Abstract
A series of new Olaparib derivatives was designed and synthesized, and their inhibitory activities against poly (ADP-ribose) polymerases-1 (PARP-1) enzyme and cancer cell line MDA-MB-436 in vitro were evaluated. The results showed that compound 5l exhibited the most potent inhibitory effects on PARP-1 enzyme (16.10 ± 1.25 nM) and MDA-MB-436 cancer cell (11.62 ± 2.15 μM), which was close to that of Olaparib. As a PARP-1 inhibitor had been reported to be viable to neuroprotection, in order to search for new multitarget-directed ligands (MTDLs) for the treatment of Alzheimer’s disease (AD), the inhibitory activities of the synthesized compounds against the enzymes AChE (from electric eel) and BChE (from equine serum) were also tested. Compound 5l displayed moderate BChE inhibitory activity (9.16 ± 0.91 μM) which was stronger than neostigmine (12.01 ± 0.45 μM) and exhibited selectivity for BChE over AChE to some degree. Molecular docking studies indicated that 5l could bind simultaneously to the catalytic active of PARP-1, but it could not interact well with huBChE. For pursuit of PARP-1 and BChE dual-targeted inhibitors against AD, small and flexible non-polar groups introduced to the compound seemed to be conducive to improving its inhibitory potency on huBChE, while keeping phthalazine-1-one moiety unchanged which was mainly responsible for PARP-1 inhibitory activity. Our research gave a clue to search for new agents based on AChE and PARP-1 dual-inhibited activities to treat Alzheimer’s disease.
Highlights
(ADP-ribose) polymerases-1 (PARP-1) is a pivotal nuclear enzyme ubiquitously expressed in eukaryotic cells
Inhibition of Poly (ADP-ribose) polymerases-1 (PARP-1) accelerates the damage of injured DNA, which especially leads to synthetic lethality in DNA-repairing-deficient cancer cells, for example BRCA1/ 2-deficient cells
In view of the important therapeutic value of PARP-1 inhibitor for cancer and potentially for Alzheimer’s disease (AD) treatment, it was interesting and deserved to further explore structural optimization of Olaparib based on the existed structure–activity relationship (SAR)
Summary
(ADP-ribose) polymerases-1 (PARP-1) is a pivotal nuclear enzyme ubiquitously expressed in eukaryotic cells. Its anticancer activity was not potent enough[7,21], and it showed dose-limiting toxicity that was more pronounced than that seen with the chemotherapeutic agents alone when it was utilized in combination with chemotherapeutic agents for cancer treatment[22] To overcome these shortcomings, several modifications based on structural skeleton of Olaparib have been reported (Figure 1)[21,22,23,24]. In view of the important therapeutic value of PARP-1 inhibitor for cancer and potentially for AD treatment, it was interesting and deserved to further explore structural optimization of Olaparib based on the existed SAR With this aim in mind, we decided to keep the 4-benzyl phthalazinone group unchanged and replace the cyclopropane group of Olaparib by substituted aryl vinyl ones to constitute 3-aromatic a, b-unsaturated carbonyl moiety. We described the synthesis and bioactivities assays of 15 Olaparib derivatives; molecular dockings were conducted to investigate their interaction fashion with the corresponding proteins
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