Antileishmanial activity and cytotoxicity of ent-beyerene diterpenoids.

We describe the in vitro activity of two natural isomeric ent-beyerene diterpenes, several derivatives and synthetic intermediates. Beyerenols 1 and 2 showed EC50 of 4.6 ±â€¯9.4 and 5.3 ±â€¯9.4 µg/mL against amastigotes of L. (V) brazilensis, with SI of 5.1 and 7.7, respectively. Beyerenol 1 was synthesized from stevioside. In vivo experiments with bereyenols showed cure in 50% of hamsters infected with L. (V) brazilensis topically applied as Cream I (beyerenol 1, 0.81%, w/w) and Cream III (beyerenol 2, 1.96%, w/w). These results suggest that beyerenols are potential candidates for cutaneous leishmaniasis chemotherapy by topical application. In vitro assays of amastigotes of L. (V) brazilensis showed EC50 of 1.1 ±â€¯0.1 and 1.3 ±â€¯0.04 µg/mL, with SI of 3.1 and 3.5 for hydrazone intermediates 10 and 11, respectively.

Chemoselective Reduction of Trichloromethyl Compounds to gem-Dichloromethyl Groups Following Appel's Reaction Protocol.

A simple and easy reduction of trichloroacetyl compounds following the modification of Appel's reaction protocol, using triphenylphosphine and methanol, afforded the corresponding dichloroacetyl compounds, with the exception of trichloroacetylmorpholine, in yields of 80-98% under very mild experimental conditions. Likewise, when trichloromethyl heterocyclic compounds contain another reactive functional group, the reaction is highly chemoselective giving the dichloromethyl derivative.

Karwinaphthopyranones from the fruits of Karwinskia parvifolia and their cytotoxic activities.

The new 2-acetyl-8-methoxynaphthol (1) and five new "dimeric" napthopyranones, karwinaphthopyranones A1 and A2 (2 and 3) and karwinaphthopyranones B1-B3 (4-6), possessing a methoxy group at C-5', were isolated together with four other known compounds from the dried fruits of Karwinskia parvifolia. The structures of compounds 2-6 were determined by spectroscopic data interpretation. Cell culture assays showed that some of these compounds possess antiproliferative activities in representative human cancer cell lines, with half-maximal growth inhibitory concentrations in the micromolar range.

Linear and cyclic dipeptides with antimalarial activity.

Several natural and synthetic polypeptides possess important antimalarial activity. Shorter peptides with potent antimalarial activity have also been described, among them linear di-, tri-, tetra- and pentapeptides and their cyclic analogs. In an attempt to find dipeptides with antimalarial activities we show that linear and cyclic dipeptides, the latter known as diketopiperazines, still retain the fundamental core to preserve antimalarial activity. Thirteen linear dipeptides and ten diketopiperazines were investigated. Eight linear dipeptides showed IC(50) values between 2.78 and 7.07 µM, while eight diketopiperazines were also active with IC(50) values between 2.26 and 4.26 µM on Plasmodium berghei schizont cultures.

Oxazolidine-2-thiones and thiazolidine-2-thiones as nucleophiles in intermolecular Michael additions.

Conjugate addition of thiazolidinethiones and oxazolidinethiones to N-crotonylthiazolidinethiones and -oxazolidinethiones was observed in the presence of excess triethylamine in dichloromethane. The addition takes place by the nitrogen of the heterocycle with high diastereoselectivity. It was observed that the stereoselective addition occurs on the anti-s-cis conformation of the N-enoyl sulfur-containing heterocycle.

Chemoselective aromatic C-H insertion of α-diazo-ß-ketoesters catalyzed by dirhodium(II) carboxylates.

The ability of α-diazo-ß-ketoesters bearing a substituent on the benzylic position to undergo aromatic C-H insertion is described. Good to excellent yields of the aromatic C-H insertion products were observed with Rh(2)(tpa)(4) or Rh(2)(esp)(2) catalysts. This is an attractive strategy to prepare tetralins carrying a methyl group on the benzylic position, a structural motif found in several types of natural products.

Diastereoselective conjugate addition of organocuprates to chiral N-enoyl oxazolidinethiones.

Addition of organocuprates, generated in situ using an excess of a 1:2 mixture of CuI·DMS and Grignard reagent, to N-enoyl oxazolidinethiones in the presence of excess TMSI gave preferentially the anti diastereomer where the addition took place when the conformation of the substrate was syn-s-cis. The reaction was investigated with indene-based and three different phenyl glycine derived oxazolidinethiones.

Evaluation of a novel photoactive and biotinylated dehydroepiandrosterone analog.

To characterize the cell surface receptor for dehydroepiandrosterone (DHEA), we synthesized a DHEA analog containing biotin and benzophenone groups (DHEA-BP-Bt). DHEA-BP-Bt was equipotent with DHEA in competing with [(3)H]DHEA for binding to solubilized plasma membranes of bovine aortic endothelial cells (BAEC). Additionally, DHEA-BP-Bt pre-conjugated to avidin and immobilized on agarose, also inhibited plasma membrane binding of [(3)H]DHEA. Furthermore, DHEA-BP-Bt activated endothelial nitric oxide synthase, similar to DHEA. Confocal micrographs showed that, upon photoirradiation, DHEA-BP-Bt bound to sites on the cell surface of BAEC in a DHEA inhibitable manner. Finally, DHEA-BP-Bt bound specifically to proteins of approximately 55 kDa and 80 kDa, either when live cells were UV irradiated with the analog and plasma membrane proteins separated by SDS-PAGE or in a ligand blot analysis. These data confirm the successful synthesis of a photoactive, biotinylated DHEA analog which is capable of cross-linking to and identifying plasma membrane DHEA binding sites and which will allow us to further purify this receptor.

Synthesis and application of a photoaffinity analog of dehydroepiandrosterone (DHEA).

We have synthesized an analog of dehydroepiandrosterone (DHEA, 1) containing both a benzophenone (BP) and a biotin (Bt) group (DHEA-BP-Bt, 8). Compound 8 was prepared by functionalization on C-17 of 1. Biocytin was reacted with 4-benzoylbenzoic acid and the product was condensed with 1 containing a diamine-hexane linker. We detected specific protein bands of approximately 55, 80, and 150 kDa by SDS-PAGE analysis of vascular endothelial cell plasma membranes which had been photoirradiated in the presence of 8.

Efficient microwave assisted syntheses of 2,5-diketopiperazines in aqueous media.

Aqueous in situ one-pot N-Boc-deprotection-cyclization of N alpha-Boc-dipeptidyl-tert-butyl and methyl esters under microwave irradiation afforded 2,5-diketopiperazines (DKPs) in excellent yields. This protocol is rapid, safe, environmentally friendly, and highly efficient, and showed that the tert-butoxy moiety is also an excellent leaving group for these cyclizations.

Diastereoselective preparation of substituted delta-valerolactones. synthesis of (3R,4S)- and (3R,4R)-simplactones.

The syntheses of simplactones (3R,4S)-1 and (3R,4R)-2 were achieved in 5 steps from N-acyl thiazolidinethione chiral auxiliaries. The syntheses feature a double diastereoselective acetate aldol reaction solely controlled by the chirality of the auxiliary. Highly diastereoselective aldol reactions with s-trioxane were also achieved with N-acyl thiazolidinethione auxiliaries and the stereochemistry of an aldol product confirmed by X-ray analysis.

A formal synthesis of the auriside aglycon.

A highly convergent formal synthesis of the auriside aglycon was achieved. An indene-based thiazolidinethione chiral auxiliary was used for the construction of both the C1-C9 and C10-C17 fragments via acetate aldol reactions. A Meinwald reaction was utilized to install the stereocenter at C2, and a conjugated addition to an ynone was used to construct the C9-C11 enone.

Indene-based thiazolidinethione chiral auxiliary for propionate and acetate aldol additions.

An indene-based thiazolidinethione chiral auxiliary was prepared in two steps from trans-1-amino-2-indanol. Chlorotitanium enolates of this chiral auxiliary delivered excellent diastereoselectivities in propionate and acetate aldol additions. The chiral auxiliary was easily removed to deliver several valuable functionalities.

Synthesis of (-)-stemoamide using a stereoselective anti-aldol step.

The synthesis of (-)-stemoamide was achieved in 11 steps from 5-acetoxy-N-crotyl pyrrolidinone. A chiral N-acyl thiazolidinethione was employed in a stereoselective addition to a cyclic N-acyl iminium ion to install the required stereochemistry of carbon C9a. This iminium ion addition product was employed in a stereoselective MgBr2-catalyzed anti-aldol reaction to install the required stereochemistry of carbons C8 and C9. The X-ray crystal analysis of (-)-stemoamide confirmed the structure and the stereochemical outcome of these selective reactions.

Stereoselective addition of the titanium enolate of N-acetyl (4S)-isopropyl-1,3-thiazolidine-2-thione to five-membered N-acyl iminium ions.

[reaction: see text] Addition of the chlorotitanium enolate of N-acetyl 4-isopropyl-1,3-thiazolidine-2-thione to five-membered, N-substituted N-acyl iminium ions furnished the corresponding Mannich-type addition products with good diastereoselectivity and in good yields. The synthetic utility of the addition product 8 was demonstrated in a chemospecific anti-aldol reaction with cinnamaldehyde. By using this strategy, we constructed three contiguous chiral centers with high stereocontrol employing the same chiral auxiliary. X-Ray crystallographic analysis of addition product 2 and aldol product 14 revealed their absolute stereochemistry.

Synthesis of bicyclic gamma-ylidenetetronates.

The bicyclic gamma-ylidenetetronate motif found in several Stemona alkaloids was prepared in a stereoselective manner by addition of lithium methyl tetronate to an alkoxy oxonium ion formed from a lactone. The corresponding mixed alkyl ketal obtained was subjected to a Lewis acid-base-promoted dealkoxylation reaction to deliver the desired products.