Medicinal Chemistry Translational Projects

Our research group is also focused on the synthesis of bioactive
N-heterocyclic chemical probes to potentiate biological processes critical in diseases that affect human health.

SLEEP APNEA — NIH UH2HL123610

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Figure reproduced from Smith, K. A.; Yuan, J. X.-J. Am. J. Physiol. Cell Physiol. 2012, 303, C911. link


The pauses in breathing that characterize sleep apnea leads to a build up of carbon dioxide in the blood stream. The carotid body is the critical sensor of arterial blood oxygen, and enhanced carotid body reflexes have been shown to play an important role in sleep-disordered breathing, which suggest that it is a potential therapeutic target to treat this condition. Recently, research into function of the carotid body has suggested that H
2S is required for hypoxic sensing.1,2 H2S is produced by several enzymes including cystathionine-γ-lyase and cystathionine-β-synthase. As part of a multi-institutional collaboration between the University of Chicago, IITRI, UIC’s Department of Medicinal Chemistry and Pharmacognosy and UIC’s Department of Chemistry, our laboratory has designed and synthesized a variety of potential small molecule inhibitors of cystathionine-γ-lyase to identify a small molecule chemotherapeutic for the treatment of sleep apnea.

Regulatorial Role of H2S

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Figure reproduced from Lin, V. S.; Chen, W.; Xian, M.; Chang, C. J. Chem. Soc. Rev. 2015, 44, 4596. link

Recently, hydrogen sulfide has emerged as an important gasotransmitter that regulates a diverse range of biological processes including vasodilation, neurotransmission and immune response. Its role to potentiate these physiological functions has inspired chemists to design and synthesize sensors for its detection. The challenge to detect H2S is its low concentration in the blood (<1μM) and how to distinguish it from other sulfides. Together with our collaborators Professors Larry Miller (UIC Chemistry), Terry Moore and Greg Thatcher (UIC Medicinal Chemistry and Pharmacognosy), we are leveraging the rapid hydrogen sulfide reduction of azides to design and synthesize H2S sensors with improved sensitivity and selectivity. We are also interested in synthesizing chemical probes to release H2S to observe its effect on enzyme activity as well as its ability to change cellular morphology with Professor David Eddington (UIC Engineering).


PULMONARY ARTERIAL HYPERTENSION

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Figure taken from www.pah-info.com

Pulmonary arterial hypertension (PAH) is a debilitating disease that involves the remodeling of arterial blood vessels of the lung that culminates in heart failure and death. There is no available cure for this fatal disease, and current treatments target vasoconstriction by producing pulmonary vasodilation and do not address the main pathological process associated with the disease: pulmonary vascular remodeling related to increased cell proliferation and apoptosis resistance of pulmonary endothelial and smooth muscle cells. Together with our collaborator, Dr. Roberto Machado, we are working on developing a safe, non-toxic clinical agent for the treatment of pulmonary arterial hypertension. The potential N-heterocyclic chemotherapeutics were synthesized using the transition metal-catalyzed amination methods developed in our laboratory.



ACUTE LUNG INJURY

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Acute lung injury is a continuum of clinical and radiographic changes affecting the lungs that is characterized by acute onset severe hypoxaemia. One of the consequences of acute lung injury is the breakdown of the endothelial cell layer of the pulmonary vasculature, which is the semipermeable barrier between the blood and the interstitial of the lung. This breakdown causes fluid and mortality seen with acute lung injuries. Currently, there are no therapies that prevent or reverse vascular barrier leak. Recently, in vitro and in vivo studies by Garcia and co-workers suggest that sphigosine-1-phosphate receptors could function as barrier protective agents to maintain the vascular barrier integrity. Together with Professor Greg Thatcher, Steve Dudek and Vishna Natarjan (UIC School of Medicine) we are synthesizing S1P ligands to investigate their effect in preventing vascular barrier leak.



BIOFILM FORMATION

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Figure reproduced from Federle, M. J.; Jimenez, J. C. Front. Cell. Infect. Microbiol. 2014, 4. link

In collaboration with Professor Michael Federle, the Anderson group and our group are designing and synthesizing chemical probes to investigate the mechanism of how Streptocussus pyogenies bacteria coordinate gene expression using cell-to-cell communication. This communication can control whether a bacteria forms a biofilm or becomes virulent. The Federle group has identified and characterized new quorum sensing pathways centered on the Rgg family of proteins. These proteins act as both cytoplasmic receptors and transcription regulators. Our goal is that our chemical probes will help to provide insight into the role of the quorum sensing network in controlling the virulence factors that contribute to disease.