A project has been initiated to synthesize proanthocyanidin oligomers found in cocoa. Natural, readily available (+)-catechin was transformed into 5,7,3‘,4‘-tetra-O-benzyl-(−)-epicatechin (14) by (a) benzylation of the phenolic oxygens; (b) oxidation of the 3-alcohol to ketone by the Dess−Martin periodinane; and (c) reduction with lithium tri-sec-butylborohydride (l-Selectride) in the presence of LiBr. The additive diminishes the extent of ketone enolization while maintaining a stereoselectivity of ≥200:1. Oxidation of 14 with DDQ was performed best from the standpoint of product purification if ethylene glycol was used as the nucleophilic trapping agent. The resulting ether 19 was condensed with 14 using TiCl4 to give a good yield of benzyl-protected epicatechin-4β,8-epicatechin (octa-O-benzylprocyanidin B2, 20) as the sole dimeric product. Hydrogenolysis of 20 yielded procyanidin B2 in the first enantiospecific synthesis of this natural product which employs protected intermediates and thereby allows the necessary product separation after the condensation step to be performed on nonpolar, nonsensitive intermediates. Acylation of 20 with tri-O-benzylgalloyl chloride followed by hydrogenolysis gave access to the title bis-gallate (24). This constitutes the first synthesis of this natural product, a compound notable for its PKC-inhibitory and anticancer activity.

We report an improved synthesis of bis(5,7,3',4'-tetra-O-benzyl)epicatechin 4beta,8-dimer (3) from 5,7,3',4'-tetra-O-benzylepicatechin (1) and 5,7,3',4'-tetra-O-benzyl-4-(2-hydroxyethoxy)epicatechin (2) by replacing the previously employed Lewis acid, titanium tetrachloride, with the clay mineral Bentonite K-10. Under the same conditions, the benzyl-protected all-4beta,8-trimer, -tetramer, and -pentamer were obtained regioselectively from their lower homologues, albeit in rapidly decreasing yields. Reaction of 2 with an organoaluminum thiolate generated from 2-mercaptobenzothiazole and trimethylaluminum followed by acetylation produced 3-O-acetyl-4-[(2-benzothiazolyl)thio]-5,7,3',4'-tetra-O-benzylepicatechin (12). Medium-sized protected oligomers with 4beta,8-interflavan linkages are obtained in improved yields by using this compound as the electrophile and silver tetrafluoroborate as activator and are isolated by reversed-phase HPLC. Their deprotection by ester saponification followed by hydrogenolysis yielded the free procyanidins, which were characterized as their peracetates. The synthetic procyanidins are identical by normal-phase HPLC with fractions isolated from cocoa. The principle of chain extension by two members was demonstrated using a dimeric electrophile obtained by self-condensation of compound 12. Both the synthetic and natural pentamer 32 inhibit the growth of several breast cancer cell lines. Using the MDA MB 231 line, it was established that this outcome is based on the induction of cell cycle arrest in the G0/G1 phase. Subsequent cell death is more likely necrotic rather than apoptotic. Control experiments demonstrate that the polyphenol itself, rather than hydrogen peroxide potentially formed by its autoxidation, is the causative agent.

After 14 years there, he spent 3 years at the Mayo Clinic and then moved on to the Georgetown University Medical Center, where he is the Director of the Drug Discovery Program. Dr. Kozikowski's interests are in the areas of drug abuse, medications development, second messenger based therapeutics for cancer, and novel chemical interventions for the treatment of Alzheimer's disease.

Despite their discovery in the early 20th century and intensive study over the last twenty years, nicotinic acetylcholine receptors (nAChRs) are still far from being well understood. Only a few chemical entities targeting nAChRs are currently undergoing clinical trials, and even fewer have reached the marketplace. In our efforts to discover novel and truly selective nAChR ligands, we designed and synthesized a series of chiral cyclopropane-containing α4β2-specific ligands that display low nanomolar binding affinities and excellent subtype selectivity, while acting as partial agonists at α4β2-nAChRs. Their favorable antidepressant-like properties were demonstrated in the classical mouse forced swim test. Preliminary ADMET studies and broad screening towards other common neurotransmitter receptors were also carried out to further evaluate their safety profile and eliminate their potential off-target activity. These highly potent cyclopropane ligands possess superior subtype selectivity compared to other α4β2-nAChR agonists reported to date, including the marketed drug varenicline, and therefore may fully satisfy the crucial prerequisite for avoiding adverse side effects. These novel chemical entities could potentially be advanced to the clinic as new drug candidates for treating depression.

To better characterize the roles of metabotropic glutamate receptors (mGluRs) in physiological and pathophysiological processes, there is an important need to learn more about the structural features relevant to the design of novel, high-affinity ligands that are family and subtype specific. To date, many of the biological studies that have been conducted in the area of mGluR research have made use of the agonist (1S,3R)-ACPD. This compound has been shown to act as an agonist at both the group I and group II receptors while showing little selectivity among the four subtypes belonging to these two groups. Moreover, (1S,3S)-ACPD, the cis isomer, shows negligible activity at group I receptors and is a good agonist of mGluR2. Since ACPD is itself somewhat flexible, with four distinctive conformations being identified from molecular modeling studies for the trans isomer and five conformations for the cis isomer, we believed that it would be of interest to examine the activity of an ACPD analogue that has been constrained through the introduction of a single carbon atom bridge. Accordingly, we have prepared an aminobicyclo[2.1.1]hexanedicarboxylic acid (ABHxD-I) analogue of ACPD. The synthesis of this compound was accomplished by use of an intramolecular [2 + 2] photocycloaddition reaction, in which four distinct isomers were isolated. Of these four compounds, only a single isomer, ABHxD-I (6a), was found to be a potent agonist of the mGluRs. This compound, which expresses the fully extended glutamate conformation, was found to be more potent than ACPD at all six of the eight mGluR subtypes that were investigated and to be comparable to or more potent than the endogenous ligand, glutamate, for these receptors. Interestingly, despite its fixed conformation, ABHxD-I, like glutamate, shows little subtype selectivity. Through modeling studies of ABHxD-I (6a), ABHD-VI, LY354740, (1S,3R)-ACPD, (1S, 3S)-ACPD, and l-glutamate, we conclude that the aa conformation of l-glutamate is the active conformation for both group I and group II mGluRs. Moreover, the modeling-based comparisons of these ligands suggest that the selectivity exhibited by LY354740 between the group I and group II mGluRs is not a consequence of different conformations of L-glutamate being required for recognition at these mGluRs but rather is related to certain structural elements within certain regions having a very different impact on the group I and group II mGluR activity. The enhanced potency of ABHxD-I relative to trans-ACPD commends it as a useful starting point in the design of subtype selective mGluR ligands.

No abstract

Benzodiazepines are among the most highly prescribed drugs due to their pharmacological action of relieving anxiety mediated through modulating the activity of γ-aminobutyric acid receptors in the central nervous system. 1 The peripheral-type benzodiazepine receptor (PBR) is another class of binding sites for benzodiazepines distinct from the aforementioned neurotransmitter receptors. The PBR was originally discovered because it binds the benzodiazepine diazepam with relatively high affinity. 2 Further studies demonstrated that in addition to the benzodiazepines, PBR binds with high affinity other classes of organic compounds, such as isoquinolines, 3 imidazopyridines, 4 indole derivatives, 5 and pyrrolobenzoxazepines. 6 In addition to these drug ligands, the polypeptide diazepam binding inhibitor, 7 porphyrins, 8 and benzodiazepine-like molecules 9 have been identified as endogenous PBR ligands. The PBR, although present in all tissues examined, was found to occur in particularly high density in steroid-producing tissues, such as adrenal,

Oligomeric procyanidins containing 4alpha-linked epicatechin units are rare in nature and have hitherto not been accessible through stereoselective synthesis. We report herein the preparation of the prototypical dimer, epicatechin-4alpha,8-epicatechin (6), by reaction of the protected 4-ketones 11a,b with aryllithium reagents derived by halogen/metal exchange from the aryl bromides 26a,b. Removal of the 4-hydroxyl group from the resulting tertiary benzylic alcohols 27a,b was effected by tri-n-butyltin hydride and trifluoroacetic acid in a completely stereoselective manner, resulting in hydride delivery exclusively from the beta face. If benzyl was chosen for protection of the 3-hydroxyls, all protective groups could subsequently be removed in a single step by hydrogenolysis. tert-Butyldimethylsilyl groups, on the other hand, permitted selective deprotection of the 3-hydroxyls in preparation for their subsequent acylation with tri-O-benzylgalloyl chloride. Only monogalloylation at the "bottom" 3-hydroxyl took place when 28c was acylated under the previously reported conditions, reflecting the increased steric hindrance of the "top" 3-hydroxyl group in 28c compared with its 4beta,8-isomer 3. The preparation of compounds 14 and 17 containing phloroglucinol trimethyl ether in the 4alpha and 4beta linkages to epicatechin is also described. The 8-position of the bromine atom in 19, previously conjectured in analogy to the structurally characterized tetramethyl ether 20, was confirmed by transformation of both compounds into the common derivative 25.