Design,Synthesis And Mechanism Investigation Of Cinnamic Acid-,Curcumin-,Cinnamaldehyde-,and Tanshinone-inspired Cancer Chemopreventive Agents

ROS act as a double-edged sword which play both suppressing and promoting roles in the progression of cancer. Thus, both prooxidant- and antioxidant-based anticancer agents have been developed. Due to the safety and multi-targeting properties, natural products such as cinnamic acid,curcumin, cinnamic aldehyde and tanshinones have attractted widespread interest in the past decade for their potential in cancer prevention and treatment. Redox dysregulation originating from metabolic alterations and dependence on mitogenic and survival signaling through ROS represents redox Achilles of cancer cells that can be selectively targeted by redox chemotherapeutics. The purpose of this work is to design natural product-inspired anticancer agents based on both ROS-scavenging and ROS-promoting strategy, and investigate their redox-directed cancer chemoprevention mechanisms. The main achievements and innovations are as follows:(1) To optimize antioxidant activity and lipophilicity of cinnamic acid derivatives (CAs)including ferulic acid, sinapic acid, 3,4-dimethoxycinnamic acid, and p-hydroxycinnamic acid,four analogs bearing an additional double bond between their aromatic ring and propenoic acid moiety were designed and synthesized based on the conjugated chain elongation strategy. The antioxidant performance of the CAs were investigated by 2,2’-diphenyl-1-picrylhydrazyl(DPPH·)-scavenging, ferric reducing/antioxidant power, cyclic voltammetry, DNA strand breakage-inhibiting and anti-haemolysis activity assays. It was found that CAs with elongation of conjugated chains display increased DPPH·-scavenging. DNA strand breakage-inhibiting and anti-haemolysis activities as compared to their parent molecules, due to their improved hydrogen atom-donating ability and lipophilicity.(2) It is demonstrated for the first time that two symmetrical hexamethoxy-diarylpentadienones (1 and 2) as cucumin analogs could act as dual-effective TrxR inhibitors, not only inactivating TrxR but also converting this antioxidant enzyme into an ROS promoter with a NADPH oxidase-like activity. This leads to a burst in PROS, falling apart of the redox buffering system and then a G2/M cell cycle arrest in NCI-H460 cells by decreasing the expression levels of cyclin B1 and Cdkl via up-regulation of p53 and p21, and down-regulation of Cdc25C. Additionally, the cell cycle arrest activity of compound 1 is derived in part from its inhibition against tubulin polymerization.(3) For a better understanding of the structural requirements for the anticancer activity of cinnamaldehyde analogs, we chose cinnamaldehyde as a chemical scaffold on which several modifications were performed, including hydroxy or trifluoromethyl ortho-substitutions and elongation of the conjugated chains. Their ROS generating capacity, ROS-dependent cell cycle arrest and apoptotic inducing activities in NCI-H460 cells along with TrxR-inhibitory activities were further researched. An interesting relationship was found between all these properties and their electrophilic reactivity. The results highlight that both the length of conjugated chains and ortho-substitutions affect the Michael pharmacophore reactivity and TrxR inhibiting activity,which mainly determine cytotoxicity of the cinnamaldyhyde analogs.(4) Our investigations on tanshinones including Tanshinone I (Tsl), Tanshinone IIA (Ts2A)and Cryptotanshinone (CTs) demonstrate that these compounds act as copper ionophores to raise intracellular copper levels and show synergistic cytotoxicity with Cu2+ against human hepatoma cells HepG2. Among them, Tsl manifests the strongest synergistic effect for cell growth inhibition and is the best copper ionophore. As a consequence of copper accumulation, increased intracellular ROS revel, disturbed redox balance and a G2/M-phase specific apoptosis are caused,after treatment with Tsl and Cu2+ in combination.