Regioselective C5-alkylation and C5-methylcarbamate formation of 2,3-dihydro-4-pyridones and C3-alkylation and C3-methylcarbamate formation of 4-(pyrrolidin-1-yl)furan-2(5H)-one

Reactions of N-alkyl-2,3-dihydro-4-pyridones and 4-(pyrrolidin-1-yl)furan-2(5H)-one with aldehydes and triethylsilane in a one-flask procedure provided C5 and C3 alkylated derivatives, respectively. Mannich-type reactions with formaldehyde and carbamates in the presence of lithium perchlorate furnished C5/C3 methylcarbamates

Direct Hiyama Cross-Coupling of Enaminones With Triethoxy(aryl)silanes and Dimethylphenylsilanol

2,3-Dihydropyridin-4(1H)-ones undergo direct C–H functionalization at C5 in the palladium(II)-catalyzed Hiyama reaction, using triethoxy(aryl)silanes and dimethylphenylsilanol. The reagent CuF2 has a dual role in the reactions with triethoxy(aryl)silanes. It is a source of fluoride to activate the silane in the Hiyama reaction and also serves as the reoxidant to convert Pd(0) to Pd(II) in the catalytic cycle

Regioselective C5-alkylation and C5-methylcarbamate formation of 2,3-dihydro-4-pyridones and C3-alkylation and C3-methylcarbamate formation of 4-(pyrrolidin-1-yl)furan-2(5H)-one

Reactions of N-alkyl-2,3-dihydro-4-pyridones and 4-(pyrrolidin-1-yl)furan-2(5H)-one with aldehydes and triethylsilane in a one-flask procedure provided C5 and C3 alkylated derivatives, respectively. Mannich-type reactions with formaldehyde and carbamates in the presence of lithium perchlorate furnished C5/C3 methylcarbamates

Total Syntheses of Arylindolizidine Alkaloids (+)-Ipalbidine and (+)-Antofine

This paper presents the first application of two recently developed reactions to natural product synthesis. The first method involves a 6-endo-trig cyclization to prepare a versatile chiral enaminone building block. The second is a direct C–H arylation reaction. As a showcase for the utility of these methods, (+)-antofine and (+)-ipalbidine were synthesized in only 8 steps and 24–26% overall yields

Synthesis of 6- and 7-membered cyclic enaminones: Scope and mechanism

Six- and seven-membered cyclic enaminones can be prepared using common, environmentally benign reagents. Amino acids are used as synthetic precursors allowing diversification and the incorporation of chirality. The key reaction in this multi-step process involves deprotection of Boc-aminoynones and subsequent treatment with methanolic K2CO3 to induce cyclization. A β-amino elimination side reaction was identified in a few labile substrates that led to either loss of stereochemical purity or degradation. This process can be mitigated in specific cases using mild deprotection conditions. NMR and deuterium labeling experiments provided valuable insight into the workings and limitations of this reaction. Although disguised as a 6-endo-dig cyclization, the reagents employed in the transformation play a direct role in bond-making and bond-breaking, thus changing the mode of addition to a 6-endo-trig cyclization. This method can be used to construct an array of monocyclic and bicyclic scaffolds, many of which are found in well-known natural products (e.g. indolizidine, quinolizidine and Stemona alkaloids)

Synthesis of a quinolone library from ynones

A library of 72 quinolones was synthesized from substituted anthranilic acids, using ynone intermediates. These masked β-dicarbonyl synthons allowed cyclization under milder conditions than previously reported quinolone syntheses

Overcoming the blood-brain barrier to taxane delivery for brain tumors and neurodegenerative diseases and brain tumors

The original publication is available at www.springerlink.comThe blood-brain barrier (BBB) effectively prevents microtubule stabilizing drugs from readily entering the central nervous system (CNS). A major limiting factor for microtubule stabilizing drug permeation across the BBB is the active efflux back into the circulation by the over-expression of the multidrug resistant gene product (MDR1) or P-glycoprotein (P-gp). This study has focused on strategies to overcome P-gp-mediated efflux of taxol analogues, microtubule (MT) stabilizing agents that could be used to treat brain tumors and, potentially, neurodegenerative diseases such as Alzheimer’s disease. However, taxol is a strong P-gp substrate which limits its distribution across the BBB and therapeutic potential in the CNS. We have found that addition of a succinate group to the C-10 position of taxol results in an agent, Tx-67, with reduced interactions with P-gp and enhanced permeation across the BBB in both in vitro and in situ models. Our studies demonstrate the feasibility of making small chemical modifications to taxol to generate analogues with reduced affinity for the P-gp but retention of MT-stabilizing properties, i.e., a taxane that may reach and treat therapeutic targets in the CNS

Artificial Neural Network Based Analysis of High Throughput Screening Data for Improved Prediction of Active Compounds

Artificial Neural Networks (ANNs) are trained using High Throughput Screening (HTS) data to recover active compounds from a large data set. Improved classification performance was obtained on combining predictions made by multiple ANNs. The HTS data, acquired from a Methionine Aminopeptidases Inhibition study, consisted of a library of 43,347 compounds, and the ratio of active to non-active compounds, RA/N, was 0.0321. Back-propagation ANNs were trained and validated using Principal Components derived from the physico-chemical features of the compounds. On selecting the training parameters carefully, an ANN recovers one-third of all active compounds from the validation set with a three-fold gain in RA/N value. Further gains in RA/N values were obtained upon combining the predictions made by a number of ANNs. The generalization property of the back-propagation ANNs was utilized to train those ANNs with the same training samples, after being initialized with different sets of random weights. As a result, only 10% of all available compounds were needed for training and validation, and the rest of the data set was screened with more than a ten-fold gain of the original RA/N value. Thus, ANNs trained with limited HTS data might become useful in recovering active compounds from large data sets

Synthesis and Interactions of 7-Deoxy-, 10-Deacetoxy, and 10-Deacetoxy-7-Deoxypaclitaxel with NCI/ADR-RES Cancer Cells and Bovine Brain Microvessel Endothelial Cells

Please note that this is an author-produced PDF of an article accepted for publication following peer review. The publisher version is available on its site.7-Deoxypaclitaxel, 10-deacetoxypaclitaxel and 10-deacetoxy-7-deoxypaclitaxel were prepared and evaluated for their ability to promote assembly of tubulin into microtubules, their cytotoxicity against NCI/ADR-RES cells and for their interactions with Pglycoprotein in bovine brain microvessel endothelial cells. The three compounds were essentially equivalent to paclitaxel in cytotoxicity against NCI/ADR-RES cells. They also appeared to interact with P-glycoprotein in the endothelial cells with the two 10-deacetoxy compounds having less interaction than paclitaxel and 7-deoxypaclitaxel. ©2000 Elsevier Science Ltd. All rights reserved

Discovery and Development of a Small Molecule Library with Lumazine Synthase Inhibitory Activity

(E)-5-Nitro-6-(2-hydroxystyryl)pyrimidine-2,4(1H,3H)-dione (9) was identified as a novel inhibitor of Schizosaccharomyces pombe lumazine synthase by high-throughput screening of a 100,000 compound library. The Ki of 9 vs. Mycobacterium tuberculosis lumazine synthase was 95 μM. Compound 9 is a structural analog of the lumazine synthase substrate, 5-amino-6-(D-ribitylamino)-2,4-(1H,3H)pyrimidinedione (1). This indicates that the ribitylamino side chain of the substrate is not essential for binding to the enzyme. Optimization of the enzyme inhibitory activity through systematic structure modification of the lead compound 9 led to (E)-5-nitro-6-(4-nitrostyryl)pyrimidine-2,4(1H,3H)-dione (26), which has a Ki of 3.7 μM vs. M. tuberculosis lumazine synthase