ABSTRACT
Several new examples of meso-(het)arylBODIPY were prepared via the Liebeskind-Srogl (L-S) cross-coupling reaction of the Biellmann BODIPYs (1a,b) and aryl- and heteroarylboronic acids in good to excellent yield. It was shown that this reaction could be carried out under microwave heating to shorten reaction times and/or increase the yield. It was illustrated that organostannanes also participate in the L-S reaction to give the corresponding BODIPY analogues in short reaction times and also with good to excellent yields. We analyze the role of the substituent at the sensitive meso position in the photophysical signatures of these compounds. In particular, the rotational motion of the aryl ring and the electron donor ability of the anchored moieties rule the nonradiative pathways and, hence, have a deep impact in the fluorescence efficiency.
ABSTRACT
A series of 14 meso-polyarylamine-BODIPY (borondipyrromethene) hybrids of the general structure A were synthesized. Two methods were used to prepare them. The first protocol involved a direct Liebeskind-Srogl cross-coupling of thiomethylbodipys 1-2 with arylaminoboronic acids (4 examples, 75-98%). The second method involves a two-step sequence: a Liebeskind-Srogl reaction to prepare 6 meso-bromoarylbodipys (58-83%) followed by a Suzuki coupling of these Br-containing BODIPYs with arylaminoboronic acids (10 examples, 44-84%). Seven of these derivatives displayed emission in the near-infrared region. The optical properties of compound 18 were rationalized in terms of its crystal structure.
Subject(s)
Boron Compounds/chemistry , Optics and Photonics , Polyamines/chemistry , Molecular Structure , StereoisomerismABSTRACT
The finding that alkyl 1,4-dihydro-4-oxoquinoline-3-carboxylate and N-alkyl-1,4-dihydro-4-oxoquinoline-3-carboxamide derivatives may be high-affinity ligands at the benzodiazepine binding site of the GABA(A) receptor, prompted a study of 3-acyl-1,4-dihydro-4-oxoquinoline (3-acyl-4-quinolones). In general, the affinity of the 3-acyl derivatives was found to be comparable with the 3-carboxylate and the 3-carboxamide derivatives, and certain substituents (e.g., benzyl) in position 6 were again shown to be important. As it is believed that the benzodiazepine binding site is situated between an alpha- and a gamma-subunit in the GABA(A) receptor, selected compounds were tested on the alpha(1)beta(2)gamma(2s), alpha(2)beta(2)gamma(2s) and alpha(3)beta(2)gamma(2s) GABA(A) receptor subtypes. The 3-acyl-4-quinolones display various degrees of selectivity for alpha(1)- versus alpha(2)- and alpha(3)-containing receptors, and high-affinity ligands essentially selective for alpha(1) over alpha(3) were developed.
Subject(s)
4-Quinolones/chemistry , 4-Quinolones/metabolism , Receptors, GABA-A/metabolism , Animals , Benzodiazepines/metabolism , Binding Sites , Ligands , Protein Binding , Protein Subunits , Structure-Activity RelationshipABSTRACT
An unprecedented synthesis of 8-substituted-borondipyrromethenes is described starting from 8-thiomethylbodipy 1. Aryl, heteroaryl, alkenyl, and organometallic boronic acids smoothly reacted with 1 in the presence of a catalytic amount of Pd(0) and a stoichiometric amount of Cu(I)-2-thienylcarboxylate under neutral conditions to give the corresponding Bodipy analogues in good to quantitative yields (20 examples). A remarkable reactivity was observed in some cases, e.g., ferrocenylboronic acid gave the product in 98% isolated yield after only 10 min at 55 degrees C.
ABSTRACT
The 3-ethoxycarbonyl-4-quinolone compound 1 has previously been identified via a database search as an interesting lead compound for ligand binding at the benzodiazepine site of GABA(A) receptors (Kahnberg et al. J. Mol. Graphics Modelling 2004, 23, 253-261). Pharmacophore-guided optimization of this lead compound yielded a number of high-affinity ligands for the benzodiazepine site including compounds 20 and 23-25 displaying sub-nanomolar affinities. A few of the compounds have been tested on the alpha(1)beta(2)gamma(2S) and alpha(3)beta(2)gamma(2S) GABA(A) receptor subtypes, and two of the compounds (5 and 19) display selectivity for alpha(1)- versus alpha(3)-containing receptors by a factor of 22 and 27, respectively. This selectivity for alpha(1)beta(2)gamma(2S) is in the same range as that for the well-known alpha(1) subunit selective compound zolpidem.
Subject(s)
4-Quinolones/chemical synthesis , 4-Quinolones/pharmacology , Benzodiazepines/chemistry , Brain/drug effects , GABA-A Receptor Antagonists , 4-Quinolones/chemistry , Animals , Binding Sites , Cell Line , Computer Simulation , Drug Evaluation, Preclinical , Humans , In Vitro Techniques , Ligands , Models, Molecular , Molecular Structure , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Pyrimidines/pharmacology , Rats , Receptors, GABA-A/chemistry , Structure-Activity RelationshipABSTRACT
To further develop and evaluate a pharmacophore model previously proposed by Cook and co-workers (Drug Des. Discovery 1995, 12, 193-248) for ligands binding to the benzodiazepine site of the GABA(A) receptor, 40 new flavone derivatives have been synthesized and their affinities for the benzodiazepine site have been determined. Two new regions of steric repulsive interactions between ligand and receptor have been characterized, and the receptor region in the vicinity of 6- and 3'-substituents has been mapped out. 2'-Hydroxy substitution is shown to give a significant increase in affinity, which is interpreted in terms of a novel hydrogen bond interaction with the previously proposed hydrogen bond-accepting site A2. On the basis of the results of these studies and the refined pharmacophore model, 5'-bromo-2'-hydroxy-6-methylflavone, the highest affinity flavone derivative reported so far (K(i) = 0.9 nM), was successfully designed. A comparison of the pharmacophore model with a recently proposed alternative model (Marder; et al. Bioorg. Med. Chem., 2001, 9, 323-335) has been made.
