Discovery of Novel Bromophenol–Thiosemicarbazone Hybrids as Potent Selective Inhibitors of Poly(ADP-ribose) Polymerase-1 (PARP-1) for Use in Cancer

Abstract

Poly(ADP-ribose) polymerase-1 (PARP-1) is a new potential target for anticancer drug discovery. A series of bromophenol−thiosemicarbazone hybrids as PARP-1 inhibitors were designed, synthesized, and evaluated for their antitumor activities. Among them, the most promising compound, 11, showed excellent selective PARP-1 inhibitory activity (IC 50 = 29.5 nM) over PARP-2 (IC 50 > 1000 nM) and potent anticancer activities toward the SK-OV-3, Bel-7402 and HepG2 cancer cell lines (IC 50 = 2.39, 5.45, and 4.60 μM), along with inhibition of tumor growth in an in vivo SK-OV-3 cell xenograft model. Further study demonstrated that compound 11 played an antitumor role through multiple anticancer mechanisms, including the induction of apoptosis and cell cycle arrest, cellular accumulation of DNA double-strand breaks, DNA repair alterations, inhibition of H 2 O 2triggered PARylation, antiproliferative effects via the production of cytotoxic reactive oxygen species, and autophagy. In addition, compound 11 displayed good pharmacokinetic characteristics and favorable safety. These observations demonstrate that compound 11 may serve as a lead compound for the discovery of new anticancer drugs.

Identification of probe-quality degraders for Poly(ADP-ribose) polymerase-1 (PARP-1)

“…The results ( Figure 5(B)) suggested that the cell cycle spectrum clearly changed in a dose-dependent manner. However, our result suggested that our degrader arrested the cell-cycle into the G1 phase, while PARP-1 inhibitors generally arrested the cell-cycle into the G2/M phase 37 . The facts that they arrested the cell-cycle into the different phases was attributed to the different mechanisms of inhibitors and degraders.…”

The Fluoro-Thiazolylhydrazone Compound TSC-3C Inhibits Triple Negative Breast Cancer (TNBC) Cell Line Activity by Promoting Apoptosis, Regulating the MAPK Pathway and Inducing Mitochondrial Dysfunction

“…Although few potent compounds have been previously reported [28][29][30]35,43], the anti-TNBC activity of fluoro-thiazolylhydrazone hybrids is reported for the first time in this work. The anticancer activity of TSC-3C for TNBC is evidence for a promising therapeutic agent that is important for drug discovery and clinical applications.…”

“…Halogenated compounds come from various sources, such as natural marine products [19], and have diverse potent activities, including antidiabetic [20], antimicrobial [21], antioxidative [22], anti-inflammatory [23], and anticancer activities [23][24][25][26][27]. In our previous work, a series of bromophenol hybrids with active anticancer moieties were designed and synthesized as potential anticancer agents [28][29][30]. The chloro-thiazolylhydrazone compound 4EGI-1 is an inhibitor that has been reported to have a structure-activity relationship (SAR) and anticancer activity [31,32].…”

“…The chloro-thiazolylhydrazone compound 4EGI-1 is an inhibitor that has been reported to have a structure-activity relationship (SAR) and anticancer activity [31,32]. Thus, we designed two series of thiazolylhydrazone derivatives containing the active moiety of the dimethoxyphenol ring, based on the structure-activity relationships (SARs) identified in our previous research studies [30,31,33]. We introduced fluorine to alter the physical properties and binding characteristics of the compound, to develop novel drugs [34].…”

An UHPLC-TOF-MS method for quantifying novel brominated anticancer compound bromophenol-thiosemicarbazone hybrid and its application to in vivo pharmacokinetic study

“…Bromophenol-thiosemicarbazone hybrid was a kind of novel synthetic brominated anticancer compound, with two bromine atoms. Pharmacological results showed that bromophenol-thiosemicarbazone hybrid showed considerable better inhibitory activity of PARP1 (IC 50 = 29.5 nmol/ L) (Guo, wang et al 2019). Generally, most naturally occurring bromine consists of a mixture of two stable isotopes: 79 Br and 81 Br (Heumann, Smith et al 1998).…”