ABSTRACT
In this paper, we describe our synthesis of four key building blocks for the total synthesis of psymberin (1) and its C4 epimer (2). Despite early difficulties in processing material to the advanced intermediate stage, we have been successful in developing high-yielding syntheses for the pyran core, natural side chain, 4-epi side chain, and aryl fragments of the molecule. Our findings from the optimization process are presented herein.
Subject(s)
Pyrones/chemical synthesis , Coumarins , Molecular Conformation , Pyrones/chemistry , StereoisomerismABSTRACT
Tridentate cross-linked histidine-phenol Cu(ii) ether and ester complexes, chemical analogs of the active site of several heme-copper oxidases, have been synthesized and crystallized.
Subject(s)
Copper/chemistry , Electron Transport Complex IV/chemistry , Histidine/chemistry , Models, Molecular , Phenol/chemistry , Cross-Linking Reagents , Electron Transport Complex IV/metabolism , Ligands , Spectrophotometry, UltravioletABSTRACT
Following the optimization of diamine-containing efflux pump inhibitors with respect to in vitro potentiation activity, in vivo stability and acute toxicity, we addressed the question of how to control the pharmacokinetic properties of the series. Upon intravenous administration in the rat, tissue levels of MC-04,124 (the lead compound) were high and prolonged compared to those in the serum. The lipophilicity and basicity of analogues of this compound were systematically varied, and effects on potency and pharmacokinetics explored. The ratio of drug levels in tissue versus serum was not significantly reduced in any of the active analogues examined.
