TCDB is operated by the Saier Lab Bioinformatics Group

2.B.91.  The Bis-IminoUrea (BIU) Famiily

 Saha et al. 2019 explored bis(iminourea) derivatives (115) (see figure below). These compounds have pKa values between 6.46 and 6.18. Thus, it was expected that protonation occurs in slightly acidic pH environments, switching on the transport activity. Using chloride-selective electrode assays in model liposomes, these compounds were found to be moderately active, and a significant increase in the transport activity was found at acidic pH values. Compounds 115c and 115d were tested in model cancer (human breast cancer MCF-7 and T-47D) and normal (Baby Hamster Kidney fibroblasts BHK-21) cell lines. MTT assays showed that compounds were cytotoxic, with calculated IC50 values of 26–29 μM for the MCF-7 and T-47D cell lines. The calculated IC50 for normal cells were approximately two-fold superior, and the impact in the viability was demonstrated to be dependent on the presence of chloride in the external buffer (Davis et al. 2020).

Bis(iminourea) derivatives 116a–i.

Debasis Manna and the group reported bis(iminourea) derivatives 10a–d that possess pKa values in the range of 6.16–6.46 (see figure below).At pH 7.2, 10c and 10d are better chloride transporters than 10a and 10b as they are more lipophilic and possess electron-withdrawing substituents. A 9-fold increase in chloride transport was observed at pH 5.5 (Fig. 13b). The molecules were found to co-transport H+/Cl at pH 5.5, and the mechanism switches to OH/Cl antiport at pH 7.2.

(a) Structures of bis(iminourea) ion transporters 10a–d. (b) Mechanism of pH-dependent chloride transport.



References associated with 2.B.91 family:

Davis, J.T., P.A. Gale, and R. Quesada. (2020). Advances in anion transport and supramolecular medicinal chemistry. Chem Soc Rev. [Epub: Ahead of Print] 32692794
Saha, A., N. Akhtar, V. Kumar, S. Kumar, H.K. Srivastava, S. Kumar, and D. Manna. (2019). pH-Regulated anion transport activities of bis(iminourea) derivatives across the cell and vesicle membrane. Org Biomol Chem 17: 5779-5788. 31135015