ABSTRACT
Two new cassaine-type diterpenoids, namely erythrofordins D (1) and E (2), sourced from a Cameroon collection of Erythrophleum suaveolens were isolated and assessed for anti-tumor activity. In the NCI-60 cancer cell assay, erythrofordins D (1) and E (2) were found to be cytotoxic in the low micro molar ranges with a mean GI50 value of 2.45 and 0.71⯵M, mean TGI value of 9.77 and 2.29⯵M, and a mean LC50 of 26.92 and 11.48⯵M for 1 and 2 respectively. Using the COMPARE algorithm, the new compounds were found to have similar NCI-60 response profiles to the known cardiac glycosides hyrcanoside and strophanthin. In addition, in an assay examining the viability and contractile function in human cardiomyocytes derived from induced pluripotent stem-cells, erythrofordins showed cardiotoxicity effects at concentrations as low as 0.03⯵g/mL.
Subject(s)
Caesalpinia/chemistry , Diterpenes/pharmacology , Myocytes, Cardiac/drug effects , Cell Survival/drug effects , Diterpenes/chemistry , Diterpenes/isolation & purification , Dose-Response Relationship, Drug , Humans , Molecular Structure , Structure-Activity RelationshipABSTRACT
The US National Cancer Institute's (NCI) Natural Product Repository is one of the world's largest, most diverse collections of natural products containing over 230,000 unique extracts derived from plant, marine, and microbial organisms that have been collected from biodiverse regions throughout the world. Importantly, this national resource is available to the research community for the screening of extracts and the isolation of bioactive natural products. However, despite the success of natural products in drug discovery, compatibility issues that make extracts challenging for liquid handling systems, extended timelines that complicate natural product-based drug discovery efforts and the presence of pan-assay interfering compounds have reduced enthusiasm for the high-throughput screening (HTS) of crude natural product extract libraries in targeted assay systems. To address these limitations, the NCI Program for Natural Product Discovery (NPNPD), a newly launched, national program to advance natural product discovery technologies and facilitate the discovery of structurally defined, validated lead molecules ready for translation will create a prefractionated library from over 125,000 natural product extracts with the aim of producing a publicly-accessible, HTS-amenable library of >1,000,000 fractions. This library, representing perhaps the largest accumulation of natural-product based fractions in the world, will be made available free of charge in 384-well plates for screening against all disease states in an effort to reinvigorate natural product-based drug discovery.
Subject(s)
Antineoplastic Agents/pharmacology , Biological Products/pharmacology , Drug Discovery/methods , Drug Screening Assays, Antitumor/methods , High-Throughput Screening Assays/methods , Neoplasms/drug therapy , Animals , Antineoplastic Agents/chemistry , Biological Products/chemistry , Humans , National Cancer Institute (U.S.) , United States , WorkflowABSTRACT
There is mounting urgency to find new drugs for the treatment of serious infectious diseases and cancer that are rapidly developing resistance to previously effective drugs. One approach to addressing this need is through drug repurposing, which refers to the discovery of new useful activities for "old" clinically used drugs through screening them against relevant disease targets. A large number of potential drug that, for various reasons, have failed to advance to clinical and commercial use can be added to the candidates available for such purposes. The application of new techniques and methodology developed through the impressive progress made in multidisciplinary, natural product-related research in recent years should aid substantially in expediting the discovery and development process. This review briefly outlines some of these developments as applied to a number of selected natural product examples, which may also include advances in chemical synthesis of derivatives with extended biological activities.
Subject(s)
Biological Products/therapeutic use , Drug Design , Neoplasms/drug therapy , Plants, Medicinal/chemistry , Humans , Molecular StructureSubject(s)
Antineoplastic Agents/chemistry , Biological Products/chemistry , Enzyme Inhibitors/chemistry , Neoplasms/drug therapy , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/therapeutic use , Biological Products/chemical synthesis , Biological Products/therapeutic use , Drug Screening Assays, Antitumor , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/therapeutic use , HumansSubject(s)
Antirheumatic Agents/pharmacology , Drug Design , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Adenosine Triphosphate/metabolism , Agammaglobulinaemia Tyrosine Kinase , Amino Acid Sequence , Animals , Antirheumatic Agents/chemistry , Antirheumatic Agents/therapeutic use , Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/enzymology , Binding Sites , Disease Models, Animal , Molecular Sequence Data , Oligopeptides/chemistry , Oligopeptides/metabolism , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/therapeutic use , Protein-Tyrosine Kinases/metabolism , Rodentia , Structure-Activity RelationshipABSTRACT
The metabolites of the tryptase inhibitor CRA-9249 were identified after exposure to liver microsomes. CRA-9249 was found to be degraded rapidly in liver microsomes from rabbit, dog, cynomolgus monkey, and human, and less rapidly in microsomes from rat. The key metabolites included cleavage of an aryl ether, in addition to an unexpected hydroxylation of the amide side chain adjacent to the amide nitrogen. The chemical structures of both metabolites were confirmed by synthesis and comparison to material isolated from the liver microsomes. Several suspected hydroxylated metabolites were also synthesized and analyzed as part of the structure identification process.
Subject(s)
Benzimidazoles/metabolism , Enzyme Inhibitors/metabolism , Serine Endopeptidases/drug effects , Animals , Chromatography, High Pressure Liquid , Dogs , Hydroxylation , Macaca fascicularis , Magnetic Resonance Spectroscopy , Rats , TryptasesABSTRACT
A series of diphenylphosphonate-based probes were developed for the trypsin-like serine proteases. These probes selectively target serine proteases rather than general serine hydrolases that are targets for fluorophosphonate-based probes. This increased selectivity allows detection of low abundance serine proteases in complex proteomes using simple SDS-PAGE methods. We present here the application of multiple probes in enzyme activity profiling of intact mast cells, a type of inflammatory cell implicated in allergy and autoimmune diseases.
