Research

Total Synthesis of Natural Products, Heterocyclic and Medicinal Chemistry, and New Synthetic Methods. We also pursue projects in catalysis, flow-, and photochemistry, and we explore novel concepts in Chemical Biology. Group Members develop unique expertise in small molecule synthesis (tactics), problem solving (strategies), and interdisciplinary research (collaborations).

Selected Publications

image

p97: An Emerging Target for Cancer, Neurodegenerative Diseases, and Viral Infections.

Donna M. Huryn, David J. P. Kornfilt, Peter Wipf. J. Med. Chem. 2019, 62, xxxx.

The AAA+ ATPase, p97, also referred to as VCP, plays an essential role in cellular homeostasis by regulating endoplasmic reticulum-associated degradation (ERAD), mitochondrial-associated degradation (MAD), chromatin-associated degradation, autophagy, and endosomal trafficking. Mutations in p97 have been linked to a number of neurodegenerative diseases, and overexpression of wild type p97 is observed in numerous cancers. Furthermore, p97 activity has been shown to be essential for the replication of certain viruses, including poliovirus, herpes simplex virus (HSV), cytomegalovirus (CMV), and influenza. Taken together, these observations highlight the potential for targeting p97 as a therapeutic approach in neurodegeneration, cancer, and certain infectious diseases. This Perspective reviews recent advances in the discovery of small molecule inhibitors of p97, their optimization and characterization, and therapeutic potential.

https://doi.org/10.1021/acs.jmedchem.9b01318.

 

image

Special Issue in Honor and Memory of Prof. Koji Nakanishi. Co(II)‐Salen Catalyzed Stereoselective Cyclopropanation of Fluorinated Styrenes.

Serene Tai, Taber S. Maskrey, Prasanth R. Nyalapatla, Peter Wipf. Chirality 2019, 31, 1014.

Cis‐selective Co(II)‐salen complexes have been developed for the asymmetric cyclopropanation of para‐fluorinated styrenes with ethyl diazoacetate. Increasing the steric reach of the C2‐symmetric ligand side chains improved the enantiomeric ratio of the reaction from 28:1 to 66:1. This methodology was exemplified by a gram‐scale synthesis of a lead compound for the treatment of castration‐resistant prostate cancer (CRPC), as well as a structurally related analog.

https://doi.org/10.1002/chir.23144.

 

image

Specific RITA Modification Produces Hyperselective Cytotoxicity While Maintaining In Vivo Antitumor Efficacy.

Brian D. Peyser, Ann Hermone, Joseph M. Salamoun, James C. Burnett, Melinda G. Hollingshead, Connor F. McGrath, Rick Gussio, Peter Wipf. Mol. Cancer Ther. 2019,18, 1765.

The preclinical antitumor agent RITA, an analog of the natural product alpha-terthiophene, failed during the development phase due to acute pulmonary toxicity in animal models. A series of synthetic modifications to RITA's heterocyclic scaffold resulted in activity ranging from broadly cytotoxic to highly selective. A selectivity index (SI) was developed to quantify this desirable feature, and there is a strong correlation between quantum mechanically calculated energy barriers for carbocation formation from sulfonated RITA analogs and SI, indicating that hyperselective RITA analogs generate reactive carbocations less readily after SULT1A1 activation. Importantly, narrowing the cytotoxicity profile of RITA did not eliminate its analogs' in vivo antitumor activity, as several new hyperselective agents displayed impressive activity against A498 xenografts in mice.

https://doi.org/10.1158/1535-7163.MCT-19-0185.

 

image

Tapping the therapeutic potential of protein tyrosine phosphatase 4A with small molecule inhibitors.

Nikhil R. Tasker, Ettore J. Rastelli, James C. Burnett, Elizabeth R. Sharlow, John S. Lazo, Peter Wipf. Bioorg. Med. Chem. Lett. 2019, 29, 2008.

Protein tyrosine phosphatases (PTPs) are emerging new targets for drug discovery. An imbalance in the phosphorylation equilibrium results in aberrant protein signaling and pathophysiological conditions. PTPs have historically been considered 'undruggable', in part due to a lack of evidence defining their relationship to disease causality and a focus on purely competitive inhibitors. In this Digest, recent syntheses and structure-activity relationships (SAR) of small molecule inhibitors (SMIs) of PTP4A1–3 are summarized, and enzyme docking studies of the most potent chemotype are highlighted. In particular, the thienopyridone scaffold has emerged as a potent lead structure to interrogate the function and druggability of this dual-specificity PTP.

https://doi.org/10.1016/j.bmcl.2019.06.048.

 

image

ETHE1 and MOCS1 deficiencies: Disruption of mitochondrial bioenergetics, dynamics, redox homeostasis and endoplasmic reticulum-mitochondria crosstalk in patient fibroblasts.

Mateus Grings, Bianca Seminotti, Anuradha Karunanidhi, Lina Ghaloul-Gonzalez, Al-Walid Mohsen, Peter Wipf, Johan Palmfeldt, Jerry Vockley, Guilhian Leipnitz. Sci. Rep. 2019, 9, 12651.

Patients suffering from hereditary ethylmalonic encephalopathy protein 1 (ETHE1) and molybdenum cofactor (MoCo) deficiencies suffer from abnormalities of the mitochondrial respiratory chain, due to catabolism of sulfur-containing amino acids. JP4-039, a promising mitochondrial-targeted reactive oxygen species (ROS) and electron scavenger, decreased high superoxide levels and increased respiratory chain activity. These data demonstrate that previously unrecognized broad disturbances of cellular function are involved in the pathophysiology of ETHE1 and MOCS1 deficiencies, and that reduction of mitochondrial superoxide by JP4-039 is a promising strategy for adjuvant therapy of these disorders.

doi.org/10.1038/s41598-019-49014-2.

 

image

Synthesis and optimization of Kv7 (KCNQ) potassium channel agonists: The role of fluorines in potency and selectivity.

Ruiting Liu, Thanos Tzounopoulos, Peter Wipf. ACS Med. Chem. Lett. 2019, 10, 929-935.

While fluorine is often used to increase the bioavailability of pharmacologically active small organic compounds, the use of fluorine in iterative core structure modifications for structure-activity studies (SAR) is still underdeveloped. This paper highlights the versatility of fluorine substituents, including F, CF3, and SF5, to span orders of magnitude of potency and selectivity in medicinal chemistry lead optimizations.

Based on our first-generation Kv7 agonist RL-81, we have prepared new lead structures with greatly improved selectivity for Kv7.2/Kv7.3 over related potassium channels, i.e. Kv7.3/Kv7.5, Kv7.4, and Kv7.4/7.5. Our most promising new analogs are potent agonists on Kv7.2/Kv7.3, but lack activity on Kv7.3/Kv7.5, Kv7.4, and Kv7.4/7.5, resulting in a selectivity index SI>10. We also identified compounds with significant selectivity for Kv7.4/Kv7.5 over Kv7.2/Kv7.3.

doi.org/10.1021/acsmedchemlett.9b00097.

Bibliography Links

In addition to SciFinder, our research abstracts and publication records can be accessed through a variety of databases, including:

A brief overview of our main research interests and pertinent recent papers is also available here.