Note of Caution for the Aqueous Behaviour of Metal‐Based Drug Candidates. (21st January 2020)

• Record Type: Journal Article
• Authors: Notaro, Anna; Gasser, Gilles; Castonguay, Annie
• Is Part Of: ChemMedChem. Volume 15:Number 4(2020)
• Page Start: 345
• Page End: 348
• Publication Date: 2020-01-21
• Subjects: aqueous behaviour -- bioinorganic chemistry -- cancer -- medicinal inorganic chemistry -- ruthenium; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201900677
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: Poor aqueous solubility is one of the recurrent drawbacks of many compounds in medicinal chemistry. To overcome this limitation, the dilution of drug candidates from stock solutions of an organic solvent is common practice. However, the precise characterisation of these compounds in aqueous solutions is often neglected, leading to some uncertainties regarding the nature of the actual active species. In this communication, we demonstrate that two ruthenium complexes previously reported by our group for their chemotherapeutic potential against cancer, namely [Ru(DIP)2 (sq)](PF6 ) and [Ru(DIP)2 (3‐methoxysq)](PF6 ), where DIP is 4, 7‐diphenyl‐1, 10‐phenanthroline, sq=semiquinonate and 3‐methoxysq=3‐methoxysemiquinonate, form colloids in water‐DMSO (1 % v/v) mixtures that are invisible to the naked eyes. [Ru(DIP)2 (3‐methoxysq)](PF6 ) was found to form a highly stable and monodispersed colloid with nanoaggregates of ∼25 nm. In contrast, [Ru(DIP)2 (sq)](PF6 ) was found to form large reticulates of mostly spherical aggregates which size was found to increase over time. The difference in size and shape distribution of drug candidates is of tremendous significance as the study of their biological activity might be severely affected. Overall, we strongly believe that these observations should be taken into account by the scientific community working on the development of metal‐based drugs with poor water solubility. Abstract : This study demonstrates how "clear solutions" of metal‐based drug candidates that result in linear UV absorption calibration curves can be dispersions of colloidal nature. Importantly, a deeper investigation of two closely related compounds showed that their small structural difference caused a dramatic effect on their self‐assembly, going from well‐defined reticulates to isolated nanoaggregates. The difference in size and shape distributions of metal‐based drug candidates is of tremendous significance as the study of their biological activity might be severely affected.