In this article, we report the design, synthesis, photodynamic properties, and in vitro evaluation of photoactivatable prodrug for the poly (ADP-ribose) polymerase 1 (PARP-1) inhibitor Talazoparib. In order to yield a photoactivatable, inactive prodrug, photoactivatable protecting groups (PPGs) were employed to mask the key pharmacophore of Talazoparib. Our study confirmed the good stability and photolytic effect of prodrugs. A PARP-1 enzyme inhibition assay and PARylation experiment showed that the inhibitory activity of the prodrug was reduced 380 times and more than 658 times, respectively, which proved that the prodrug’s expected activity was lost after PPG protection. InBRCA1- andBRCA2-deficient cell lines, the inhibitory activity of the compound was significantly restored after ultraviolet (UV) irradiation. The results indicate that the photoactivatable prodrug strategy is an interesting approach for studying PARP inhibitors. Meanwhile, the described photoactivatable prodrug also provided a new biological tool for the mechanism research of PARP.Keywords:Talazoparib;PARP inhibitor;prodrug;o-nitro-benzyl;photoactivatable protecting groups
Li Kaiqi,Chen Long,Xiong Zuochun,Xiong Chengdong,Chen Dongliang
Amino-functionalized six-membered cyclic carbonate tert-butyl(2-oxo-1,3-dioxan-5-yl) carbamate (TBC) was synthesized with tert-Butyloxycarbonyl (Boc) as protected group. Due to its thermal properties, ring-opening polymerization (ROP) carried out in a relatively low temperature, and Sn (Oct) 2 as catalyst. A series of copolymers were prepared with L-lactide (LA), ε-Caprolactone (CL) as co-monomers, searching for proper components and ratios. The protecting Boc-group was easy to remove by using trifluoroacetic acid (TFA). The structures of TBC and copolymers were confirmed by 1 H NMR and 13 C NMR analysis. Copolymers were characterized by DSC, GPC and water contact angle analysis. The introduction of pendant amino groups resulted in a significant enhancement of hydrophilicity of the copolymers.
Maillard intermediates, especially Amadori compounds, played a crucial role in the formation of flavor or adverse Maillard products, directly influencing the sensorial and organoleptic properties of foodstuff. Here, in order to modulate the degradation products of Amadori compounds, the active hydroxyl and carboxyl groups on the Amadori skeleton were protected, then two new Amadori derivatives based on leucine (Leu-AD) and glutamic acid (Glu-AD) were obtained with relatively high yield. The subsequent TG-DTG and DSC tests showed that both Leu-AD and Glu-AD were stable at room temperature and could be fully degraded at 400 °C. The TG-DTG curve of Glu-AD was more complicated than that of Leu-AD due to the asynchronous degradation of the two carboxyl groups on Glu-AD. Their pyrolytic products also exhibited great difference, specifically, the flavor products released from Leu-AD were mainly pyrroles and Strecker degradation products, while the pyrolytic products of Glu-AD mainly included methyl substituted furans derived from the pyranose ring and esters resulting from the degradation of glutamic acid moiety. Comparatively, the species and relative content of their (Leu-AD and Glu-AD) pyrolytic products were distinct to the reported flavor products generated from the corresponding Amadori compounds and glucose-leucine/glutamic acid mixtures, indicating Amadori derivatives could be an alternative flavor precursors generating Maillard-type aroma.
Amino-functionalized six-membered cyclic carbonate 5-((2-nitrobenzyl) amino)-1,3-dioxan-2-one (NBAC) was synthesized with 2-nitrobenzyl group as photolabile protecting group. The following copolymerization was carried out by using l -lactide as comonomer and Sn (Oct) 2 as catalyst. The amino-functionalized polymer P(LA- co -AC) was obtained by ultraviolet irradiation of P(LA- co -NBAC) to remove the protecting group. The structures of products were confirmed by 1 H nuclear magnetic resonance (NMR) and 13 C NMR analysis. The pendant amino groups not only resulted in an enhancement of the hydrophilicity, but also played a role of antibacterial effect due to the positive charge imparted to the material.
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