ABSTRACT
Solubility is recognised as one of the most important physicochemical parameters necessary for a successful clinical candidate. Despite that, there are few articles in the medicinal chemistry literature with a specific focus on solubility-driven optimisation of lead compounds. This could be because the importance of measuring solubilities as part of the optimisation process is relatively underappreciated, or the fact that obtaining sufficient high quality solubility data is difficult. This review gives examples of solubility-driven optimisation programs from the last fifteen years, and explores recent developments in solubility measurement techniques. Quantitative NMR methods are highlighted; these offer the potential to provide high quality solubility measurements in a cost-effective and high-throughput manner.
Subject(s)
Drug Discovery/methods , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacokinetics , Anti-Bacterial Agents/pharmacology , Ciprofloxacin/analogs & derivatives , Ciprofloxacin/chemistry , Ciprofloxacin/pharmacokinetics , Ciprofloxacin/pharmacology , Drug Resistance, Bacterial , Magnetic Resonance Spectroscopy , Molecular Structure , Prodrugs/chemistry , Prodrugs/pharmacokinetics , Prodrugs/pharmacology , Solubility , Structure-Activity RelationshipABSTRACT
Bridgehead lithiations have successfully been carried out on substrates derived from catechinic acid, which possess the core bicyclo[3.3.1]nonane-1,3,5-trione structure present in garsubellin A. Using an external quench method, various electrophiles have been incorporated at the C-5 bridgehead position in a one-step process that appears to be sensitive to the substitution pattern on the bicyclic system. Regioselective lithiation at the C-3 sp(2) centre was achieved by changing the base used from LDA to LTMP. Following the introduction of a prenyl substituent by bridgehead substitution, annulation of a THF ring, analogous to that in garsubellin A, was possible via an epoxidation-ring opening sequence. Oxidative modification of the catechol substituent of the catechinic acid core was possible to give systems with muconic acid, ortho-quinone or furan 2-carboxylic acid side chains.
Subject(s)
Biomimetic Materials/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Catechin/analogs & derivatives , Terpenes/chemical synthesis , Biomimetic Materials/chemistry , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Models, Molecular , Molecular Structure , Oxidation-Reduction , Terpenes/chemistryABSTRACT
The synthesis of polyprenylated phloroglucinol natural products, including clusianone, nemorosone, and garsubellin A, was pursued by a strategy involving construction of a core bicyclo[3.3.1]nonanetrione structure and subsequent elaboration via organolithium intermediates. Appropriate bridged core structures were obtained through the cyclization of a suitably substituted cyclohexanone enol ether or enol silane with malonyl dichloride. Additional substituents were then introduced by means of regioselective lithiation reactions, including the generation of bridgehead enolates, thus enabling the total synthesis of clusianone and also of an advanced intermediate toward nemorosone. In the case of garsubellin A, an additional THF-like ring was elaborated by a biomimetic 5-exo-tet cyclization of an enol ether (or enol) with a side-chain epoxide. This enabled a formal synthesis of racemic garsubellin A by accessing one of the late intermediates in the Danishefsky synthesis.
Subject(s)
Bridged Bicyclo Compounds/chemical synthesis , Neoprene/chemistry , Phloroglucinol/chemistry , Terpenes/chemical synthesis , Acylation , Alkylation , Benzophenones , Benzoquinones , Bridged Bicyclo Compounds/chemistry , Chlorine/chemistry , Copper/chemistry , Cyclization , Ether/chemistry , Molecular Structure , Silanes/chemistry , Stereoisomerism , Terpenes/chemistryABSTRACT
[Structure: see text] A concise synthesis of the polyprenylated acylphloroglucinol natural product, clusianone, in racemic form, is described. An Effenburger cyclization generated a core bicyclo[3.3.1]nonane-trione structure, which was then elaborated by means of regioselective lithiation reactions.
