Fluorinated Compounds in Medicinal Chemistry
The incorporation of a fluorinated substituent on a target molecule can alter many physicochemical (PC) and pharmacokinetic (PK) properties related to the design of therapeutics. For instance, fluorination typically alters hydrophilicity and lipophilicity, electrostatic and electronic properties, metabolic, thermal and oxidative stability, conformational rigidity, acid/base properties, and binding interactions between the small molecule and the biological target. Because of these perturbations, the ability to access fluorinated compounds is critical for developing new therapeutics and agrochemical agents.
Within this field, the Altman Group aims to develop innovative reactions, reagents and synthetic strategies for accessing unique fluorinated functional groups with biomedical relevance. Further, the group explores physical organic chemistry related to these new reactions and reagents, and products, which provides insight for developing improved reagents and catalyst systems. Finally, the group aims to employ its own synthetic transformations access new biological probes with improved drug-like properties.
Decarboxylative Strategies for Fluoroalkylation
Decarboxylative coupling represents a powerful method for the construction of C–C bonds, and has gained special appreciation in non-fluorous chemistry. This strategy exhibits several appealing features, including: 1) the use of inexpensive and readily accessible starting materials; 2) the ability to selectively generate and couple reactive species under mild reaction conditions; 3) the release of CO2 as a benign and easily removed by-product. Because of these benefits, the Altman group uses decarboxylative strategies for developing new methods that streamline the synthesis of target molecules, and provide access to new fluorinated substructures that are challenging to access otherwise. In this area, the group collaborates with the Cheong Group at Oregon State University whose expertise in computational chemisty provides mechanistic insights into unusual reacitivities.
Fluorinated Peptidomimetics for Delivering Peptides into the Central Nervous System
Endogenous opioid peptides regulate activity within the central nervous system (CNS), and are particularly interesting for treating pain, depression, and anxiety. Unfortunately, clinical use of peptide-based agents is restricted by poor physicochemical and biophysical properties, which limit penetration into the CNS. Therefore, many peptide-based probes cannot be employed clinically for treating many disease states.
To address this problem, the Altman group explores the use of fluorinated peptidomimetics (FPMs) to improve the drug-like properties of peptides, and to deliver peptides into the CNS. Recent efforts have provided rationally designed orally bioavailable FPM-based analogs of opioid peptides that cross the blood-brain-barrier. To access these unique target molecules, the group has developed new synthetic methods and strategies, which should be broadly applicable for accessing FPMs to address many disease states. The target FPM molecules are typically subjected to several in vitro and in vivo assays to evaluate pharmacodynamic, antinociception, distribution, metabolism, and pharmacokinetic properties. Data from the study will used to develop computational models to predict opioid activity and drug-like properties, which will facilitate the design of new analogs. This overarching strategy should be amenable for modulating physicochemical and biophysical properties of a broad spectrum of neuropeptides, with the ultimate goal of converting small peptide-based probes into CNS-active clinical candidates. To support this project, the Altman group collaborates with the Van Rijn Group at Purdue University, and KU's Biotechnology Innovation and Optimization Center.
Regulating the Kynurenine Pathway
The kynurenine pathway (KP) regulates tryptophan metabolism and generates many modulatory biomolecules that in turn directly correlate to affect various aspects of neurotransmission, neurotoxicity, neuroprotection, inflammation, and other immunological functions. Further, dysregulation of this pathway directly correlates to many disease states, including neurological disorders, infectious diseases, and cancer, thus making small molecule modulators of the KP critical for understanding the diseases states, and for providing potential therapies.
Within this area, the Altman group works collaboratively to develop small molecule probes for studying and modulating enzymes in the kynurenine pathway. In some cases, these probes are used to study unique aspects of KP enzymology, while other efforts aim to develop small-molecule probes for modulating in vitro and in vivo models of various disease states. Long-term, these biological probes might serve as leads for downstream medicinal chemistry optimization. To support this project, the group actively collaborates with the research groups of Prof. Aimin Liu and Prof. Thomas Forsthuber, whose groups bring expertise in biochemistry and immunology to the project.
Adjuvants to Circumvent Resistance to Antibiotics
Diminishing efforts by the pharmaceutical industry to bring new antibiotics to market have weakened the antibiotic pipeline, leaving mankind increasingly vulnerable to virulent multidrug resistant microorganisms bacteria. As a result, this expanding global public health problem threatens many significant achievements of modern medicine. One major mechanism of resistance involves modification and inactivation of drugs by bacterial enzymes. To combat this mode of resistance, drugs that inhibit these enzymes could restore bacterial susceptibility, as demonstrated for the case of beta-lactam antibiotics. However to date, no clinically employed resistance modifying agents exist for other classes of antibiotics.
The Altman group uses it's expertise in synthetic chemistry to develop new adjuvants that circumvent bacterial resistance to FDA-approved antibiotics. In collaboration with Professor Molly Steed, and KU's High Throughput Screening Laboratory, the group has identified identified several small molecule chemotypes that overcome resistance to antibiotics, and have sufficiently wide therapeutic indexes for development. Ongoing work employs a structure-guided design approach to optimize resistance-modifying activity and host toxicity, while also maintaining appropriate distribution, metabolism and pharmacokinetic properties for clinical use. To support this project, the group also collaborates with KU's Protein Production Group and Protein Structure Laboratory.