ABSTRACT
A series of lobelane and GZ-793A analogues that incorporate aromatic 4-hydroxy and 4-(2-fluoroethoxy) substituents were synthesized and evaluated for inhibition of [(3)H]dopamine (DA) uptake at the vesicular monoamine transporter-2 (VMAT2) and the dopamine transporter (DAT), and [(3)H]serotonin uptake at the serotonin transporter (SERT). Most of these compounds exhibited potent inhibition of DA uptake at VMAT2 in the nanomolar range (Ki=30-70nM). The two most potent analogues, 7 and 14, both exhibited a Ki value of 31nM for inhibition of VMAT2. The lobelane analogue 14, incorporating 4-(2-fluoroethoxy) and 4-hydroxy aromatic substituents, exhibited 96- and 335-fold greater selectivity for VMAT2 versus DAT and SERT, respectively, in comparison to lobelane. Thus, lobelane analogues bearing hydroxyl and fluoroethoxy moieties retain the high affinity for VMAT2 of the parent compound, while enhancing selectivity for VMAT2 versus the plasmalemma transporters.
Subject(s)
Dopamine Uptake Inhibitors/chemistry , Dopamine Uptake Inhibitors/pharmacology , Lobeline/analogs & derivatives , Vesicular Monoamine Transport Proteins/metabolism , Chemistry Techniques, Synthetic , Dopamine Plasma Membrane Transport Proteins/antagonists & inhibitors , Dopamine Plasma Membrane Transport Proteins/metabolism , Drug Evaluation, Preclinical/methods , Lobeline/chemical synthesis , Lobeline/chemistry , Lobeline/pharmacology , Serotonin Plasma Membrane Transport Proteins/metabolism , Selective Serotonin Reuptake Inhibitors/chemistry , Selective Serotonin Reuptake Inhibitors/pharmacology , Structure-Activity Relationship , Vesicular Monoamine Transport Proteins/antagonists & inhibitorsABSTRACT
Paclitaxel (PTX) is a potent chemotherapy for many cancers but it suffers from very poor solubility. Consequently, the TAXOL formulation uses copious amounts of the surfactant Cremophor EL to solubilize the drug for injection, resulting in severe hypersensitivity and neutropenia. In contrast to Cremophor EL, presented is a way to solubilize PTX by conjugation of a dicarboxylic fatty acid for specific binding to the ubiquitous protein, serum albumin. The conjugation chemistry was simplified to a single step using the activated anhydride form of 3-pentadecylglutaric (PDG) acid, which is reactive to a variety of nucleophiles. The PDG derivative is less cytotoxic than the parent compound and was found to slowly hydrolyze to PTX (≈ 5% over 72 h) in serum, tumor cytosol, and tumor tissue homogenate. When injected intravenously to tumor-bearing mice, [(3) H]-PTX in the TAXOL formulation was cleared rapidly with a half-life of 7 h. In the case of the PDG derivative of PTX, the drug is quickly distributed and approximately 20% of the injected dose remained in the vasculature experiencing a 23 h half-life. These improvements from modifying PTX with the PDG fatty acid present the opportunity for PDG to become a generic modification for the improvement of many therapeutics.
Subject(s)
Antineoplastic Agents, Phytogenic/pharmacokinetics , Colorectal Neoplasms/metabolism , Drug Carriers , Fatty Acids/chemistry , Glutarates/chemistry , Paclitaxel/pharmacokinetics , Serum Albumin/metabolism , Animals , Antineoplastic Agents, Phytogenic/administration & dosage , Antineoplastic Agents, Phytogenic/blood , Antineoplastic Agents, Phytogenic/chemistry , Biotransformation , Cell Line, Tumor , Cell Survival/drug effects , Chemistry, Pharmaceutical , Colorectal Neoplasms/pathology , Drug Stability , Fatty Acids/toxicity , Female , Glutarates/toxicity , Half-Life , Humans , Hydrolysis , Injections, Intravenous , Mice , Mice, Inbred BALB C , Paclitaxel/administration & dosage , Paclitaxel/analogs & derivatives , Paclitaxel/blood , Paclitaxel/chemistry , Protein Binding , Serum Albumin/chemistry , Serum Albumin/toxicity , Serum Albumin, Human , Technology, Pharmaceutical/methods , Tissue DistributionABSTRACT
The enantioselective total synthesis of the dual-specificity phosphatase inhibitor (-)-bitungolide F has been achieved using two convergent routes. Both strategies feature an asymmetric boron-mediated pentenylation, a stereoselective aldol, and a hydroxyl-directed 1,3-anti-reduction in order to control the stereogenic centers at C4, C5, C9, and C11. Whereas the first total synthesis was achieved in 11 steps and 14.6% overall yield using an Evans-type asymmetric alkylation, the second was completed in 9 steps and 11.4% overall yield using a highly enantioselective organocatalytic Michael addition as a key step and a protecting group free strategy.
