53339-53-0Relevant articles and documents
Thiol-responsive pro-fluorophore labeling: Synthesis of a pro-fluorescent labeled oligonucleotide for monitoring cellular uptake
Akai, Shoji,Ohta, Takayuki,Ono, Akira,Saneyoshi, Hisao,Yamamoto, Yuta
, (2020)
Pro-fluorescent labeled oligonucleotides are potential alternative tools to classical fluorescently labeled oligonucleotides for monitoring cellular uptake. Here, we report the design and synthesis of a thiol-responsive pro-fluorophore labeled oligonucleotide, and its fluorescence responsivity to glutathione in the test tube and live cells.
Investigation of the effect of different linker chemotypes on the inhibition of histone deacetylases (HDACs)
Linciano, Pasquale,Benedetti, Rosaria,Pinzi, Luca,Russo, Fabiana,Chianese, Ugo,Sorbi, Claudia,Altucci, Lucia,Rastelli, Giulio,Brasili, Livio,Franchini, Silvia
, (2020/11/24)
Histone Deacetylases (HDACs) are among the most attractive and interesting targets in anticancer drug discovery. The clinical relevance of HDAC inhibitors (HDACIs) is testified by four FDA-approved drugs for cancer treatment. However, one of the main drawbacks of these drugs resides in the lack of selectivity against the different HDAC isoforms, resulting in severe side effects. Thus, the identification of selective HDACIs represents an exciting challenge for medicinal chemists. HDACIs are composed of a cap group, a linker region, and a metal-binding group interacting with the catalytic zinc ion. While the cap group has been extensively investigated, less information is available about the effect of the linker on isoform selectivity. To this aim, in this work, we explored novel linker chemotypes to direct isoform selectivity. A small library of 25 hydroxamic acids with hitherto unexplored linker chemotypes was prepared. In vitro tests demonstrated that, depending on the linker type, some candidates selectively inhibit HDAC1 over HDAC6 isoform or vice versa. Docking calculations were performed to rationalize the effect of the novel linker chemotypes on biologic activity. Moreover, four compounds were able to increase the levels of acetylation of histone H3 or tubulin. These compounds were also assayed in breast cancer MCF7 cells to test their antiproliferative effect. Three compounds showed a significant reduction of cancer proliferation, representing valuable starting points for further optimization.
Stabilizing p-Dithiobenzyl Urethane Linkers without Rate-Limiting Self-Immolation for Traceless Drug Release
Zheng, Yiwu,Shen, Yang,Meng, Xiaoting,Wu, Yaqi,Zhao, Yibing,Wu, Chuanliu
, p. 1196 - 1203 (2019/05/28)
Exploiting the redox sensitivity of disulfide bonds is a prevalent strategy in targeted prodrug designs. In contrast to aliphatic disulfides, p-thiobenzyl-based disulfides have rarely been used for prodrug designs, given their intrinsic instability caused by the low pKa of aromatic thiols. Here, we examined the interplay between steric hindrance and the low-pKa effect on thiol–disulfide exchange reactions and uncovered a new thiol–disulfide exchange process for the self-immolation of p-thiobenzyl-based disulfides. We observed a central leaving group shifting effect in the α,α-dimethyl-substituted p-dithiobenzyl urethane linkers (DMTB linkers), which leads to increased disulfide stability by more than two orders of magnitude, an extent that is significantly greater than that observed with typical aliphatic disulfides. In particular, the DMTB linkers display not only high stability, but also rapid self-immolation kinetics due to the low pKa of the aromatic thiol, which can be used as a general and robust linkage between targeting reagents and cytotoxic drugs for targeted prodrug designs. The unique and promising stability characteristics of the present DMTB linker will likely inspire the development of novel targeted prodrugs to achieve traceless release of drugs into cells.
