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A series of camptothecin open-ring lactone tripartate conjugates were synthesized, in which polyamine side chains with different architecture (ethane-1,2-diamine, spermidine, homospermidine, spermine, and 4,8,13,17-tetraza-icosane-1,20-diamine) are linked to the 21-carboxylic function through an amidic bond, while the 17-CH(2)OH is acetylated. The rationale for the synthesis of these compounds was to explore the influence of the polyamine architecture on the activity of these CPT conjugates into cells, since the positively charged ammonium cations would favor interaction through electrostatic binding to the negatively charged DNA backbone. Topoisomerase I-mediated DNA cleavage assay was used to investigate the ability of these compounds to stimulate the DNA damage. The cleavage pattern was found to be similar to that of SN38 for all the new CPTs. The CPT tripartates were tested for growth inhibition ability against the human non-small-cell lung cancer carcinoma NCI-H460 cell line. Although these compounds were less potent than topotecan, SN38, and CPT after 1 h of treatment, the antiproliferative effects greatly increased after 72 h of exposure. The growth inhibition potency during long-term exposure is correlated with the number of charges of the 21-amide substituent. Both cleavage assay and in vitro effects support the interpretation that the compounds may have inhibitory activity also in the open-ring form. The architecture of the polyamine moiety is important for antiproliferative activity, and a balance between the hydrophilic and lipophilic properties of the polyamine is critical for CPT potency.

A very efficient three-component synthesis of a series of syn α-hydroxy-β-amino esters, obtained in high diastereoselection and yield, was realized starting from an aldehyde, benzylamine, and the ketene silyl acetals derived from Ley's lactones. The synthetic protocol was optimized and the above compounds were obtained without the isolation of intermediates. The origin of the observed diastereoselection was investigated through a computational model of the key reaction step.

The synthesis of new D-seco-C-nor-taxane derivatives in which the D-ring has been deleted and the C-ring has been transformed into a new pentatomic ring, i.e., the polyfunctionalized tetrahydrofuranosyl and cyclopentenyl or cyclopentyl ring, was performed starting from baccatin III derivatives. The synthetic strategy adopted took advantage of the oxetane ring opening and disconnection of the C4-C5 bond, followed by an intramolecular condensation. The formation of furanosyl or cyclopentyl rings is strictly dependent on the presence of unprotected or protected oxygen at C-7 in the starting material. The reactions proceeded with good diastereoselectivity with control of the stereochemistry of one or two stereocenters.

The synthesis and the X-ray structure of 16a-thiocamptothecin (TCPT), the thiopyridone analog of camptothecin (CPT), are accomplished. The crystal contains two structurally identical, yet independent molecules. Both of them are connected to other molecules via two intermolecular hydrogen bonds. S-methylation of TCPT leads to the cleavage of the C-ring. The cytotoxic activity of TCPT was evaluated against different human tumor cell lines using CPT as reference compound.

New 3-O-glycosyl-3-demethylthiocolchicines containing natural and unnatural sugar moieties were prepared and tested on gamma-aminobutyric acid (GABA) and strychnine-sensitive glycine receptors present in rat brain and spinal cord. Two different synthetic approaches were used with the readily available 3-O-demethylthiocolchicine (1b) and thiocolchicoside (2a). Glycosyl compounds 2a-g were obtained from 1b and 1-fluorosugars 4. 6'-Heterosubstituted glycosyl compounds 6-12 and the 6'-desoxy derivative 2h were prepared from 2a.

14beta-Hydroxybaccatin III, a compound with limited availability by natural sources, is the starting material for the synthesis of the second-generation anticancer taxoid ortataxel. The 7-tert-butoxycarbonyl (1a) and 7-triethylsilyl (1b) derivatives of 14beta-hydroxybaccatin III 1,14-carbonate were synthesized from 10-deacetylbaccatin III (3). The crucial steps were (a) the C(14)beta hydroxylation of the corresponding 13-oxobaccatin III derivatives by oxaziridine-mediated electrophilic oxidation and (b) the reduction of the C(13) carbonyl group with sodium or alkylammonium borohydrides. This protocol provides a practical way for the semisynthesis of ortataxel from 10-deacetylbaccatin III, a compound readily available from various yews.

A number of strains of Lactobacillus spp. from foods were screened for their ability to convert meso-2,3-butanediol into 2-butanol. Only three strains of L. brevis transformed the meso-diol into the secondary alcohol. These strains as well as the others unable to metabolize meso-2,3-butanediol exhibited the capacity to hydrogenate 2-butanone to 2-butanol. In both types of lactobacilli, an inverse relationship was observed between the diol or ketone concentration and the abundance of the R form of 2-butanol. This fact has been interpreted in terms of a co-occurrence of two dehydrogenases, both acting on the ketone with different kinetic parameters and opposite enantioselectivities. These results represent a further support to the assumption that 2-butanol present in distillates originates from the enzymatic activity of lactobacilli growing on mashes and give the most likely explanation of the enantiomeric excess of (R)-2-butanol generally found in distillates. Keywords: 2-Butanol; meso-2,3-butanediol; lact...

A new compound was isolated from a commercial sample of Cape aloe, and its structure was determined by spectral analysis. This benzo[f]chroman-3-one (1) occurs in the drug in racemic form. The synthesis of an analogous chromanone (9) via intramolecular thermal acid-catalyzed cyclization of the 2-naphthyl cinnamate (11) strongly supports the formation of 1 as a process product. Keywords: Cape aloe; process product; benzo[f]chroman-3-ones; polyketides; p-coumaric acid

Further investigation of Cape aloe led to the isolation of two new 5-methylchromones. Their structures have been established as 2-acetonyl-7-hydroxy-8-(3-hydroxyacetonyl)-5-methyl-chromone (2) and 2-acetonyl-8-(2-furoylmethyl)-7-hydroxy-5-methylchromone (3) on the basis of spectroscopic data. A mechanistic hypothesis to account for their occurrence in the drug is presented.