ABSTRACT
Peptide nucleic acids (PNAs) derivatized with functional molecules are increasingly used in diverse biosupramolecular applications. PNAs have proven to be highly tolerant to modifications and different applications benefit from the use of modified PNAs, in particular modifications at the γ position. Herein we report simple protocols to access modified PNAs from iterative Ugi couplings which allow modular modifications at the α, ß or γ position of the PNA backbone from simple starting materials. We demonstrate the utility of the method with the synthesis of several bioactive small molecules (a peptide ligand, a kinase inhibitor and a glycan)-PNA conjugates.
Subject(s)
Peptide Nucleic Acids/chemical synthesis , Small Molecule Libraries/chemical synthesis , Solid-Phase Synthesis Techniques/methods , Glycoconjugates/chemical synthesis , Glycoconjugates/chemistry , Ligands , Peptide Nucleic Acids/chemistry , Peptides/chemical synthesis , Peptides/chemistry , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Small Molecule Libraries/chemistry , Solid-Phase Synthesis Techniques/economicsABSTRACT
BACKGROUND AND AIM: In the last years we have seen an ever increasing number of patients with haematologic disorders who need hematopoietic stem cell transplantation (HSCT). The whole sector of HSCT results, infact to be in a continous scientific and technological clinical progress, offering a very advanced care. Despite this, some aspects are underconsidered, some of which could be fundamental to determine the success of the care pathway, such as the experience of the illness by the patient. Using a Narrative Based Medicine approach we wanted to investigate clinical, psychosocial and organizational aspects of the patient's journey whilst undergoing HSCT. METHOD: Various narrative interviews were conducted using non-structured approach. Results were analysed by thematic contents. RESULTS: Psycological dimension is the most compromised: above all emerged sentiments of oppression linked to the isolation period in the Low Bacterial Load (LBL) room. To note are also the different dynamics with which the patients perceive the organisation and hospital structures, and how much these factors can influence their care experience. CONCLUSIONS: Results suggest the need in clinical practice of an integration between qualitative and clinical approach, so as to permit the psychosocial and relational necessities to emerge, often unexpressed by patients undergoing HSCT.
Subject(s)
Hematopoietic Stem Cell Transplantation , Narrative Medicine , Needs Assessment , HumansABSTRACT
BACKGROUND: The emergence and spread of drug resistance to current antimalarial therapies remains a pressing concern, escalating the need for compounds that demonstrate novel modes of action. Diversity-Oriented Synthesis (DOS) libraries bridge the gap between conventional small molecule and natural product libraries, allowing the interrogation of more diverse chemical space in efforts to identify probes of novel parasite pathways. METHODS: We screened and optimized a probe from a DOS library using whole-cell phenotypic assays. Resistance selection and whole-genome sequencing approaches were employed to identify the cellular target of the compounds. RESULTS: We identified a novel macrocyclic inhibitor of Plasmodium falciparum with nanomolar potency and identified the reduction site of cytochrome b as its cellular target. Combination experiments with reduction and oxidation site inhibitors showed synergistic inhibition of the parasite. CONCLUSIONS: The cytochrome b oxidation center is a validated antimalarial target. We show that the reduction site of cytochrome b is also a druggable target. Our results demonstrating a synergistic relationship between oxidation and reduction site inhibitors suggests a future strategy for new combination therapies in the treatment of malaria.
Subject(s)
Antimalarials/pharmacology , Cytochromes b/antagonists & inhibitors , Drug Discovery/methods , Malaria, Falciparum/drug therapy , Plasmodium falciparum/drug effects , Protozoan Proteins/antagonists & inhibitors , Antimalarials/chemical synthesis , Antimalarials/chemistry , Base Sequence , Catalytic Domain , Cytochromes b/chemistry , Cytochromes b/genetics , Drug Resistance , Drug Synergism , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , High-Throughput Nucleotide Sequencing , High-Throughput Screening Assays , Humans , Lactams, Macrocyclic/chemical synthesis , Lactams, Macrocyclic/chemistry , Lactams, Macrocyclic/pharmacology , Malaria, Falciparum/parasitology , Molecular Sequence Data , Oxidation-Reduction , Phenylurea Compounds/chemical synthesis , Phenylurea Compounds/chemistry , Phenylurea Compounds/pharmacology , Plasmodium falciparum/enzymology , Plasmodium falciparum/genetics , Protozoan Proteins/chemistry , Protozoan Proteins/genetics , Small Molecule Libraries , Ubiquinone/metabolismABSTRACT
Here, we describe medicinal chemistry that was accelerated by a diversity-oriented synthesis (DOS) pathway, and in vivo studies of our previously reported macrocyclic antimalarial agent that derived from the synthetic pathway. Structure-activity relationships that focused on both appendage and skeletal features yielded a nanomolar inhibitor of P. falciparum asexual blood-stage growth with improved solubility and microsomal stability and reduced hERG binding. The build/couple/pair (B/C/P) synthetic strategy, used in the preparation of the original screening library, facilitated medicinal chemistry optimization of the antimalarial lead.
Subject(s)
Antimalarials/chemistry , Antimalarials/pharmacology , Chemistry, Pharmaceutical/methods , Structure-Activity Relationship , Antimalarials/metabolism , Chemistry Techniques, Synthetic , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/metabolism , Lactams, Macrocyclic/chemistry , Lactams, Macrocyclic/pharmacology , Plasmodium falciparum/drug effects , SolubilityABSTRACT
Here, we describe the discovery of a novel antimalarial agent using phenotypic screening of Plasmodium falciparum asexual blood-stage parasites. Screening a novel compound collection created using diversity-oriented synthesis (DOS) led to the initial hit. Structure-activity relationships guided the synthesis of compounds having improved potency and water solubility, yielding a subnanomolar inhibitor of parasite asexual blood-stage growth. Optimized compound 27 has an excellent off-target activity profile in erythrocyte lysis and HepG2 assays and is stable in human plasma. This compound is available via the molecular libraries probe production centers network (MLPCN) and is designated ML238.