Jinhui Hu

Synthesis, Evaluation, and Mechanism Study of Novel Indole-Chalcone Derivatives Exerting Effective Antitumor Activity Through Microtubule Destabilization in Vitro and in Vivo

Twenty-nine novel indole-chalcone derivatives were synthesized and evaluated for antiproliferative activity. Among them, 14k exhibited most potent activity, with IC50 values of 3-9 nM against six cancer cells, which displayed a 3.8-8.7-fold increase in activity when compare with compound 2. Further investigation revealed 14k was a novel tubulin polymerization inhibitor binding to the colchicine site. Its low cytotoxicity toward normal human cells and nearly equally potent activity against drug-resistant cells revealed the possibility for cancer therapy. Cellular mechanism studies elucidated 14k arrests cell cycle at G2/M phase and induces apoptosis along with the decrease of mitochondrial membrane potential. Furthermore, good metabolic stability of 14k was observed in mouse liver microsomes. Importantly, 14k and its phosphate salt 14k-P inhibited tumor growth in xenograft models in vivo without apparent toxicity, which was better than the reference compound CA-4P and 2. In summary, 14k deserves consideration for cancer therapy.

Synthesis, biological evaluation and mechanism study of chalcone analogues as novel anti-cancer agents

A series of novel chalcone analogues were designed, synthesized and evaluated as anticancer agents. The results of antiproliferative activity tests showed that most of the analogues exhibited moderate to very good antiproliferative activities with GI50 values in the micromol to sub-micromol range. Especially compound 10a gave 0.026 μM to 0.035 μM GI50 for five cancer cell lines. The mechanistic studies including tubulin polymerization inhibition, disruption of microtubule dynamics and cell cycle arrest assay demonstrated that compound 10a could effectively inhibit in vitro cellular tubulin polymerization, interfere with the mitosis, resulting in a prolonged G2/M cell cycle arrest and ultimately lead to cell apoptosis of cancer cells. Taken together, these results suggested that 10a may became a promising lead compound for development of new anticancer drugs.

A novel synthetic compound exerts effective anti-tumour activity in vivo via the inhibition of tubulin polymerisation in A549 cells.

Microtubules are critical elements that are involved in a wide range of cellular processes, and thus, they have become an attractive target for many anticancer drugs. A novel synthesised compound, 12P, was identified as new microtubule inhibitor. This compound inhibits tubulin polymerisation through binding to the colchicine-binding site of tubulin. 12P exhibits excellent anti-proliferative activities against a panel of human cancer cell lines, with IC₅₀ values range from 9 to 55nM. Interestingly, compound 12P also displayed equally potent cytotoxicity against several drug-resistant cell lines, and it showed high selectivity for active human umbilical vein endothelial cells (HUVECs). Further flow cytometric analysis showed that 12P induces G₂/M phase arrest and apoptosis in A549 cells. Cellular studies have revealed that the induction of apoptosis by 12P was associated with a collapse of mitochondrial membrane potential (MMP), accumulation of reactive oxygen species (ROS), alterations in the expression of some cell cycle-related proteins (e.g. Cyclin B1, Cdc25c, Cdc2) and some apoptosis-related proteins (e.g. Bax, Bad, Bcl-2, Bcl-xl). Importantly, 12P significantly reduced the growth of xenograft tumours of A549 cells in vivo (tumour inhibitory rate of 12P: 84.2%), without any loss of body weight. Taken together, these in vitro and in vivo results suggested that 12P may become a promising lead compound for the development of new anticancer drugs.

Synthesis, biological evaluation and mechanism study of a class of benzylideneindanone derivatives as novel anticancer agents

A series of new benzylideneindanone derivatives were designed, synthesized and evaluated as antitumor agents. Structure–activity relationship (SAR) studies showed that derivatives with 4,5,6-trimethoxyl on an indanone moiety displayed good anti-proliferative activities. Especially, compound 5a demonstrated the most potent inhibitory activity, with GI50 values from 0.172 to 0.57 μM for five kinds of cancer cell lines. Further investigation showed that 5a could inhibit microtubule polymerization and thus induce G2/M phase arrest and apoptosis in A549 cells. Our findings revealed the benzylideneindanone moiety as a new attractive scaffold for mitosis-targeting drug discovery.

Design, synthesis, and evaluation of multitarget-directed ligands against Alzheimer's disease based on the fusion of donepezil and curcumin

By fusing donepezil and curcumin, a novel series of compounds were obtained as multitarget-directed ligands against Alzheimers disease. Among them, compound 11b displayed potent acetylcholinesterase (AChE) inhibition (IC50=187nM) and the highest BuChE/AChE selectivity (66.3). Compound 11b also inhibited 45.3% Aβ1-42 self-aggregation at 20μM and displayed remarkable antioxidant effects. The metal-chelating property of compound 11b was elucidated by determining the 1:1 stoichiometry for the 11b-Cu(II) complex. The excellent blood-brain barrier permeability of 11b also indicated the potential for the compound to penetrate the central nervous system.

Synthesis and Biological Evaluation of Selenium-Containing 4-Anilinoquinazoline Derivatives as Novel Antimitotic Agents

Twenty-eight novel selenium-containing 4-anilinoquinazoline derivatives were designed, synthesized, and evaluated as antiproliferative agents. Most of them had significant in vitro activities, particularly for compounds 23a, 25a, and 25d, which also exhibited the most potent antitumor activities against cisplatin-resistant cell lines and the doxorubicin-resistant cell lines, good selectivity toward normal cells, and obvious inhibitory effect on migration of A549 cell lines. Further mechanistic studies revealed that 23a, 25a, and 25d induce G2/M phase arrest and apoptosis in A549 cells, which was associated with a collapse of the mitochondrial membrane potential, alterations in the expression of some cell cycle-related and apoptosis-related proteins, and increasing the intracellular ROS level. Finally, compounds 23a, 25a, and 25d also effectively inhibited the tumor growth in the A549 xenograft model without obvious hints of toxicity. Taken together, these in vitro and in vivo results suggest that 23a, 25a, and 25d may be promising microtubule-stabilizing agents and can be used as a promising lead for the development of new antitumor agents.

Synthesis, biological evaluation and mechanism study of a class of cyclic combretastatin A-4 analogues as novel antitumour agents

In the course of our search for novel antitumor agents, a series of cyclic combretastatin A-4 (CA-4) analogues bearing an amide group, A–B or B–C ring condensation, and CC or CN bond in the B ring were designed, synthesized and identified as new microtubule inhibitors. The structure–activity relationship (SAR) studies showed that the hexa-cyclic compounds bearing B–C ring condensation, containing a CC bond in the B ring (4a) provided excellent antiproliferative activities at nanomolar concentrations against various cancer cell lines (IC50 = 46–80 nM). 4a inhibited tubulin assembly at a micromolar range (IC50 = 2.56 ± 0.15 μM) as evidenced by a molecular docking study, which revealed that 4a exerted tubulin polymerisation inhibitory activity by binding to the colchicine binding site of tubulin. Further molecular biology studies showed that 4a disrupted intracellular microtubule polymerisation and thus induced G2/M phase arrest and apoptotsis in A549 cells. Altogether, these results we obtained can guide the design of novel potent molecules for future development.

Design, synthesis, and biological evaluation of histone deacetylase inhibitors possessing glutathione peroxidase-like and antioxidant activities against Alzheimer’s disease

A series of hybrids containing the pharmacophores of the histone deacetylase (HDAC) inhibitor, SAHA, and the antioxidant ebselen were designed and synthesized as multi-target-directed ligands against Alzheimers disease. An in vitro assay indicated that some of these molecules exhibit potent HDAC inhibitory activity and ebselen-related pharmacological effects. Specifically, the optimal compound 7f was found to be a potent HDAC inhibitor (IC50 = 0.037 μM), possessing rapid hydrogen peroxide scavenging activity and glutathione peroxidase-like activity (ν0 = 150.0 μM min-1) and good free oxygen radical absorbance capacity (value of ORAC: 2.2). Furthermore, compound 7f showed significant protective effects against damage induced by H2O2 and the ability to prevent ROS accumulation in PC12 cells.

Design, Synthesis, and Biological Evaluation of Dual-Target Inhibitors of Acetylcholinesterase (AChE) and Phosphodiesterase 9A (PDE9A) for the Treatment of Alzheimer’s Disease

A series of dual-target AChE/PDE9A inhibitor compounds were designed, synthesized, and evaluated as anti-Alzheimers Disease (AD) agents. Among these target compounds, 11a (AChE: IC50 = 0.048 μM; PDE9A: IC50 = 0.530 μM) and 11b (AChE: IC50 = 0.223 μM; PDE9A: IC50 = 0.285 μM) exhibited excellent and balanced dual-target AChE/PDE9A inhibitory activities. Meanwhile, those two compounds possess good blood-brain barrier (BBB) penetrability and low neurotoxicity. Especially, 11a and 11b could ameliorate learning deficits induced by scopolamine (Scop). Moreover, 11a could also improve cognitive and spatial memory in Aβ25-35-induced cognitive deficit mice in the Morris water-maze test. In summary, our research developed a series of potential dual-target AChE/PDE9A inhibitors, and the data indicated that 11a was a promising candidate drug for the treatment of AD.