Synthesis and biological characterisation of a new prodrug releasing a thiol-containing HDAC inhibitor under bioreductive stimuli Elena Ermini a , Annalaura Brai a , Federica Finetti a , Giuseppe Giannini b , Lucrezia Paradisi a , Federica Poggialini a , Lorenza Trabalzini a and Maurizio Taddei a a University of Siena, Italy, b Translational Medicine & Clinical Pharmacology Corporate & D - Alfasigma SpA Thiols are a particular class of molecules having essential roles in biological systems and are present as pharmacophoric groups in several drugs. They can work as potent metallo-enzyme inhibitors, complex metals present in proteins and they are excellent electron donors. Thanks to this wide range of activities, thiols are potentially useful compounds in therapy, although the diversity of targets makes them often non-selective. The weakness of drugs containing thiols is often the lack of selectivity and the use of pro-drugs or bioconjugation are potential solutions to the issue. However, the weak acidity of thiols makes them not suitable for self- immolative spacer groups. The use of thiocarbonate or thiocarbamate as pro-drug is also limited by the instability of these groups in water/organic based media. 1 Moreover, the stimuli-sensitive release of thiols from conjugated prodrugs is limited to their conversion to disulphides, which, however, have limited stability in various tissues and blood. In this communication we describe a new 1-6 self-immolative spacer suitable for enzyme mediated release of thiols. As the aromaticity of the system is supposed to influence the disassembly kinetics of these spacers, we thought that poorly aromatic five membered heterocycles could be useful as scaffolds for the release of low acidity compounds such as thiols. We applied this linker, the 5-nitropyrrolylmethanol, to ST7612AA1, a powerful HDAC inhibitors containing thiol with in vitro activity in the nanomolar range (IC 50 = 50 nM on NCI-H460 cells) associated with a remarkable in vivo antitumor activity. 2 The release kinetic was done through reduction of the nitro moiety obtained by mild chemical reduction in water with NaBH 4 under Fe/Pd nanoparticle micellar catalysis or by incubation with bacterial nitroreductase (NTR), an enzyme over-expressed in hypoxic conditions including solid tumour cells and bacterial infected tissues. 3 Reduction of the nitro group to the amine triggers 1-6 elimination, which occurs via some sort of aza-pyrrolin-2-one methide, releasing the drug. This process also occurs in cell lines overexpressing NTR under hypoxic conditions, with a decrease in cell viability observed from 95 to 55% after 48 hours. References 1. A. Alouane, R. Labruère, T. Le Saux, F. Schmidt, L. Jullien, Angew. Chem. Int. Ed . 2015 , 54 , 7492. 2. F. M. Milazzo, L. Vesci, A. M. Anastasi, C. Chiapparino, A. Rosi, G. Giannini, M. Taddei, E. Cini, V. Faltoni, E. Petricci, et al., Front. Oncol. 2020 , 9 , 1534. 3. Z. He, Y. Chou, H. Zhou, H Zhang, T. Cheng, G. Liu, Org. Biomol. Chem. 2018 , 16 , 3266.
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