In cancer cells, metabolism is elevated and allows them to maintain a higher proliferative rate and resist some cell death signals. This phenomenon, known as the “Warburg effect”, has become the focus of intensive efforts in the discovery of new therapeutic targets and new cancer drugs. Glycolysis, although enhanced in cancer cells, is no longer a source of biosynthetic precursors. In cancer cells such as those of breast cancer and glioblastoma, glutaminolysis is the primary source of biosynthetic precursors, fueling the TCA cycle with glutamine-derived α-ketoglutarate. The enhanced production of α-ketoglutarate is critical for cancer cells because it provides carbons for the citric acid cycle to produce glutathione, fatty acids, and nucleotides, and contributes nitrogens to produce hexosamines, nucleotides, and many nonessential amino acids. Recent efforts to develop amino acid derivatives to inhibit glutamine metabolism in cancer have been extensive . Our lab is working to develop novel glutamine-based compounds to inhibit glutaminolysis for the treatment of cancer.
1) Akins, N. S.; Nielson, T. C.; Le, H. V.* Inhibition of Glycolysis and Glutaminolysis: An Emerging Drug Discovery Approach to Combat Cancer. Curr. Top. Med. Chem. 2018, 18, 494–504.
2) Hossain, M. I.; Thomas, A. G.; Mahdi, F.; Adam, A. T.; Akins, N. S.; Woodard, M. M.; Paris, J. J.; Slusher, B. S.; Le, H. V.* An Efficient Synthetic Route to L-γ-Methyleneglutamine and Its Amide Derivatives, and Their Selective Anticancer Activity. RSC Adv. 2021, 11, 7115–7128.
3) Khan, M. I. H.; Mahdi, F.; Penfornis, P.; Akins, N. S.; Hossain, M. I.; Kim, S. J.; Sulochana, S. P.; Adam, A. T.; Tran, T. D.; Tan, C.; Claudio, P. P.; Paris, J. J.; Le, H. V.* Synthesis and Biological Evaluation of tert-Butyl Ester and Ethyl Ester Prodrugs of L-γ-Methyleneglutamic Acid Amides for Cancer. Bioorg. Med. Chem. 2022, under review. Preprint at ChemRxiv 2022, doi: 10.26434/chemrxiv-2022-rhjcx-v2
Kappa opioid receptor (KOR) is a member of the opioid receptor system, the G protein-coupled receptors that are expressed throughout the peripheral and central nervous systems and play crucial roles in the modulation of antinociception and a variety of behavioral states like anxiety, depression, and drug abuse. KOR agonists are known to produce potent analgesic effects and have been used clinically for the treatment of pain, while KOR antagonists have shown efficacy in the treatment of anxiety and depression. Overall, KOR is an important player in treatment therapies for a variety of diseases that greatly impact the quality of human health, and the discovery and development of novel KOR ligands will help alleviate the suffering of patients. Salvinorin A is the main active ingredient of the hallucinogenic plant Salvia divinorum that has been safely used by the Mazatec for centuries in religious rituals. It is one of the most potent, naturally occurring opioid agonists, with high selectivity and affinity for KOR. It has the potential to be beneficial in treatment therapies for various central nervous system disorders. Salvinorin A has been used as an important prototype for the development of related drug candidates. Our lab is working to develop novel salvinorin-based opioid receptor modulators for the treatment of addiction.
1) Xu, J.; Chen, F.; Wang, S.; Akins, N. S.; Hossain, M. I.; Zhou, Y.; Huang, J.; Ji, J.; Xi, J.; Lin, W.; Grothusen, J.; Le, H. V.; Liu, R.* Kappa Opioid Receptors Internalization Is Protective Against Oxygen-glucose Deprivation Through β-Arrestin Activation and Akt-mediated Signaling Pathway. Neurochem. Int. 2020, 137, 104748.
2) Akins, N. S.; Mishra, N.; Harris, H. M.; Dudhipala, N.; Kim, S. J.; Keasling, A. W.; Majumdar, S.; Zjawiony, J. K.; Paris, J. J.; Ashpole, N. M.; Le, H. V.* 6,5-Fused Ring, C2-Salvinorin Ester, Dual Kappa and Mu Opioid Receptor Agonists as Analgesics Devoid of Anxiogenic Effects. ChemMedChem 2022, 17, e202100684.
3) Cichon, J.; Liu, R.*; Le, H. V.* Therapeutic Potential of Salvinorin A and Its Analogues in Various Neurological Disorders. Transl. Perioper. Pain Med. 2022, 9, 452–457.
4) Khan, M. I. H.; Sawyer, B. J.; Akins, N. S.; Le, H. V.* A Systematic Review on the Kappa Opioid Receptor and Its Ligands: New Directions for the Treatment of Pain, Anxiety, Depression, and Drug Abuse. Eur. J. Med. Chem. 2022, 243, 114785.
5) Akins, N. S.; Mohammed, S. F.; Pandey, P.; Kim, S. J.; Mahdi, F.; Khan, M. I. H.; Moss, E.; Worth, C. J.; Keane, M. M.; Chittiboyina, A. G.; Doerksen, R. J.; Paris, J. J.; Le, H. V.* Alleviation of Cocaine Withdrawal and Pertinent Interactions Between Salvinorin-Based Antagonists and Kappa Opioid Receptor. ACS Chem. Neurosci. 2022, under review. Preprint at ChemRxiv 2022, doi: 10.26434/chemrxiv-2022-dpn5j-v2
Combination antiretroviral therapy (cART) has greatly reduced the risk of acquired immunodeficiency syndrome (AIDS) in patients infected with human immunodeficiency virus type 1 (HIV-1). However, cART accumulates poorly in the CNS and does not target latent CNS viral reservoirs (in microglia/ macrophages and astrocytes). As such, ~50% of HIV+ patients suffer from neurocognitive and neuropsychiatric disorders (collectively referred to as “neuroHIV”). NeuroHIV mechanisms are believed to involve neurotoxic viral proteins, including trans-activator of transcription (Tat) and glycoprotein 120 (gp120). Tat is a multifunctional viral regulatory protein that drives HIV-1 transcription. It is present in post-mortem brain tissues and promotes neuronal damage and excitotoxicity by direct or indirect activation of cation channels and pro-inflammatory cytokine release. These effects occur alone or in concert with gp120, the HIV-1 coat protein. Both proteins disrupt mitochondrial function, creating a bioenergetic crisis. Using animal models, our collaborators in the Paris lab and others found that Tat and/or gp120 recapitulated a neuroHIV-like phenotype, increasing anxiety- and depression-like behaviors, behavioral disinhibition, and cognitive deficits. We are working to develop novel neurosteroid analogues to inhibit Tat for the treatment of neuroHIV.
1) Salahuddin, M. F.; Qrareya, A. N.; Mahdi, F.; Moss, E.; Akins, N. S.; Li, J.; Le, H. V.; Paris, J. J.* Allopregnanolone and NeuroHIV: Potential Benefits of Neuroendocrine Modulation in the Era of Antiretroviral Therapy. J. Neuroendocrinol. 2022, 34, e13047.
1,4-Naphthoquinone forms the central chemical structure of many natural products, including vitamin K, juglone, plumbagin, lawsone, and droserone. Even though many are cytotoxic, 1,4-naphthoquinone derivatives have significant antibacterial, antifungal, antiviral, insecticidal, anti-inflammatory, and antipyretic properties. For example, atovaquone, sold under the brand name Mepron, is a hydroxy-1,4-naphthoquinone that is FDA-approved for the treatment of malaria, Pneumocystis jirovecii pneumonia (PCP), and toxoplasmosis. We are working to develop novel 1,4-naphthoquinone derivatives for the treatment of infectious diseases.
1) Sawyer, B. J.; Khan, M. I. H.; Le, H. V.* Antimalarial Drugs. In Medicinal Chemistry of Chemotherapeutic Agents; Elsevier/Academic Press: San Diego; 1st Edition; 2022. (the book can be preordered here on the Elsevier website).
Because natural products are synthesized by living organisms, they are naturally optimized for various biological functions, such as binding to specific biomolecules or target proteins. Natural products possess a tremendous structural and unique chemical diversity and continue to provide an unmatched source of new therapeutic agents and chemical scaffolds for drug discovery. We are also working on bio-guided isolation of active compounds from medicinal plants.
1) Madkhali, H.; Tarawneh, A.; Ali, Z.; Le, H. V.; Cutler, S. J.; Khan, I. A.; Shariat-Madar, Z.* Identification of Human Kinin-forming Enzyme Inhibitors from Medicinal Herbs. Molecules 2021, 26, 4126.
2) Kdimy, A.; Yadini, M. E.; Guaâdaoui, A.; Bourais, I.; El Hajjaji, S.*; Le, H. V.* Phytochemistry, Biological Activities, Therapeutic Potential, and Socioeconomic Value of the Caper Bush (Capparis spinosa L.). Chem. Biodiversity 2022, 19, e202200300.
3) Kdimy, A.; Kim, S. J.; Ali, Z.; Khan, M. I. H.; Tripathi, S. K.; El Hajjaji, S.*; Le, H. V.* Isolation of Bis(2-Ethylhexyl) Terephthalate and Bis(2-Ethylhexyl) Phthalate from Capparis Spinosa L. Leaves. ACS Food Sci. Technol. 2022, under review. Preprint at ChemRxiv 2022, doi: 10.26434/chemrxiv-2022-b0gz4
We use organic synthesis and computational modeling as primary tools to design and synthesize potential therapeutic agents and collaborate with other research groups to evaluate their biological activities and investigate their molecular mechanisms of action. When necessary, we will develop novel methodologies to form strategic bonds to provide easy access to libraries of important scaffolds for biological activity screening. These newly synthesized compounds can also be used as chemical tools to study and expose new areas of biology. When we discover new chemical transformations or new methods for the synthesis of highly substituted and functionalized heterocycles, we will explore and report them.
1) Hossain, M. I.; Khan, M. I. H.; Kim, S. J.; Le, H. V.* Synthesis of 3,4,5-Trisubstituted Isoxazoles in Water via a [3+2]-Cycloaddition of Nitrile Oxides and 1,3-Diketones, β-Ketoesters, or β-Ketoamides. Beilstein J. Org. Chem. 2022, 18, 446–458.