(E)-N'-Arylidene-2-(4-oxoquinazolin-4(3H)-yl) acetohydrazides: Synthesis and evaluation of antitumor cytotoxicity and caspase activation activity

Abstract

In our search for novel small molecules activating procaspase-3, we have designed and synthesised a series of novel acetohydrazides incorporating quinazolin-4(3H)-ones (5, 6, 7). Biological evaluation revealed eight compounds with significant cytotoxicity against three human cancer cell lines (SW620, colon cancer; PC-3, prostate cancer; NCI-H23, lung cancer). The most potent compound 5t displayed cytotoxicity up to 5-fold more potent than 5-FU. Analysis of structure-activity relationships showed that the introduction of different substituents at C-6 position on the quinazolin-4(3H)-4-one moiety, such as 6-chloro or 6-methoxy potentially increased the cytotoxicity of the compounds. In term of caspase activation activity, several compounds were found to exhibit potent effects, (e.g. compounds 7 b, 5n, and 5l). Especially, compound 7 b activated caspases activity by almost 200% in comparison to that of PAC-1. Further docking simulation also revealed that this compound potentially is a potent allosteric inhibitor of procaspase-3.

New Acetohydrazides Incorporating 2‐Oxoindoline and 4‐Oxoquinazoline: Synthesis and Evaluation of Cytotoxicity and Caspase Activation Activity

“…The second step involved a reaction of the intermediates 2a – 2e with ethyl chloroacetate. This was a nucleophilic substitution reaction which best occurred in acetone as a solvent and K 2 CO 3 was used as a base . A small amount of KI was used to facilitate the reaction.…”

“…All target compounds synthesized were structurally confirmed by spectroscopic data, including IR, MS, 1 H‐ and 13 C‐NMR. All 1 H‐NMR spectra of compounds 5a – 5t showed typical peaks around 4.81–5.22 ppm, which were attributable for two methylene protons . The methylene carbons, meanwhile, appeared around 44–46 ppm in the 13 C‐NMR spectra.…”

“…Up to date, however, it still lacks a zinc‐bound crystal structure of procaspase‐3. To address this issue, we followed the same protocol published recently . We selected a homologous structure of caspase‐3, that is caspased‐6 inhibited by zinc ion whose crystallographic coordinates was determined at acceptable resolution (2.85 Å) .…”

“…Yields, physical properties and spectroscopic data of the compounds are described below. The data for compounds 5a have been reported previously …”

“…The X‐ray crystal structure of caspase‐6 was retrieved from the Protein Data Bank (PDB ID: 4FXO) as the protein model for the docking studies. Docking simulations were carried out by using the MOE Triangle Matcher placement method, keeping the protein rigid and the ligands flexible . The cofactor zinc ion and water molecules insight the binding site were conserved as they are an integral part of allosteric mechanisms .…”