Novel 3-O-glycosyl-3-demethylthiocolchicines as ligands for glycine and gamma-aminobutyric acid receptors.

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.

3-demethoxy-3-glycosylaminothiocolchicines: Synthesis of a new class of putative muscle relaxant compounds.

A novel class of 3-demethoxy-3-glycosylaminothiocolchicines (7) was prepared and tested for muscle relaxant activity. The syntheses were performed starting from the new 3-amino-3-demethoxythiocolchicine (5) prepared in good yield from 3-O-demethylthiocolchicine (1c) using the Buchwald-Hartwig reaction. The condensation of 5 with a series of pentose and hexose sugars (6) gave a series of 3-demethoxy-3-glycosylaminothiocolchicines (7). Their preparation was accomplished by adapting and improving a previous procedure for the preparation of N-arylglycosylamines. In particular, replacing traditional heating with microwave irradiation represents the key improvement of the process. The biological activity of the 3-demethoxy-3-glycosylaminothiocolchicines (7) was evaluated on GABA and strychnine-sensitive glycine receptors present in rat brain and spinal cord.

Isothiazole dioxide derivative 6n inhibits vascular smooth muscle cell proliferation and protein farnesylation.

Isothiazole dioxides have been shown to inhibit Trypanosoma brucei protein farnesyltransferase (PFTase) in isolated enzyme, but elicited only a minor effect on mammalian PFTase. In the present study we have evaluated the effect of 3-diethylamino-4-(4-methoxyphenyl)-isothiazole 1,1-dioxides with different substituents at C5, on rat PFTase and protein geranylgeranyltransferase-I (PGGTase-I) with the final aims to improve the potency against mammalian PFTase and to identify new compounds with antiproliferative properties. For these purposes, in vitro and cell culture models have been utilized. The results showed that isothiazole dioxides with C4-C5 double bond and sulfaryl substituted at the C5 position but none of the dihydro-derivatives, were able to inhibit in vitro PFTase in a concentration dependent manner (IC50 ranging from 8.56 to 1015 microM). Among those, compound 6n (C5; methyl-S) displayed 500-fold higher inhibitory potency on PFTase than PGGTase-I. Compound 6n was shown to affect rat smooth muscle cell (SMC) proliferation at concentrations similar (IC50 = 61.4 microM) to those required to inhibit [3H]-farnesol incorporation into cellular proteins (-44.1% at 100 microM). Finally, compound 6n interferes with rat SMC proliferation by blocking the progression of G0/G1 phase without inducing apoptosis, as assessed by [3H]-thymidine incorporation assay and flow cytometry analysis. Taken together, we described a new PFTase inhibitor containing the isothiazole dioxide moiety that affects mammalian protein farnesylation and SMC proliferation by inhibiting G0/G1 phase of the cell cycle.

New taxane derivatives: synthesis of baccatin[14,1-d]furan-2-one nucleus and its condensation with the norstatine side chain.

New taxanes 15 and 18, containing the unsaturated and saturated baccatin[14,1-d]furan-2-one nucleus, respectively, were prepared starting from the readily available 13-oxo-7-Tes-baccatin III (3). Sequential formation of the enolate of 3 and reaction with ethyl glyoxylate gave the 13-oxo-7-Tes-baccatin[14,1-d]-3,4-dehydrofuran-2-one 4. The reduction of 4 can result in the formation of a mixture of compounds corresponding to 13-hydroxy alcohol 5 and 13-enol derivative 6. Both 5 and 6 were transformed into 13-oxo-7-Tes-baccatin[14,1-d]furan-2-one 8 by treatment with a base. Further reduction of 8 gave 13-hydroxy compound 9. Esterification of 6 and 9 with N,O-protected norstatine 12, followed by deprotection, gave the new promising anticancer taxanes 15 and 18, respectively.

Diastereoselective 14beta-hydroxylation of baccatin III derivatives.

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.

Isothiazole dioxides: synthesis and inhibition of Trypanosoma brucei protein farnesyltransferase.

A series of isothiazole dioxides was synthesized and evaluated as inhibitors of protein farnesyltransferase from the parasite that causes African sleeping sickness (Trypanosoma brucei). The most potent compound in the series inhibited the parasite enzyme with an IC(50) of 2 microM and blocked the growth of the bloodstream parasite in vitro with an ED(50) of 10 microM. The same compound inhibited rat protein farnesyltransferase and protein geranylgeranyltransferase type I only at much higher concentration.