Note of Caution for the Aqueous Behaviour of Metal-Based Drug Candidates.,ChemMedChem

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Note of Caution for the Aqueous Behaviour of Metal-Based Drug Candidates.
ChemMedChem ( IF 3.6 ) Pub Date : 2019-12-16 , DOI: 10.1002/cmdc.201900677
Anna Notaro ₁ , Gilles Gasser ₁ , Annie Castonguay ₂

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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.

中文翻译：

金属基药物候选对象的水性行为注意事项。

水溶性差是药物化学中许多化合物反复出现的缺点之一。为了克服该限制，通常从有机溶剂的储备溶液中稀释候选药物。但是，通常忽略了这些化合物在水溶液中的精确表征，导致有关实际活性物质的性质存在一些不确定性。在本通讯中，我们证明了我们小组先前报道的两种钌配合物对癌症的化学治疗潜力，即[Ru（DIP）2（sq）]（PF6）和[Ru（DIP）2（3-甲氧基sq）]（ PF6）（其中DIP为4,7-二苯基-1,10-菲咯啉，sq =半喹啉酸酯和3-甲氧基sq = 3-甲氧基半醌酸酯）在水-DMSO（1％v / v）混合物中形成胶体，肉眼看不见眼睛。发现[Ru（DIP）2（3-甲氧基sq）]（PF6）形成具有约25 nm纳米聚集体的高度稳定的单分散胶体。相反，发现[Ru（DIP）2（sq）]（PF6）形成了大部分为球形聚集体的大网状结构，发现其尺寸会随着时间而增加。候选药物的大小和形状分布的差异具有重大意义，因为其生物学活性的研究可能会受到严重影响。总体而言，我们坚信，致力于开发水溶性差的金属基药物的科学界应考虑到这些观察结果。候选药物的大小和形状分布的差异具有重大意义，因为其生物学活性的研究可能会受到严重影响。总体而言，我们坚信，致力于开发水溶性差的金属基药物的科学界应考虑到这些观察结果。候选药物的大小和形状分布的差异具有重大意义，因为其生物学活性的研究可能会受到严重影响。总体而言，我们坚信，致力于开发水溶性差的金属基药物的科学界应考虑到这些观察结果。

更新日期：2020-01-22

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