ABSTRACT
On the basis of our earlier discovered natural product penipyridone G with potential lipid-lowering utility, 35 penipyridone derivatives were designed, synthesized and characterized. Based on the oleic acid-induced HepG2 cell lipid accumulation model, compounds 12c, 14, 15f, 15k, 15o, 15p and 16f showed potent lipid-lowering activities among the synthetic compounds at 10 µM. In particular, compounds 4, 15k, 15o showed significant activities on inhibiting lipid accumulation in insulin resistant HepG2 cells, and these three compounds were safe and non-toxic within the concentration range of 400 µM. In comparison, 15o possessed the best lipid-lowering activity. Compared with the vehicle group, the triglyceride inhibition rate of 15o was about 30.2%, and the total cholesterol inhibition rate was about 14.8% at 20 µM, which was equipotent to Simvastatin. Our research indicates that 15o may serve as a promising lead compound for the development of hypolipidemic drugs.
Subject(s)
Drug Design , Hypolipidemic Agents/pharmacology , Lipids/antagonists & inhibitors , Pyridones/pharmacology , Dose-Response Relationship, Drug , Humans , Hypolipidemic Agents/chemical synthesis , Hypolipidemic Agents/chemistry , Molecular Structure , Pyridones/chemical synthesis , Pyridones/chemistry , Structure-Activity RelationshipABSTRACT
Owing to the emergence of drug resistance and high morbidity and mortality, the need for novel anti-influenza A virus (IAV) drugs with divergent targets is highly sought after. Herein, we reveal the discovery of an anti-IAV agent as a dual inhibitor to block hemagglutinin-mediated adsorption and membrane fusion using a chemoreactive ortho-quinone methide (o-QM) equivalent. Based on the o-QM equivalent nonenzymatically multipotent behavior, we created a series of clavatol-derived pseudo-natural products and found that penindolone (PND), a new diclavatol indole adduct, exhibited potent and broad-spectrum anti-IAV activities with low risk of inducing drug resistance. Distinct from current anti-IAV drugs, PND possesses a novel scaffold and is the first IAV inhibitor targeting both HA1 and HA2 subunits of virus hemagglutinin to dually block the IAV adsorption and membrane fusion process. More importantly, intranasal and oral administration of PND can protect mice against IAV-induced death and weight loss, superior to the effects of the clinical drug oseltamivir. Thus, the use of chemoreactive intermediates could expand our understanding of chemical diversity and aid in the development of anti-IAV drugs with novel targets.
Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Drug Discovery , Hemagglutinin Glycoproteins, Influenza Virus/metabolism , Influenza A virus/drug effects , Influenza A virus/physiology , Membrane Fusion/drug effects , Acetophenones/chemistry , Acetophenones/pharmacokinetics , Acetophenones/pharmacology , Adsorption/drug effects , Animals , Antiviral Agents/pharmacokinetics , Dogs , Drug Resistance, Viral/drug effects , Female , Influenza A virus/metabolism , Madin Darby Canine Kidney Cells , Mice , Tissue Distribution , Virus Internalization/drug effects , Virus Replication/drug effectsABSTRACT
The core structure of marine natural products aspergiolides A (1a) and B (1b) was achieved via a concise, two-step procedure with satisfactory yield. Based on this protocol, a natural products mimic library containing 25 structural simplified analogues of 1a was then constructed. Several prepared analogues showed potential cytotoxic activity against five different tumor cell lines, and compound 7bb, in particular, exhibited cytotoxicity comparable to that of 1a.
Subject(s)
Anthraquinones/chemistry , A549 Cells , Anthraquinones/chemical synthesis , Anthraquinones/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Drug Screening Assays, Antitumor , HL-60 Cells , HeLa Cells , Humans , K562 Cells , Models, MolecularABSTRACT
An asymmetric organocatalytic direct arylation approach to construct arylated quaternary stereogenic centers with a catalyst loading of 1 mol % is reported. The formation of the hemiketal moiety in stabilizing the hydroquinone intermediate proves to be important in leading to hydroquinone products instead of oxidation quinone products obtained in previously reported methods. A series of structurally and stereochemically complex heterocyclic frameworks are obtained, including spiro-, dispiro-, fused, and bridged heterocycles.