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Sirtiun 5 (SIRT5) is a NAD+-dependent protein lysine deacylase. It is emerging as a promising target for the development of drugs to treat cancer and metabolism-related diseases. In this study, we screened 5000 compounds and identified a hit compound 14 bearing a pyrazolone functional group as a novel SIRT5-selective inhibitor. Structure-based optimization of 14 resulted in compound 47 with an IC 50 value of 0.21 ± 0.02 μM and a 100-fold improved potency. Compound 47 showed substantial selectivity for SIRT5 over SIRT1-3 and SIRT6. Biochemical studies suggest that 47 does not occupy the NAD + -binding pocket and acts as a substrate-competitive inhibitor. The identified potent and selective SIRT5 inhibitors allow further studies as research tools and therapeutic agents. [Display omitted] • Hit compound 14 bearing a pyrazolone skeleton was identified as a SIRT5 inhibitor. • Extensive SAR studies guided by molecular docking were conducted. • Compound 47 showed a 100-fold increased potency as compared to the original hit. [ABSTRACT FROM AUTHOR]

Since tyrosine kinase inhibitor (TKI) could reverse ABCG2-mediated drug-resistance, novel chlorin e 6 -based conjugates of Dasatinib and Imatinib as photosensitizer (PS) were designed and synthesized. The results demonstrated that conjugate 10b showed strongest phototoxicity against HepG2 and B16-F10 cells, which was more phototoxic than chlorin e 6 and Talaporfin. It could reduce efflux of intracellular PS by inhibiting ABCG2 in HepG2 cells, and localize in mitochondria, lysosomes, golgi and ER, resulting in higher cell apoptosis rate and ROS production than Talaporfin. Moreover, it could induce cell autophagy and block cell cycle in S phase, and significantly inhibit tumor growth and prolong survival time on BALB/c nude mice bearing HepG2 xenograft tumor to a greater extent than chlorin e 6. Consequently, compound 10b could be applied as a promising candidate PS due to its good water-solubility and stability, low drug-resistance, high quantum yield of 1O 2 and excellent antitumor efficacy in vitro and in vivo. [Display omitted] • The conjugates of chlorin e 6 with Dasatinib or Imatinib were synthesized. • In vitro PDT antitumor activities of all target compounds were investigated. • In vivo antitumor potency and mechanism of preferred compound 10b were evaluated. • In vitro PDT antitumor efficacy of 10b was better than chlorin e 6 and talaporfin. • In vivo PDT antitumor efficacy of 10b was superior to chlorin e 6. [ABSTRACT FROM AUTHOR]

Inducing protein degradation by proteolysis targeting chimera (PROTAC) has provided great opportunities for scientific research and industrial applications. Histone deacetylase (HDAC)-PROTAC has been widely developed since the first report of its ability to induce the degradation of SIRT2 in 2017. To date, ten of the eighteen HDACs (HDACs 1–8, HDAC10, and SIRT2) have been successfully targeted and degraded by HDAC-PROTACs. HDAC-PROTACs surpass traditional HDAC inhibitors in many aspects, such as higher selectivity, more potent antiproliferative activity, and the ability to disrupt the enzyme-independent functions of a multifunctional protein and overcome drug resistance. Rationally designing HDAC-PROTACs is a main challenge in development because slight variations in chemical structure can lead to drastic effects on the efficiency and selectivity of the degradation. In the future, HDAC-PROTACs can potentially be involved in clinical research with the support of the increased amount of in vivo data, pharmacokinetic evaluation, and pharmacological studies. [Display omitted] • Ten of the eighteen HDACs have been successfully degraded by PROTAC. • HDAC-PROTAC surpass traditional HDAC inhibitors in many aspects. • Rationally designing HDAC-PROTAC is a main challenge in development. [ABSTRACT FROM AUTHOR]

The combination of photodynamic therapy (PDT) and chemotherapy is a prospective strategy to improve antitumor efficacy. Herein, a series of novel cytotoxic chlorin-based derivatives as dual photosensitizers (PSs) and histone deacetylase inhibitors (HDACIs) were synthesized and investigated for biological activity. Among them, compound 15e showed definite HDAC2 and 10 inhibitory activities by up-regulating expression of acetyl-H4 and highest phototoxicity and dark-toxicity, which was more phototoxic than Talaporfin as a PS while with stronger dark-toxicity compared to vorinostat (SAHA) as a HDACI. The biological assays demonstrated that 15e was liable to enter A549 cells and localized in mitochondria, lysosomes, golgi and endoplasmic reticulum (ER) etc. multiple organelles, resulting in higher cell apoptosis rate and ROS production compared to Talaporfin. Moreover, it could induce tumor cell autophagy as a dual PS and HDACI. All results suggested that compound 15e could be applied as a potential dual cytotoxic drug for PDT and chemotherapy. [Display omitted] • The dual-mode cytotoxic chlorin-based derivatives as PSs and HDACIs were synthesized. • HDAC inhibitory activities of target compounds were investigated. • Photo-cytotoxicity and dark-cytotoxicity for target compounds were evaluated. • Compound 15e exhibited the strongest PDT and chemotherapy efficacies. • Dual-mode cytotoxic mechanism of compound 15e was further studied. [ABSTRACT FROM AUTHOR]

This study aimed to improve the biological effectiveness and pharmacokinetic properties of chlorin e 6 , a second-generation photosensitizer (PS), for tumor photodynamic therapy (PDT). Herein, the novel 31-hexyloxy chlorin e 6 -based 152- or 131-amino acid derivatives 3a , 3b , 3c and 8 were synthesized and their photophysical properties and in vitro bioactivities such as phototoxicity against A549, HeLa and melanoma B16–F10 cells, reactive oxygen species (ROS) production and subcellular localization were evaluated. In addition, preferred target compounds were also investigated for their in vivo pharmacokinetic in SD rats and in vivo antitumor efficacies in C57BL/6 mice bearing melanoma B16–F10 cells. Apparently, simultaneous introduction of amino acid residue and n -hexyloxy chain in chlorin e 6 made a significant improvement in photophysical properties, ROS production, in vitro and in vivo PDT efficacy. Encouragingly, all target compounds showed higher in vitro phototoxicity than Talaporfin, and that 3c (152-Lys) exhibited strongest phototoxicity and highest dark toxicity/phototoxicity ratio, followed by 8 (131-Asp), 3a (152-Asp) and 3b (152-Glu). Moreover, in vivo PDT antitumor efficacy of 3a , 3c and 8 was all better than that of Talaporfin, and that both 3c and 8 had stronger PDT antitumor efficiency than 3a. The overall results suggested that these novel 31-hexyloxy chlorin e 6 -based 152- or 131-amino acid derivatives, especially 3c and 8 , might be potential antitumor candidate drugs for clinical treatment of melanoma by PDT. Image 1 • The 31-hexyloxy chlorin e 6 -based 152- or 131-amino acid derivatives were synthesized. • In vitro photodynamic activity and mechanism of target compounds were investigated. • In vivo antitumor potency and pharmacokinetic of target compounds were evaluated. • In vitro and in vivo PDT antitumor efficacy of 3a , 3c , 8 were better than Talaporfin. • In vitro and in vivo PDT antitumor efficacy of 3c and 8 were superior to 3a. [ABSTRACT FROM AUTHOR]