14^th World Congress on Medicinal Chemistry and Drug Design June 10-11, 2019 Edinburgh, Scotland

James K Bashkin completed his D.Phil. at the age of 24 years from Oxford University and postdoctoral studies from Harvard University’s Department of Chemistry. He is Professor of Chemistry and Biochemistry at the University of Missouri-St. Louis and Co-Founder and Director of Chemistry at NanoVir LLC, an antiviral company. He also worked at Monsanto, Pharmacia, and Pfizer, has published more than 73 papers in reputed journals, and has served as an editorial board member and/or associate editor of numerous journals, most notably as an Editorial Advisory Board member of Chemical Reviews from 1991-2014.

Approximately 5,000 women die each year in the US from cervical cancer, and the worldwide mortality is 300,000 per year, yet this is only one type of cancer caused by human papillomavirus (HPV). In addition to the broad use of vaccines, anti-HPV drugs are needed for those who are already infected. Off-label, non-blinded clinical studies performed with formulations of the active pharmaceutical ingredient chloroquine, a well-known antimalarial, showed strong anti-HPV activity and restored normal skin tissue health to patients with both high- and low-risk HPV diseases. Confirmation of specific anti-HPV activity in cell culture was obtained by studies in three independent laboratories via the National Institutes of Health. We present cell data and before and after data from patients with a range of high- and low-risk HPV infections, including orphan diseases. Successful treatment includes patients with Bowen’s disease, oral papillomas, cervical intraepithelial neoplasia (CIN) grades I and II, and genital warts. In several cases, independent labs ran DNA tests that showed no evidence of HPV after treatment with topical chloroquine formulations. Patients were treated in the US, Nigeria, China, and other locations, with nearly one hundred patients undergoing treatment to date. Chloroquine and related molecules have been found to reactivate p53 expression in tumors, leading to tumor shrinkage by autophagy and related processes, and this has led the antimalarial class to be studied as anticancer drugs in eight or more clinical trials, some reaching Phase III. We suspect that the importance of eliminating p53 as part of the HPV lifecycle, as carried out by the viral E6 oncoprotein which ubiquitinates p53, and the documented recovery of p53 expression in tumors caused by chloroquine, play a role in the observed patient results. Patient data will be shown after the ten day to two-week topical treatment course via a cream, douche, or mouthwash. Drug development is currently underway to gain FDA approval of chloroquine formulations as treatments for a wide range of HPV-derived diseases, allowing it to prevent cervical and other cancers and to eliminate genital, oral, laryngeal, and other papillomas that plague the general population and orphan population groups. We are also pursuing the mechanism of action to provide details at the molecular level.

Maud Bollenbach joined the Balskus Lab in the summer of 2017 as a postdoc fellow after obtaining her PhD in Chemistry from the University of Strasbourg. As a graduate student, she worked under the supervision of Drs. Jean-Jacques Bourguignon and Martine Schmitt, and her research focused on the development of small molecules for the treatment of neuropathic pain. In the Balskus Lab, Maud is designing inhibitors of gut microbial TMA generation, which can be involved in human pathologies.

The human body is colonized by trillions of microorganisms (the human microbiota), the majority of which are present in the gut. These microorganisms can produce a wide variety of small-molecule metabolites that may influence host health. Indeed, metabolomics experiments have showed strong correlations between levels of human serum metabolites made or modified by gut microbes and both health and disease states. Anaerobic choline metabolism by gut microbes exemplifies the challenges involved in studying microbial activities. While choline is an essential nutrient for the host (contributing to cell membrane function, methyl transfer events and neurotransmission), its conversion into trimethylamine (TMA) by the gut microbiota is implicated in a number of diseases, including nonalcoholic fatty liver disease, cardiovascular disease, chronic kidney disease and trimethylaminuria (fish malodor syndrome). The correlation between microbial choline metabolism and disease, as well as its prevalence in the human gut microbiota, make this metabolic activity a prominent target for manipulation and further study. Our group recently discovered and biochemically characterized the central TMA-generating enzyme choline-TMA lyase (CutC).1,2 In collaboration with Prof. Catherine Drennan’s group, we also have been able to co-crystallize CutC with its substrate choline.2 By identifying key active site residues involved in binding and catalysis, we have been able to rationally design choline analogs. These molecules were tested for inhibition of anaerobic choline metabolism by the cut gene cluster-containing human gut isolate Escherichia coli MS 200-1. Betaine aldehyde emerged as promising inhibitor (EC50 = 0.4 mM).3 We also showed its efficacy against additional Gram-positive (Clostridium sporogenes ATCC 1559) and Gram-negative (Proteus mirablis BB2000, Escherichia coli MS 69-1, Klebsiella sp. MS 93-2), with EC50s values ranging from 1 to 5 mM. Finally betaine aldehyde inhibited the conversion of choline to TMA by a human fecal suspension ex vivo, confirming its efficacy in a complex setting more reminiscent of the gut microbiota.

Alex R. Khomutov, principle investigator, Engelhardt Institute of Molecular Biology, Moscow, Russia. He graduated Chemical Faculty of Moscow State University in 1976. He got PhD and later D.Sc. degrees in Bioorganic Chemistry in Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow. The main field of the interests are design and synthesis of the inhibitors/unnatural substrates of the enzymes of amino acids metabolism, including those related to biosynthesis and catabolism of biogenic polyamines spermine and spermidine, and investigation of the interaction of these analogues with enzymes and activity in cell cultures. In 2017 he was a chair of Polyamines Gordon Research Conference. A.R.Khomutov is a co-author of more than 120 papers in per-reviewed Journals.

Statement of the Problem: The polyamines, spermidine (1,8-diamino-4-azaoctane, Spd) and spermine (1,12- diamino-4,9-diazadodecane, Spm) are ubiquitous organic polycations present in all eukaryotic cells in µM-mM concentrations and involved in the regulation of numerous vital processes including the differentiation and growth of cells1. Disturbances of polyamines metabolism are associated with the development of many diseases, including malignant tumors, decreased immune response, some types of pancreatitis, Snyder-Robinson's syndrome, and even type 2 diabetes1. Biological evaluation of rationally designed polyamine analogs is one of the cornerstones of polyamine research having obvious basic and practical values. Here we synthesized and characterized C-methylated Spm and Spd analogues possessing a biochemically useful set of properties. Methodology & Theoretical Orientation: The synthesis of title compounds was performed using known methods starting from amino alcohols by subsequent elongation of polyamine backbone, or using convergent synthesis in the case of bis-methylated Spm derivatives2. Findings: Obtained data demonstrated that the biochemical properties of C-methylated polyamine analogs can be regulated by changing the position of the methyl substituent, and at more precise level by changing the configuration of chiral center2-4. Hidden stereospecificity (natural substrates are achiral) was shown for the enzymes of polyamine metabolism using title compounds2. An original approach to alter stereospecificity of FAD-dependent N-acetylpolyamine oxidase (APAO) and to alter stereospecificity and regioselectivity of yeast polyamine oxidase (Fms1) was suggested2,4. Conclusion & Significance: The first metabolically stable functionally active mimetics of Spd, i.e. (R)-1,8-diamino-3-methyl-4-azaoctane and Spm, i.e. (R,R)-2,13-diamino-5,10- diazatetradecane, being suitable for the investigation of the individual cellular functions of partly interchangeable and easily interconvertible Spm and Spd were found2,3.

Shengtao Xu, PhD, is currently an assistant professor in the Department of Medicinal Chemistry and has published over 30 peer-reviewed journal articles and filed more than 10 patent applications at China Pharmaceutical University (Nanjing, China). Shengtao Xu completed his PhD studies in Medicinal Chemistry in China Pharmaceutical University in 2015, and his research focuses on medicinal chemistry and drug discovery. Shengtao Xu mainly strives to develop natural products and their analogues by using approaches of total synthesis, semi-synthesis and chemical modification, as well as to explore and clarify the role and mechanisms how the newly-developed small-molecule therapeutics combat cancer, neurodegenerative diseases and metabolic diseases.

23-Hydroxybetulinic acid (23-HBA) is an anticancer polycyclic triterpenoid isolated from the root of Pulsatilla chinensis. In this study, a series of C-23 modified novel 23-HBA derivatives were synthesized and evaluated for their antiproliferative activity against a panel of cancer cell lines (A2780, A375, B16, MCF-7 and HepG2). The biological screening results showed that all of the derivatives exhibited more potent antiproliferative activity than the parent compound 23-hydroxybetulinic acid, and compound 6e exhibited the most potent activity with IC50 values of 2.14 μM, 2.89 μM and 3.97 μM against A2780 cells, B16 cells, MCF-7 cells. Further anticancer mechanism studies revealed that compound 6e induced the generation of intracellular ROS and reduction of mitochondrial membrane potential of B16 cells in a dose-dependent manner. Moreover, western blot analysis indicated compound 6e downregulated the expression of anti-apoptotic protein Bcl-2 and upregulated the expression of proapoptotic protein Bax, activation of caspase 3 for causing cell apoptosis. Meanwhile, compound 6e significantly inhibited the phosphorylation of MEK, ERK and Akt without affecting the expression of MEK, ERK and Akt.

Jinyi Xu, PhD, is a professor at China Pharmaceutical University. Jinyi Xu obtained her PhD at China Pharmaceutical University in 1998, and then pursued her postdoctoral research at Kindai University, Japan. In 2002, Dr. Jinyi Xu joined the Department of Medicinal Chemistry at China Pharmaceutical University. Her research field includes design, synthesis, and pharmacological investigation of small molecules in metabolic disorders, infectious disease, and oncology therapeutics. She has published more than 150 peer-reviewed scientific papers, over 20 patents, one book and three book chapters. Dr. Jinyi Xu has been invited to numerous lectures and seminars, and her research has been awarded at the national and international level.

Alzheimer's disease (AD), which is characterized by dementia, memory loss, cognitive impairment and ultimately death, is a progressive neurodegenerative disease. It is estimated that over 132 million elderly people will be affected by AD at 2050. Although considerable researches have been devoted to the pathogenetic mechanisms of AD, the etiology of AD still remain unclear. Several pathological hallmarks including acetylcholinesterase (AChE) have been verified to play vital roles in the pathogenesis of AD. In this study, a series of novel isothio- and isoselenochromanone derivatives were designed, synthesized and evaluated as AChE inhibitors. Most of the target compounds exhibited potent anti-AChE activities with IC50 values in nanomolar ranges. Among which, compound 15a exhibited the most potent anti-AChE activity (IC50 = 2.7 nM) and the highest AChE / BuChE selectivity (SI > 163) with low neurotoxicity. Moreover, the kinetic and docking studies revealed that compound 15a was a mixed-type inhibitor, which binds to PAS and CAS of AChE. Those results suggested that compound 15a might be a potential agent for AD treatment.