ABSTRACT
The lysosomal aspartyl protease, cathepsin D, has been suggested to play a role in the metastatic potential of several types of cancer. Cathepsin D is secreted by malignant cells, and is believed to be involved in the breakdown of the extracellular matrix. High levels of active cathepsin D have been found in colon cancer, prostate cancer, uterine cancer and ovarian cancer. Also cathepsin D has recently been associated with the development of Alzheimer's disease. Hydroxyethyl isosteres with cyclic tertiary amine have proven to be clinically useful as inhibitors of aspartyl proteases similar to cathepsin D in activity, such as the HIV-1 aspartyl protease. In the present study twenty-eight compounds containing (hydroxyethyl)amine isosteres with cyclic tertiary amines have been synthesized. These compounds show significant activity as cathepsin D inhibitors, many with IC(50) values in the nanomolar range. For example, the compounds that contain hydroxyethylamines where the amine is formed from N-piperazine-2-carboxylic acid methyl ester, 4y-bb, show IC(50) values ranging from 2.5 to 15 nM.
Subject(s)
Cathepsin D/antagonists & inhibitors , Ethylamines/chemistry , Extracellular Matrix/drug effects , Protease Inhibitors/chemical synthesis , Alzheimer Disease/drug therapy , Alzheimer Disease/pathology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Aspartic Acid Endopeptidases/antagonists & inhibitors , Aspartic Acid Endopeptidases/metabolism , Carboxylic Acids/chemistry , Cathepsin D/metabolism , Esters/chemistry , Ethylamines/pharmacology , Extracellular Matrix/metabolism , Female , HIV Protease Inhibitors/chemical synthesis , HIV Protease Inhibitors/pharmacology , HIV-1/drug effects , HIV-1/enzymology , Humans , Male , Neoplasms/drug therapy , Neoplasms/pathology , Piperazine , Piperazines/chemistry , Protease Inhibitors/pharmacology , Tumor Cells, CulturedABSTRACT
The anatomical organization of neutrons and synaptic pathways in tentacles of sea anemones is poorly understood. Transmission electron microscopy of serial thin sections was carried out on various regions of tentacles of the sea anemone Calliactis parasitica in order to locate and characterize typical epidermal neutrons and synapses. Both surface-oriented sensory cells with ciliary cones and basally located ganglion cells lacking a cilium have Golgi-derived granular or faintly cored vesicles. Similar vesicles are present at synaptic loci on some ganglion and muscle cells. The synaptic contacts on the longitudinal muscle cells are generally en passant rather than terminal. They vary from single neuromuscular synapses to pairs of neurites innervating the same muscle cell or one neurite innervating two or more muscle cells. Both two-way and one-way interneuronal synapses with vesicles aligned at paired synaptic membranes with dense material in a 14-20-nm-wide cleft are present in the epidermal nerve plexus. The vesicles average from 50 to 80 nm in diameter and vary from electron lucent to faintly cored. The results of this study demonstrate the presence of a complex system of epidermal neuronal pathways with specific synaptic loci in this modern representative of a first-evolved nervous system.
Subject(s)
Epidermis/innervation , Neurons/ultrastructure , Sea Anemones/ultrastructure , Synapses/ultrastructure , Animals , Microscopy, ElectronABSTRACT
Light microscopic studies have shown that the sea anemone neuropeptides Antho-RWamides I (
