ABSTRACT
Glaucoma affects millions of people worldwide and causes optic nerve damage and blindness. The elevation of the intraocular pressure (IOP) is the main risk factor associated with this pathology, and decreasing IOP is the key therapeutic target of current pharmacological treatments. As potential ocular hypotensive agents, we studied compounds that act on two receptors (serotonin 2A and adrenergic α1 ) linked to the regulation of aqueous humour dynamics. Herein we describe the design, synthesis, and pharmacological profiling of a series of novel bicyclic and tricyclic N2-alkyl-indazole-amide derivatives. This study identified a 3,4-dihydropyrazino[1,2-b]indazol-1(2H)-one derivative with potent serotonin 2A receptor antagonism, >100-fold selectivity over other serotonin subtype receptors, and high affinity for the α1 receptor. Moreover, upon local administration, this compound showed superior ocular hypotensive action inâ vivo relative to the clinically used reference compound timolol.
Subject(s)
Indazoles/therapeutic use , Ocular Hypertension/drug therapy , Pyrazines/therapeutic use , Receptor, Serotonin, 5-HT2A/drug effects , Receptors, Adrenergic, alpha-1/drug effects , Animals , Drug Discovery , Indazoles/chemistry , Indazoles/pharmacology , Intraocular Pressure/drug effects , Pyrazines/chemistry , Pyrazines/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
In this review the synthetic work in the field of aphidicolane, stemodane and stemarane diterpenoids, in which readily available (+)-podocarpic acid (4) was used as chiral template for the construction of their polycyclic structures, is described as it developed along the years. In the frame of this work (+)-podocarpic acid (4) was a very useful tool in a model study leading to the syntheses of tetracyclic ketones 7 and 8, models of key intermediates 5a and 6 in the syntheses of (+)-aphidicolin (1) and (+)-stemodin (2a), respectively. (+)-Podocarpic acid (4) was also converted into (+)-2-deoxystemodinone (2d), allowing confirmation of the stemodane diterpenoids absolute configuration, into (+)-aphidicol-15-ene (36) and into Stemodia chilensis tetracyclic diterpenoid (+)-19-acetoxystemodan-12-ol (2f), allowing confirmation of its structure. (+)-Podocarpic acid (4) was then extensively used in the work which led to the synthesis of (+)-stemar-13-ene (57) and (+)-18-deoxystemarin (3b). Finally, (+)-4 was converted into (+)-2-deoxyoryzalexin S (66), which made it possible to demonstrate that the structure of (+)-66 could not be attributed to a Chilean Calceolaria isolated diterpenoid to which this structure had been assigned.
Subject(s)
Abietanes/chemistry , Abietanes/chemical synthesis , Calceolariaceae/chemistry , Plantaginaceae/chemistryABSTRACT
The first synthesis of (+)-19-acetoxystemodan-12-ol (1), a stemodane diterpenoid isolated from Stemodia chilensis, is described. The structure was supported by an X-ray crystallographic analysis of intermediate (+)-9a, which confirmed the proposed structure and excluded the structure of (-)-19-hydroxystemod-12-ene as a possible candidate for the Chilean Calceolaria diterpenoid to which the (-)-19-hydroxystemar-13-ene structure (9b) had been erroneously assigned.
Subject(s)
Abietanes/chemistry , Plantaginaceae/chemistry , Chile , Crystallography, X-Ray , Diterpenes , Microbial Sensitivity Tests , Molecular Conformation , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , StereoisomerismABSTRACT
In a previous investigation, cationic liposomes formulated with new 5-FU derivatives, differing for the length of the polyoxyethylenic spacer that links the N(3) position of 5-FU to an alkyl chain of 12 carbon atoms, showed a higher cytotoxicity compared to free 5-FU, the cytotoxic effect being directly related to the length of the spacer. To better understand the correlation of the spacer length with toxicity, we carried out initial rate studies to determine inhibition, equilibrium and kinetic constants (KI, KM, kcat), and get inside inhibition activity of the 5-FU derivatives and their mechanism of action, a crucial information to design structural variations for improving the anticancer activity. The experimental investigation was supported by docking simulations based on the X-ray structure of thymidine phosphorylase (TP) from Escherichia coli complexed with 3'-azido-2'-fluoro-dideoxyuridin. Theoretical and experimental results showed that all the derivatives exert the same inhibition activity of 5-FU either as monomer and when embedded in lipid bilayer.
Subject(s)
Escherichia coli Proteins/metabolism , Fluorouracil/metabolism , Thymidine Phosphorylase/metabolism , Thymidine/metabolism , Antimetabolites/chemistry , Antimetabolites/metabolism , Antimetabolites/pharmacology , Binding Sites , Binding, Competitive , Dimyristoylphosphatidylcholine/chemistry , Dimyristoylphosphatidylcholine/metabolism , Dimyristoylphosphatidylcholine/pharmacology , Escherichia coli/enzymology , Escherichia coli Proteins/antagonists & inhibitors , Escherichia coli Proteins/chemistry , Fluorouracil/chemistry , Fluorouracil/pharmacology , Kinetics , Liposomes/chemistry , Liposomes/metabolism , Liposomes/pharmacology , Molecular Docking Simulation , Molecular Structure , Protein Binding , Protein Structure, Tertiary , Thymidine/chemistry , Thymidine Phosphorylase/antagonists & inhibitors , Thymidine Phosphorylase/chemistryABSTRACT
(+)-2-Deoxyoryzalexin S (1), the nominal enantiomer of a diterpenoid isolated in Chile from Calceolaria species, was regio- and diastereoselectively synthesized from (+)-podocarpic acid. (+)-2-Deoxyoryzalexin S (1) was characterized also as its acetyl derivative, (+)-2, whose structure was confirmed by X-ray crystallographic analysis. Surprisingly, comparison of the data recorded for (+)-1 and (+)-2 and those reported in the literature for the Calceolaria isolated diterpenoid 1 and its derivative (-)-2 showed some differences, suggesting that the latter do not possess the proposed structures.
Subject(s)
Abietanes/chemistry , Scrophulariaceae/chemistry , Chile , Crystallography, X-Ray , Diterpenes , Models, Molecular , Molecular Structure , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The problem of constructing diastereoselectively the C/D ring system of stemarane diterpenes from a bicyclo[2.2.2]octane intermediate was solved resulting in very simple synthesis of (+)-13-stemarene 1. The obtaining of the latter represents also a formal synthesis of (+)-18-deoxystemarin 2. In the key step, the epimeric mixture 10, dissolved in toluene, was converted by the action of TsOH into (+)-stemar-13-en-15-one 28.
Subject(s)
Diterpenes/chemical synthesis , Cyclization , Diterpenes/chemistry , Molecular Structure , StereoisomerismABSTRACT
New 17beta-estradiol (E2) derivatives 1-11 were synthesized from an estrone derivative by addition of organometallic reagents prepared from protected alpha,omega-alkynols and further elaboration of the addition products. The estrogenic activity of these novel compounds was determined using in vitro binding competition assay and transactivation analysis. Among the E2 derivatives synthesized, compound 2 showed the highest transactivation potency and was therefore tested for its ability to modulate cutaneous wound healing in vivo. Compound 2's ability to accelerate wound healing in ovariectomized mice and decrease the production of inflammatory molecules was comparable to that of E2. However, the activity of compound 2 was not superimposable to E2 with regard to the cells involved in the wound repairing process. When locally administered, compound 2 did not show any systemic activity on ER. This class of compounds with clear beneficial effects on wound healing and suitable for topical administration may lead to the generation of innovative drugs for an area of unmet clinical need.
Subject(s)
Estradiol/pharmacology , Estrogens/pharmacology , Skin/drug effects , Wound Healing/drug effects , Animals , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Estradiol/analogs & derivatives , Estradiol/chemistry , Estrogens/chemistry , Female , Humans , Mice , Mice, Inbred C57BL , Ovariectomy , Receptors, Estrogen/metabolism , Skin/injuries , Skin/metabolism , Transcriptional Activation/drug effectsABSTRACT
Boron neutron capture therapy (BNCT) is a promising binary modality used to treat malignant brain gliomas. To optimize BNCT effectiveness a non-invasive method is needed to monitor the spatial distribution of BNCT carriers in order to estimate the optimal timing for neutron irradiation. In this study, in vivo spatial distribution mapping and pharmacokinetics evaluation of the (19)F-labelled boronophenylalanine (BPA) were performed using (19)F magnetic resonance imaging ((19)F MRI) and (19)F magnetic resonance spectroscopy ((19)F MRS). Characteristic uptake of (19)F-BPA in C6 glioma showed a maximum at 2.5 h after compound infusion as confirmed by both (19)F images and (19)F spectra acquired on blood samples collected at different times after infusion. This study shows the ability of (19)F MRI to selectively map the bio-distribution of (19)F-BPA in a C6 rat glioma model, as well as providing a useful method to perform pharmacokinetics of BNCT carriers.
Subject(s)
Boron Compounds , Boron Neutron Capture Therapy/methods , Fructose/analogs & derivatives , Glioma/radiotherapy , Animals , Boron Compounds/pharmacokinetics , Brain/metabolism , Brain/pathology , Brain Neoplasms/metabolism , Brain Neoplasms/radiotherapy , Cell Line, Tumor , Demography , Fluorine Radioisotopes/blood , Fructose/pharmacokinetics , Glioma/metabolism , Magnetic Resonance Imaging , Magnetic Resonance Spectroscopy , Male , Neoplasms, Experimental/physiopathology , Rats , Rats, WistarABSTRACT
Paclitaxel (1a), a well known antitumor agent adopted mainly for the treatment of breast and ovarian cancer, suffers from significant disadvantages such as low solubility, certain toxicity and specific drug-resistance of some tumor cells. To overcome these problems extensive research has been carried out. Among the various proposed strategies, the conjugation of paclitaxel (1a) to a biocompatible polymer, such as hyaluronic acid (HA, 2), has also been considered. Coupling a bioactive compound to a biocompatible polymer offers, in general, many advantages such as better drug solubilization, better stabilization, specific localization and controlled release. Hereafter the design, synthesis and applications of hyaluronic acid-paclitaxel bioconjugates are reviewed. An overview of HA-paclitaxel combinations is also given.
Subject(s)
Antineoplastic Agents, Phytogenic/chemical synthesis , Drug Design , Hyaluronic Acid/chemical synthesis , Paclitaxel/chemical synthesis , Animals , Antineoplastic Combined Chemotherapy Protocols , Drug Screening Assays, Antitumor , Humans , Hyaluronic Acid/chemistry , Paclitaxel/chemistryABSTRACT
6-endo- and 6-exo-Hydroxybicyclo[2.2.2]octan-2-one and 1-methyl-6-endo- and 6-exo-hydroxybicyclo[2.2.2]octan-2-one ethylene acetals and ethylene dithioacetals 1-4 have been characterized by 1D and 2D NMR methods.
Subject(s)
Acetals/chemistry , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Ethylenes/chemistry , Sulfur/chemistry , Magnetic Resonance Spectroscopy , Molecular Structure , StereoisomerismABSTRACT
Reaction yield optimization for the synthesis and the complexation of a boron neutron capture therapy agent (19)F-labelled, (10)B-enriched p-boronophenylalanine-fructose ((19)F-BPA-fr) complex was obtained. (1)H, (19)F, (13)C and (10)B magnetic resonance spectroscopy (MRS) of the (19)F-BPA-fr complex in aqueous and rat blood solution phantoms and its spatial distribution mapping using (19)F magnetic resonance imaging (MRI) results are reported. 7 T and 9.4 T magnetic fields were used to perform MRI and MRS respectively. Our in vitro results suggest that in vivo studies on (19)F-BPA through (19)F NMR will be feasible.