ABSTRACT
The review chronologically considers the main classes of the currently available anthelminthic substances: early anthelmintic compounds, benzimidazoles, imidazolthiazoles, tetrahydropyrimidines, avermectins and milbemycins, and salicylanilides. Great attention is paid to novel substances (emodepside, monepantel, derquantel, tribendimidine) and promising developments. Some aspects of the molecular mechanisms of action of anthelmintics, their resistance, and alternative dehelmintization methods are discussed.
Subject(s)
Anthelmintics/classification , Cestoda/drug effects , Drug Design , Nematoda/drug effects , Trematoda/drug effects , Aminoacetonitrile/analogs & derivatives , Aminoacetonitrile/chemical synthesis , Aminoacetonitrile/pharmacology , Animals , Anthelmintics/chemical synthesis , Anthelmintics/pharmacology , Biological Products/chemistry , Biological Products/pharmacology , Cestoda/physiology , Cestode Infections/diagnosis , Cestode Infections/drug therapy , Cestode Infections/parasitology , Depsipeptides/chemical synthesis , Depsipeptides/pharmacology , Humans , Indoles/chemical synthesis , Indoles/pharmacology , Medicine, Traditional , Nematoda/physiology , Nematode Infections/diagnosis , Nematode Infections/drug therapy , Nematode Infections/parasitology , Oxepins/chemical synthesis , Oxepins/pharmacology , Phenylenediamines/chemical synthesis , Phenylenediamines/pharmacology , Trematoda/physiology , Trematode Infections/diagnosis , Trematode Infections/drug therapy , Trematode Infections/parasitologyABSTRACT
Cathepsin B is a lysosomal cysteine protease that is implicated in a number of physiological processes, including protein turnover in lysosomes. Changes in its expression are associated with a variety of pathological processes, including cancer. Due to the structural feature, termed the occluding loop, cathepsin B differs from other cysteine proteases in possessing both, endopeptidase and exopeptidase activity. Here we investigated the impact of both cathepsin B activities on intracellular and extracellular collagen IV degradation and tumour cell invasion using new selective synthetic inhibitors, 2-{[(8-hydroxy-5-nitroquinoline-7-yl)methyl]amino}-acetonitrile (1), 8-(4-methylpiperidin-1-yl)-5-nitroquinoline (2) and 7-[(4-methylpiperidin-1yl)methyl]-5-nitroquinolin-8-ol (3). All three compounds (5 µM) reduced extracellular degradation of collagen IV by MCF-10A neoT cells by 45-70% as determined by spectrofluorimetry and they (50 µM) attenuated intracellular collagen IV degradation by 40-60% as measured with flow cytometry. Furthermore, all three compounds (5 µM) impaired MCF-10A neoT cell invasion by 40-80% as assessed by measuring electrical impedance in real time. Compounds 1 and 3 (5 µM), but not compound 2, significantly reduced the growth of MMTV-PyMT multicellular tumour spheroids. Collectively, these data suggest that the efficient strategy to impair harmful cathepsin B activity in tumour progression may include simultaneous and potent inhibition of cathepsin B endopeptidase and exopeptidase activities.
Subject(s)
Aminoacetonitrile/analogs & derivatives , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Cathepsin B/antagonists & inhibitors , Cathepsin B/metabolism , Extracellular Matrix/drug effects , Extracellular Matrix/metabolism , Neoplasm Invasiveness/prevention & control , Nitroquinolines/pharmacology , Piperidines/pharmacology , Protease Inhibitors/pharmacology , Aminoacetonitrile/chemical synthesis , Aminoacetonitrile/chemistry , Aminoacetonitrile/pharmacology , Breast Neoplasms/enzymology , Cell Survival/drug effects , Dose-Response Relationship, Drug , Female , Humans , Molecular Structure , Nitroquinolines/chemical synthesis , Nitroquinolines/chemistry , Piperidines/chemical synthesis , Piperidines/chemistry , Protease Inhibitors/chemical synthesis , Protease Inhibitors/chemistry , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
A new series of amino-acetonitrile derivatives (AAD) have been discovered that exhibit high anthelmintic activity against parasitic nematode species such as Haemonchus contortus and Trichostrongylus colubriformis. Significantly, these compounds also demonstrate activity against nematode strains resistant to the currently available broad-spectrum anthelmintics. The discovery, synthesis, structure-activity relationship and biological results are presented.
Subject(s)
Aminoacetonitrile/pharmacology , Anthelmintics/pharmacology , Haemonchus/drug effects , Trichostrongylus/drug effects , Aminoacetonitrile/analogs & derivatives , Aminoacetonitrile/chemical synthesis , Animals , Anthelmintics/chemical synthesis , Dose-Response Relationship, Drug , Models, Chemical , Parasitic Sensitivity Tests , Structure-Activity RelationshipABSTRACT
The orthosteric agonist neurokinin A (NKA) interacts with the tachykinin NK2 receptors (NK2Rs) via an apparent sequential binding process, which stabilizes the receptor in at least two different active conformations (A1L and A2L). The A1L conformation exhibits fast NKA dissociation kinetics and triggers intracellular calcium elevation; the A2L conformation exhibits slow NKA dissociation kinetics and triggers cAMP production. The new compound LPI805 is a partial and noncompetitive inhibitor of NKA binding to NK2Rs. Analysis of NKA dissociation in the presence of LPI805 suggests that LPI805 decreases the number of NKA-NK2R complexes in A2L conformation while increasing those in the A1L conformation. Analysis of signaling pathways of NK2Rs shows that LPI805 dramatically inhibits the NKA-induced cAMP response while slightly enhancing the NKA-induced calcium response. Analysis of NKA association kinetics reveals that LPI805 promotes strong and specific destabilization of the NKA-NK2R complexes in the A2L conformation whereas access of NKA to the A1L conformations is unchanged. Thus, to our knowledge, LPI805 is the first example of a conformation-specific allosteric antagonist of a G-protein-coupled receptor. This work establishes the use of allosteric modulators in order to promote functional selectivity on certain agonist-receptor interactions.
Subject(s)
Aminoacetonitrile/analogs & derivatives , Naphthalenes/pharmacology , Receptors, Neurokinin-2/antagonists & inhibitors , Allosteric Regulation , Aminoacetonitrile/chemical synthesis , Aminoacetonitrile/pharmacology , Animals , Calcium/metabolism , Calcium Signaling/drug effects , Cell Line/drug effects , Cyclic AMP/biosynthesis , Cyclic AMP-Dependent Protein Kinases/metabolism , Fluorescence Resonance Energy Transfer , Fluorescent Dyes/analysis , Genes, Reporter , Humans , Kidney , Kinetics , Naphthalenes/chemical synthesis , Neurokinin A/analogs & derivatives , Neurokinin A/analysis , Protein Binding , Protein Conformation/drug effects , Rats , Receptors, Neurokinin-2/chemistry , Receptors, Neurokinin-2/genetics , Recombinant Fusion Proteins/antagonists & inhibitors , Second Messenger Systems/drug effects , Structure-Activity Relationship , Substrate SpecificityABSTRACT
A new series of nonpeptidic cathepsin K inhibitors that are based on a beta-substituted cyclohexanecarboxamide motif has been developed. Lead optimization yielded compounds with sub-nanomolar potency and exceptional selectivity profiles against cathepsins B, L, and S. Use of fluorine atoms to block metabolism on the cyclohexyl ring led to compounds with excellent pharmacokinetic properties. Considering the well-established role of cathepsin K in osteoclast-mediated bone turnover, compounds such as (-)-34a (hrab Cat K IC(50) 0.28 nM; >800-fold selectivity vs Cat B, L, and S; PK data in dogs: F 55%, t(1/2) = 15 h) exhibit great potential for development as an orally bioavailable therapeutic for treatment of diseases that involve bone loss.
Subject(s)
Amides/chemical synthesis , Aminoacetonitrile/analogs & derivatives , Cathepsins/antagonists & inhibitors , Cyclohexanes/chemical synthesis , Amides/chemistry , Amides/pharmacology , Aminoacetonitrile/chemical synthesis , Aminoacetonitrile/chemistry , Aminoacetonitrile/pharmacology , Animals , Biological Availability , Cathepsin K , Cathepsins/chemistry , Crystallography, X-Ray , Cyclohexanes/chemistry , Cyclohexanes/pharmacology , Dogs , Half-Life , Male , Models, Molecular , Rats , Rats, Sprague-Dawley , Stereoisomerism , Structure-Activity RelationshipABSTRACT
(Cyanomethylene)trimethylphosphorane (CMMP) mediates Mitsunobu-type reactions, which are a versatile method for the alkylation of various nucleophiles (HA) with alcohols (ROH) to give RA. CMMP is quite effective for the reaction of carbon nucleophiles whose pK(a) value are higher than 13. CMMP, which is very sensitive to air and moisture, was synthesized in two steps starting from chloroacetonitrile.