Research Interests and Funding Source

Our research interests are in the general area of synthetic medicinal chemistry and bioorganic chemistry. We are interested in the design of anticancer prodrugs for the site-specific activation in tumor tissues, enzyme mechanism and inhibition, design of inhibitors of protein-protein interactions, and the development of organic synthetic methodology. Specifically, efforts are being focused on the design, synthesis and evaluation of anticancer prodrugs for the treatment of advanced prostate cancer, the development of Eph receptor antagonists to interfere with the protein-protein interactions between Eph receptors and their protein ligand ephrins, and the discovery of small molecule inhibitors of Keap1-Nrf2 interaction.

1. Design, Synthesis and Evaluation of Anticancer Prodrugs

Many anticancer agents in current clinical use lack the desired tumor-selectivity and are associated with systemic side effects. Prodrug design is one approach that could potentially improve the target-selectivity of anticancer agents. Efforts in our laboratory have been focused on designing analogs of cyclophosphamide and phosphoramide mustard (PM) to move the site of activation from the liver to tumor tissues through the incorporation of reductive and proteolytic triggers.

A series of nitroaromatic analogs and peptide aminoarylmethyl conjugates has been designed to efficiently release the active phosphoramide mustard in a site-specific manner in tumor tissues, thus increasing the selectivity in killing cancer cells and decreasing systemic toxicity. Traceless linkers have been designed and optimized to efficiently release the active phosphoramide mustard through the incorporation of fluorine substitutions. We also successfully developed a new amidation reaction for the preparation of peptide-aminoarylmethyl PM conjugates using selenocarboxylates and azides, thus avoiding the use of unstable basic nucleophilic amine intermediates. The prodrugs were shown to be stable under physiological conditions including whole blood. The nitroaryl phosphoramidates were shown to be excellent substrates of E. coli nitroreductase and highly cytotoxic towards nitroreductase-expressing V79 and SKOV3 cells. When the peptide used is a substrate of prostate-specific antigen (PSA), the peptide-aminoarylmethyl PM conjugates were activated by PSA and have been shown to be selectively more cytotoxic to PSA-producing LNCaP prostate cancer cells than to DU145 cells that do not express PSA. These prodrugs could potentially be developed into clinically useful chemotherapeutic agents for the targeted treatment of cancer.

2. Development of Eph receptor antagonists

Protein-protein interactions are involved in a wide variety of physiological as well as pathological processes and inhibition of these interactions might provide new opportunities in controlling various diseases. Eph receptors are the largest family of receptor tyrosine kinases. Together with their protein ligand ephrins, they play an important role in embryogenesis, neuronal development, vasculogenesis, pathological angiogenesis as well as in cancer progression and metastasis.

In our structure-based approach, we began by examining the X-ray crystal structure of the EphB2/ephrin-B2 complex and identified a “hot spot” in the receptor-ligand interface, a G-H loop region consisting of around six amino acids protruding deep into a channel on the Eph receptor surface. We are employing several state-of-the-art drug design principles including conformational restriction, molecular modeling, and scaffold-based design of peptidomimetics to obtain high affinity Eph receptor-specific antagonists or agonists as pharmacological probes for the elucidation of ephrin and Eph receptor function in various physiological and pathological processes and as potential antiangiogenic and anticancer agents for the treatment of cancer.

3. Discovery of small molecule inhibitors of Keap1-Nrf2 interaction

Keap1-Nrf2-antioxidant response element (ARE) system represents a key signaling pathway in cancer chemoprevention. Many natural products like sulforaphane, curcumin, and epigallocatechol gallate from natural sources such as fruits, vegetables, and tea products work through modification of sensitive cysteine residues found in the redox “sensor” protein Keap1 leading to the dissociation of Keap1-Nrf2 complex, the subsequent translocation of Nrf2 to the nucleus, and the transcriptional activation of ARE genes. The resulting upregulation of oxidative stress response enzymes functions as a cytoprotective shield against carcinogens and reactive oxygen species generated during inflammation. But, there are safety concerns over the general use of these natural thiol-reactive compounds in a purified form and the high doses of administration over extended periods needed for chemoprevention purposes. We are designing ways to discover small molecule compounds specifically for the direct inhibition of the Keap1-Nrf2 interaction. These novel selective Keap1-Nrf2 inhibitors would mimic the actions of reactive oxygen species and electrophiles in the induction of cytoprotective enzymes but without the associated side effects.

4. Development of Synthetic Methodologies

We are also interested in developing synthetic methodologies for the synthesis of biologically active compounds and these include protecting group strategies, functional group transformation, and the synthesis of heterocyclic compounds. We have published on various aspects of protection and deprotection conditions for MOM, silyl ether, DMNA, and imidazolidine protecting groups, the development of reaction conditions for efficient Baylis-Hillman coupling reactions, the development of a new condition for the chemoselective reduction of aromatic nitro groups, and the discovery of a new amidation reaction using selenocarboxylates and azides.

Our research has been funded by grants from the National Institutes of Health, the Department of Defense Prostate Cancer Research Program, American Cancer Society, Pardee Foundation, the State of New Jersey Commission of Cancer Research, the Gallo Prostate Cancer Center of the Cancer Institute of New Jersey, and the Charles and Johanna Busch Memorial Fund at Rutgers University.


ACS :: Exploring Ways to Leave Healthy Cells Unharmed

Rutgers Research Highlights

An Academic Excellence Award ($250,000) to purchase a Biacore 3000 Biosensor


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Longqin Hu · Rutgers University School of Pharmacy · Department of Medicinal Chemistry