Chunlin Zhuang

Rapid Identification of Keap1–Nrf2 Small-Molecule Inhibitors through Structure-Based Virtual Screening and Hit-Based Substructure Search

In this study, rapid structure-based virtual screening and hit-based substructure search were utilized to identify small molecules that disrupt the interaction of Keap1-Nrf2. Special emphasis was placed toward maximizing the exploration of chemical diversity of the initial hits while economically establishing informative structure-activity relationship (SAR) of novel scaffolds. Our most potent noncovalent inhibitor exhibits three times improved cellular activation in Nrf2 activation than the most active noncovalent Keap1 inhibitor known to date.

Discovery, synthesis, and biological evaluation of orally active pyrrolidone derivatives as novel inhibitors of p53-MDM2 protein-protein interaction.

The p53-MDM2 interaction has been proved to be a valuable target to develop effective antitumor agents. Novel p53-MDM2 inhibitors bearing pyrrolidone scaffolds were successfully identified by structure-based design. The nanomolar inhibitor 5 possessed good p53-MDM2 inhibitory activity (K(i) = 780 nM) due to its hydrophobic and hydrogen bonding interactions with MDM2. Further hit optimization led to the discovery of a number of highly potent pyrrolidone derivatives with improved p53-MDM2 inhibitory activity and in vitro antiproliferative potency. Compounds 41 (K(i) = 260.0 nM) and 60a (K(i) = 150.0 nM) showed good and selective activity against tumor cells with deleted p53. In addition, these two compounds also effectively inhibited the tumor growth in the A549 xenograft model. Interestingly, compound 41 was proved to be a potent MDM2/MDMX dual inhibitor. The novel pyrrolidone p53-MDM2 inhibitors represent promising lead structures for the development of novel antitumor agents.

Chalcone: A Privileged Structure in Medicinal Chemistry

Privileged structures have been widely used as an effective template in medicinal chemistry for drug discovery. Chalcone is a common simple scaffold found in many naturally occurring compounds. Many chalcone derivatives have also been prepared due to their convenient synthesis. These natural products and synthetic compounds have shown numerous interesting biological activities with clinical potentials against various diseases. This review aims to highlight the recent evidence of chalcone as a privileged scaffold in medicinal chemistry. Multiple aspects of chalcone will be summarized herein, including the isolation of novel chalcone derivatives, the development of new synthetic methodologies, the evaluation of their biological properties, and the exploration of the mechanisms of action as well as target identification. This review is expected to be a comprehensive, authoritative, and critical review of the chalcone template to the chemistry community.

Double-Edged Swords as Cancer Therapeutics: Novel, Orally Active, Small Molecules Simultaneously Inhibit p53–MDM2 Interaction and the NF-κB Pathway

Simultaneous inactivation of p53 and hyperactivation of nuclear factor-κB (NF-κB) is a common occurrence in human cancer. Currently, antitumor agents are being designed to selectively activate p53 or inhibit NF-κB. However, there is no concerted effort yet to deliberately design inhibitors that can simultaneously do both. This paper provided a proof-of-concept study that p53-MDM2 interaction and NF-κB pathway can be simultaneously targeted by a small-molecule inhibitor. A series of pyrrolo[3,4-c]pyrazole derivatives were rationally designed and synthesized as the first-in-class inhibitors of p53-MDM2 interaction and NF-κB pathway. Most of the compounds were identified to possess nanomolar p53-MDM2 inhibitory activity. Compounds 5q and 5s suppressed NF-κB activation through inhibition of IκBα phosphorylation and elevation of the cytoplasmic levels of p65 and phosphorylated IKKα/β. Biochemical assay for the kinases also supported the fact that pyrrolo[3,4-c]pyrazole compounds directly targeted the NF-κB pathway. In addition, four compounds (5j, 5q, 5s, and 5u) effectively inhibited tumor growth in the A549 xenograft model. Further pharmacokinetic study revealed that compound 5q exhibited excellent oral bioavailability (72.9%).

A new strategy to improve the metabolic stability of lactone: discovery of (20S,21S)-21-fluorocamptothecins as novel, hydrolytically stable topoisomerase I inhibitors.

Lactone is a common structural motif in biologically active natural products. However, the metabolic instability of lactone significantly reduces their in vivo potency. In the present investigation, a new strategy to improve the metabolic stability of lactone was provided by the design of α-fluoro ether as a novel bioisostere of lactone. The effectiveness of the α-fluoro ether/lactone replacement was validated by the discovery of (20S,21S)-21-fluorocamptothecins as hydrolytically stable topoisomerase I inhibitors. A highly potent camptothecin derivative, 8l, was successfully identified, which showed excellent in vitro and in vivo antitumor activities and represents a promising lead for the discovery of novel antitumor agents. Interestingly, this study also provided a new structure-activity relationship for the C21-carbonyl group of camptothecin, which has been regarded as an essential pharmacophore. Our results revealed that the conserved C21-carbonyl group can be replaced by a fluorine substituent. α-Fluoro ether may have general application in improving the metabolic stability of lactone.

Design, synthesis and biological activity of piperlongumine derivatives as selective anticancer agents.

In an effort to expand the structure-activity relationship of the natural anticancer compound piperlongumine, we have prepared sixteen novel piperlongumine derivatives with halogen or morpholine substituents at C2 and alkyl substituents at C7. Most of 2-halogenated piperlongumines showed potent in vitro activity against four cancer cells and modest selectivity for lung normal cells. The highly active anticancer compound 11h exhibited obvious ROS elevation and excellent in vivo antitumor potency with suppressed tumor growth by 48.58% at the dose of 2 mg/kg. The results indicated that halogen substituents as electrophilic group at C2 played an important role in increasing cytotoxicity.

Structure–activity relationship and antitumor activity of thio-benzodiazepines as p53–MDM2 protein–protein interaction inhibitors

In order to discuss the structure-activity relationship (SAR) of the thio-benzodiazepine compounds which showed excellent activity against p53-MDM2 protein-protein interaction, we designed and synthesized twenty compounds with electrophilic and nucleophilic groups on the benzene ring. Among them, compounds 8i (K(i) = 91 nM) and 8n (K(i) = 89 nM) showed better binding activity than that of the reference drug Nutlin-3a (K(i) = 121 nM). In addition, in vitro antitumor activity against Saos-2, U-2 OS, A549 and NCI-H1299 cell-lines were assayed by the MTT method. Especially, compounds 8i and 8n possessed excellent biological activity and good selectivity comparable to Nutlin-3a, which were promising candidates for further evaluation.

Synthesis and biological evaluation of thio-benzodiazepines as novel small molecule inhibitors of the p53-MDM2 protein-protein interaction.

A series of thio-benzodiazepine p53-MDM2 inhibitors were designed and synthesized based on the principle of bioisosterism. Most of the thio-benzodiazepines had nanomolar to micromolar affinity toward MDM2. Particularly, compounds 8a (K(i) = 0.52μM) and 8f (K(i) = 0.32 μM) showed binding activity comparable to the positive drug nutlin-3a (K(i) = 0.23 μM). Meanwhile, compound 8j exhibited excellent antitumor activity against the U-2 OS human osteosarcoma cell line with an IC(50) value of 1.06 μM, which was about 23 times higher than that of nutlin-3a. The docking model also successfully predicted that this class of compounds mimicked three p53 critical residues binding to MDM2. The thio-benzodiazepines represent a promising class of non-peptide inhibitors of the p53-MDM2 interaction.

Synthesis and biological evaluation of novel 7-acyl homocamptothecins as Topoisomerase I inhibitors

A series of novel 7-acyl derivatives of homocamptothecin (hCPT) were designed and synthesized with the purpose to improve antitumor activity of hCPT, via Minisci free-radical reaction from 10-methoxyhomocamptothecin. All the compounds were evaluated for in vitro cytotoxicity against three cancer cell lines (A549, MDA-MB-435 and HCT116). For MDA-MB-435 cell line, compounds, 6a, 6b, 6k and all of 7-alkylcabonyl homocamptothecin derivatives showed higher in vitro inhibitory activities than topotecan (TPT). Furthermore, compounds 6d, 6e, and 6k showed highly potent inhibitory activities with the IC50 values from less than 1 nM to 2.2 nM. In Topoisomerase I (Topo I)-induced DNA cleavage assay, compounds 6a, 6d, and 6k, as compared to CPT, revealed higher Topo I inhibitory activity.

Design, synthesis and structure–activity relationships of new triazole derivatives containing N-substituted phenoxypropylamino side chains

The incidence of invasive fungal infections and resistance to antifungal agents is increasing dramatically. It is highly desirable to develop novel azoles with improved biological profiles. The structure-activity relationship (SAR) of the N-substitutions was investigated in this study. In vitro antifungal activities revealed that sterically large groups were not favored for the N-substitutions. The removal of the N-substitutions had little effect on the antifungal activity. Two compounds with free amine group (i.e.9a and 10a) showed excellent activity with broad antifungal spectrum. The SAR results were supported by molecular docking and the N-substitutions were found to be important for the conformation of the side chains. The SAR and binding mode of the azoles are useful for further lead optimization.