Fluorinated Compounds in Medicinal and Agricultural Chemistries
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 and agricultural chemicals. 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. Thus, the ability to access fluorinated compounds is critical for the 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 and agrochemical relevance. Further, the group explores physical organic chemistry related to these new reactions and reagents and products that are produced by the transformations, which will provide 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. 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.
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. Current efforts aim to synthesize rationally designed FPM-based analogs of opioid peptides. 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. After completing the synthetic phase of the project, the target FPM molecules will be subjected to in vitro and in vivo distribution, metabolism, and pharmacokinetic studies. Data from the study will used to develop computational models to predict opioid activity and drug-like properties, which will be used to design 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 KU's Biotechnology Innovation and Optimization Center.
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