Christopher Wild

Novel Nitrogen-Enriched Oridonin Analogues with Thiazole-Fused A‑Ring: Protecting Group-Free Synthesis, Enhanced Anticancer Profile, and Improved Aqueous Solubility

Oridonin (1), a complex ent-kaurane diterpenoid isolated from the traditional Chinese herb Isodon rubescens , has demonstrated great potential in the treatment of various human cancers due to its unique and safe anticancer pharmacological profile. Nevertheless, the clinical development of oridonin for cancer therapy has been hampered by its relatively moderate potency, limited aqueous solubility, and poor bioavailability. Herein, we report the concise synthesis of a series of novel nitrogen-enriched oridonin derivatives with thiazole-fused A-ring through an efficient protecting group-free synthetic strategy. Most of them, including compounds 7-11, 13, and 14, exhibited potent antiproliferative effects against breast, pancreatic, and prostate cancer cells with low micromolar to submicromolar IC50 values as well as markedly enhanced aqueous solubility. These new analogues obtained by rationally modifying the natural product have been demonstrated not only to significantly induce the apoptosis and suppress growth of triple-negative MDA-MB-231 breast cancer both in vitro and in vivo but also effective against drug-resistant ER-positive MCF-7 clones.

Oridonin Ring A-Based Diverse Constructions of Enone Functionality: Identification of Novel Dienone Analogues Effective for Highly Aggressive Breast Cancer by Inducing Apoptosis

Oridonin (1) has attracted considerable attention in recent years because of its unique and safe anticancer pharmacological profile. Nevertheless, it exhibits moderate to poor effects against highly aggressive cancers including triple-negative and drug-resistant breast cancer cells. Herein, we report the rational design and synthesis of novel dienone derivatives with an additional α,β-unsaturated ketone system diversely installed in the A-ring based on this class of natural scaffold that features dense functionalities and stereochemistry-rich frameworks. Efficient and regioselective enone construction strategies have been established. Meanwhile, a unique 3,7-rearrangement reaction was identified to furnish an unprecedented dienone scaffold. Intriguingly, these new analogues have been demonstrated to significantly induce apoptosis and inhibit colony formation with superior antitumor effects against aggressive and drug-resistant breast cancer cells in vitro and in vivo while also exhibiting comparable or lower toxicity to normal human mammary epithelial cells in comparison with 1.

Small Molecule InhibitorsTargeting Activator Protein1 (AP-1): Miniperspective

Activator protein 1 (AP-1) is a pivotal transcription factor that regulates a wide range of cellular processes including proliferation, apoptosis, differentiation, survival, cell migration, and transformation. Accumulating evidence supports that AP-1 plays an important role in several severe disorders including cancer, fibrosis, and organ injury, as well as inflammatory disorders such as asthma, psoriasis, and rheumatoid arthritis. AP-1 has emerged as an actively pursued drug discovery target over the past decade. Excitingly, a selective AP-1 inhibitor T-5224 (51) has been investigated in phase II human clinical trials. Nevertheless, no effective AP-1 inhibitors have yet been approved for clinical use. Despite significant advances achieved in understanding AP-1 biology and function, as well as the identification of small molecules modulating AP-1 associated signaling pathways, medicinal chemistry efforts remain an urgent need to yield selective and efficacious AP-1 inhibitors as a viable therapeutic strategy for human diseases.

Overcoming Synthetic Challenges of Oridonin A-Ring Structural Diversification: Regio- and Stereoselective Installation of Azides and 1,2,3-Triazoles at the C-1, C-2, or C-3 Position

Efficient and concise synthetic approaches have been developed for the rapid and diverse installation of azide functionalities at the C-1, C-2, or C-3 positions of oridonin (1) with highly controlled regio- and stereoselectivity, while keeping key reactive pharmacophores intact by utilizing unique preactivation strategies based on the common synthon 4. Further functionalization of these azides through click chemistry yielding triazole derivatives successfully provides access to an expanded natural scaffold-based compound library for potential anticancer agents.

Discovery and development of natural product oridonin-inspired anticancer agents

Natural products have historically been, and continue to be, an invaluable source for the discovery of various therapeutic agents. Oridonin, a natural diterpenoid widely applied in traditional Chinese medicines, exhibits a broad range of biological effects including anticancer and anti-inflammatory activities. To further improve its potency, aqueous solubility and bioavailability, the oridonin template serves as an exciting platform for drug discovery to yield better candidates with unique targets and enhanced drug properties. A number of oridonin derivatives (e.g. HAO472) have been designed and synthesized, and have contributed to substantial progress in the identification of new agents and relevant molecular mechanistic studies toward the treatment of human cancers and other diseases. This review summarizes the recent advances in medicinal chemistry on the explorations of novel oridonin analogues as potential anticancer therapeutics, and provides a detailed discussion of future directions for the development and progression of this class of molecules into the clinic.

Small molecule inhibitors targeting activator protein 1 (AP-1).

Activator protein 1 (AP-1) is a pivotal transcription factor that regulates a wide range of cellular processes including proliferation, apoptosis, differentiation, survival, cell migration, and transformation. Accumulating evidence supports that AP-1 plays an important role in several severe disorders including cancer, fibrosis, and organ injury, as well as inflammatory disorders such as asthma, psoriasis, and rheumatoid arthritis. AP-1 has emerged as an actively pursued drug discovery target over the past decade. Excitingly, a selective AP-1 inhibitor T-5224 (51) has been investigated in phase II human clinical trials. Nevertheless, no effective AP-1 inhibitors have yet been approved for clinical use. Despite significant advances achieved in understanding AP-1 biology and function, as well as the identification of small molecules modulating AP-1 associated signaling pathways, medicinal chemistry efforts remain an urgent need to yield selective and efficacious AP-1 inhibitors as a viable therapeutic strategy for human diseases.

Direct Activation of Bax Protein for Cancer Therapy

Bax, a central cell death regulator, is an indispensable gateway to mitochondrial dysfunction and a major proapoptotic member of the B‐cell lymphoma 2 (Bcl‐2) family proteins that control apoptosis in normal and cancer cells. Dysfunction of apoptosis renders the cancer cell resistant to treatment as well as promotes tumorigenesis. Bax activation induces mitochondrial membrane permeabilization, thereby leading to the release of apoptotic factor cytochrome c and consequently cancer cell death. A number of drugs in clinical use are known to indirectly activate Bax. Intriguingly, recent efforts demonstrate that Bax can serve as a promising direct target for small‐molecule drug discovery. Several direct Bax activators have been identified to hold promise for cancer therapy with the advantages of specificity and the potential of overcoming chemo‐ and radioresistance. Further investigation of this new class of drug candidates will be needed to advance them into the clinic as a novel means to treat cancer.

ent-Kaurane-based regio- and stereoselective inverse electron demand hetero-Diels–Alder reactions: synthesis of dihydropyran-fused diterpenoids

A mild and concise approach for the construction of a 3,4-dihydro-2H-pyran ring integrated into the A-ring of the natural product oridonin using an optimized inverse electron demand hetero-Diels-Alder (IED HDA) reaction is reported herein. A self-dimerization of the exocyclic enone installed in the A-ring through a homo-HDA reaction was identified to exclusively give a dimeric ent-kaurane diterpenoid with the spirochroman core. Moreover, efficient cross-HDA cycloadditions of this enone with various vinyl ethers or vinyl sulfides, instead of its own homo-HDA dimerization, were achieved in a regio- and stereoselective manner, thus providing access to novel dihydropyran-fused diterpenoids as potential anticancer agents to overcome chemoresistance.

A Combined Bioinformatics and Chemoinformatics Approach for Developing Asymmetric Bivalent AMPA Receptor Positive Allosteric Modulators as Neuroprotective Agents

PAMs new in town! An effective, combined bioinformatics and chemoinformatics approach was applied to the design of novel asymmetric bivalent α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor positive allosteric modulators (PAMs) with marked potency in vitro and efficacy in vivo for preventing neuroapoptosis. The novel chemotype could provide pharmacological probes and potential therapeutic agents for glutamatergic hypofunction and its related neurological and psychiatric disorders.

Discovery of Potent Anticancer Agent HJC0416, an Orally Bioavailable Small Molecule Inhibitor of Signal Transducer and Activator of Transcription 3 (STAT3)

In a continuing effort to develop orally bioavailable small-molecule STAT3 inhibitors as potential therapeutic agents for human cancer, a series of novel diversified analogues based on our identified lead compound HJC0149 (1) (5-chloro-N-(1,1-dioxo-1H-1λ(6)-benzo[b]thiophen-6-yl)-2-hydroxybenzamide, Eur. J. Med. Chem. 2013, 62, 498-507) have been rationally designed, synthesized, and pharmacologically evaluated. Molecular docking studies and biological characterization supported our earlier findings that the O-alkylamino-tethered side chain on the hydroxyl group is an effective and essential structural determinant for improving biological activities and druglike properties of these molecules. Compounds with such modifications exhibited potent antiproliferative effects against breast and pancreatic cancer cell lines with IC50 values from low micromolar to nanomolar range. Among them, the newly discovered STAT3 inhibitor 12 (HJC0416) displayed an intriguing anticancer profile both in vitro and in vivo (i.p. & p.o.). More importantly, HJC0416 is an orally bioavailable anticancer agent as a promising candidate for further development.