized less.

 metal-organic trefoil knots

A schematic representation of the mechanism of action of the metal-organic trefoil knots. Internalized via active mechanism, in the acidic environment of cancer cells, the knots fall apart and trigger toxicity via the formation of reactive oxygen species (ROS). Credit: Jumaanah Alhashemi

In the next stage of developing M-TKs, research efforts will focus on the mechanism of action of the M-TKs to determine whether their ROS-mediated toxicity involves specific intracellular targets.

These findings confirm the viability of studying the effects of these compounds in whole vertebrates, as the M-TKs were well tolerated by zebrafish and appeared to selectively attack dividing cells.

Farah Benyettou, et al.
Potent and selective in vitro and in vivo antiproliferative effects of metal–organic trefoil knots
Chem. Sci., 2019, DOI: 10.1039/C9SC01218D

Top Image: Jumaanah Alhashemi