ABSTRACT
Heat shock proteinâ 90 (Hsp90) is a molecular chaperone (90â kDa) that functions as a dimer. This protein facilitates the folding, assembly, and stabilization of more than 400â proteins that are responsible for cancer development and progression. Inhibiting Hsp90's function will shut down multiple cancer-driven pathways simultaneously because oncogenic clients rely heavily on Hsp90, which makes this chaperone a promising anticancer target. Classical inhibitors that block the binding of adenine triphosphate (ATP) to the N-terminus of Hsp90 are highly toxic to cells and trigger a resistance mechanism within cells. This resistance mechanism comprises a large increase in prosurvival proteins, namely, heat shock proteinâ 70 (Hsp70), heat shock proteinâ 27 (Hsp27), and heat shock factorâ 1 (HSF-1). Molecules that modulate the C-terminus of Hsp90 are effective at inducing cancer-cell death without activating the resistance mechanism. Herein, we describe the design, synthesis, and biological binding affinity for a series of dimerized C-terminal Hsp90 modulators. We show that dimers of these C-terminal modulators synergistically inhibit Hsp90 relative to monomers.
Subject(s)
HSP27 Heat-Shock Proteins/chemistry , HSP72 Heat-Shock Proteins/chemistry , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Dimerization , HSP27 Heat-Shock Proteins/metabolism , HSP72 Heat-Shock Proteins/metabolism , HSP90 Heat-Shock Proteins/chemistry , HSP90 Heat-Shock Proteins/metabolism , Protein BindingABSTRACT
As the most abundant protein in mammals and a major structural component in extracellular matrix, collagen holds a pivotal role in tissue development and maintaining the homeostasis of our body. Persistent disruption to the balance between collagen production and degradation can cause a variety of diseases, some of which can be fatal. Collagen remodeling can lead to either an overproduction of collagen which can cause excessive collagen accumulation in organs, common to fibrosis, or uncontrolled degradation of collagen seen in degenerative diseases such as arthritis. Therefore, the ability to monitor the state of collagen is crucial for determining the presence and progression of numerous diseases. This review discusses the implications of collagen remodeling and its detection methods with specific focus on targeting native collagens as well as denatured collagens. It aims to help researchers understand the pathobiology of collagen-related diseases and create novel collagen targeting therapeutics and imaging modalities for biomedical applications.
Subject(s)
Collagen/metabolism , Diagnostic Imaging/methods , Drug Delivery Systems/methods , Extracellular Matrix/metabolism , Peptides/pharmacology , Collagen/chemistry , Humans , Peptides/chemistry , Peptides/metabolism , Protein Binding , Protein DenaturationABSTRACT
Heterocycle-containing macrocycles are an emerging class of molecules that have therapeutic efficacy. Many biologically active natural products that have interesting biological properties fall into this class of molecules. The highly specific and selective biological activity is often attributed to the unique conformation of these macrocycles, which is affected by the elements of the macrocycles as well as its surroundings in biological systems. In this review, the structure-activity relationship studies of several recently developed biologically active heterocycle-containing macrocycles have been discussed in order to facilitate an understanding on how unpredictable structures can be controlled.
Subject(s)
Anti-Bacterial Agents/chemistry , Antineoplastic Agents/chemistry , Antiparasitic Agents/chemistry , Macrocyclic Compounds/chemistry , Peptides/chemistry , Animals , Anti-Bacterial Agents/pharmacology , Antineoplastic Agents/pharmacology , Antiparasitic Agents/pharmacology , Bacteria/drug effects , Bacterial Infections/drug therapy , Humans , Macrocyclic Compounds/pharmacology , Molecular Conformation , Neoplasms/drug therapy , Parasitic Diseases/drug therapy , Peptides/pharmacology , Structure-Activity RelationshipABSTRACT
Heat shock protein 90 (hsp90) accounts for 1-2% of the total proteins in normal cells and it functions as a dimer. Hsp90 behaves as a molecular chaperone that folds, assembles, and stabilizes client proteins. We have developed a novel hsp90 inhibitor, and herein we describe the synthesis and biological activity of the dimerized variant of this inhibitor. Tethering a monomer inhibitor together produced a dimerized compound that more effectively inhibits hsp90 over the monomer.
Subject(s)
Dimerization , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Macrocyclic Compounds/chemistry , Macrocyclic Compounds/pharmacology , Drug Design , Models, Molecular , Molecular Conformation , Polyethylene Glycols/chemistry , Protein Refolding/drug effects , SolubilityABSTRACT
We report the first synthesis of sanguinamide B analogues. Substituting N-methylated (N-Me) amino acids, glycine (Gly), and L- or D-phenylalanine (Phe) into the backbone of sanguinamide B showed that only l- and d-Phe residues controlled the macrocycle conformation. The N-methylated and glycine analogues all had multiple conformations, whereas the L- and D-Phe derivatives only had a single conformation. Testing of all conformer analogues showed that inclusion of an L- or D-Phe was a superior design element than incorporating the N-Me moiety that is often utilized to control macrocyclic conformation. Finally, we show that there is an ideal Phe residue (in this case L-Phe) for generating compounds that have the greatest inhibitory effect on bacterial motility. Our data support the hypothesis that the macrocyclic conformation is dictated by the benzyl moiety requiring a "pseudoequatorial" position, and all other energy considerations are secondary.
Subject(s)
Amino Acids/chemistry , Oxazoles/chemistry , Oxazoles/chemical synthesis , Peptides, Cyclic/chemistry , Peptides, Cyclic/chemical synthesis , Thiazoles/chemistry , Thiazoles/chemical synthesis , Amino Acids/chemical synthesis , Magnetic Resonance Spectroscopy , Molecular Conformation , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Peptidomimetic-based macrocycles typically have improved pharmacokinetic properties over those observed with peptide analogs. Described are the syntheses of 13 peptidomimetic derivatives that are based on active Sansalvamide A structures, where these analogs incorporate heterocycles (triazoles, oxazoles, thiazoles, or pseudoprolines) along the macrocyclic backbone. The syntheses of these derivatives employ several approaches that can be applied to convert a macrocyclic peptide into its peptidomimetic counterpart. These approaches include peptide modifications to generate the alkyne and azide for click chemistry, a serine conversion into an oxazole, a Hantzsch reaction to generate the thiazole, and protected threonine to generate the pseudoproline derivatives. Furthermore, we show that two different peptidomimetic moieties, triazoles and thiazoles, can be incorporated into the macrocyclic backbone without reducing cytotoxicity: triazole and thiazole.