Synthesis and antiproliferative activity of selenoindirubins and selenoindirubin-N-glycosides.

Selenoindirubins and selenoindirubin-N-glycosides were prepared by the reaction of isatins and isatin-N-glycosides with 3-acetoxy-benzo[b]selenophene, respectively. While selenoindirubin-N-glycosides have not been reported before, three non-glycosylated selenoindirubins were previously reported, but without quantities, yields, scales, experimental details and spectroscopic data. In addition, the work could, in our hands, not be reproduced to prepare pure products. The present paper includes an optimized procedure for the synthesis of selenoindirubins and their complete characterization. Both selenoindirubins and selenoindirubin-N-glycosides showed antiproliferative activity in lung cancer cell lines. In melanoma cells, antiproliferative effects were further accompanied by induced apoptosis in combination with the death ligand TRAIL.

Evaluation of anti-inflammatory effect of synthetic 1,5-bis(4-acetoxy-3-methoxyphenyl)-1,4-pentadien-3-one, HB2.

This work describes the synthesis and anti-inflammatory properties of a pentadienone derivative, HB2. The treatment with HB2 produced anti-oedematogenic, anti-inflammatory and antinociception without change locomotors performance. Finally, HB2 reduced the nitric oxide and prostaglandin E(2) production on RAW 264.7 cells stimulated with LPS without changing the cell viability. Taken together, our results show, for the first time, that HB2 can modulate the inflammatory response when administered to mice.

Synthesis of compounds with antiproliferative activity as analogues of prenylated natural products existing in Brazilian propolis.

This work describes the syntheses and antitumoral properties of five prenyl compounds from which antiproliferative activities were predicted by using the TOPS-MODE approach, a computational method for drug design. The syntheses of 2-(3-methylbut-2-enyloxy)acetophenone (2), 2-hydroxy-5-(3-methylbut-2-enyl)acetophenone (3), 2-hydroxy-3-(1,1-dimethylallyl)acetophenone (4), and 5-(3-methylbut-2-enyl)-2-(3-methylbut-2-enyloxy)acetophenone (5) were realized by O-prenylation of phenolic compounds with prenyl bromide and by Claisen rearrangement, respectively. Reaction of 2-hydroxy-5-(3-methylbut-2-enyl)acetophenone 3 under Vilsmeier-Haack conditions with phosphoryl chloride and N,N-dimethylformamide yielded 6-(3-methylbut-2-enyl)chromone-3-carbaldehyde (6). The compounds were tested for their cytotoxicity toward a diverse panel of cultured human tumor cell lines. Compound 3 showed significant selective cytotoxic activity (IC(50) < 9 microg/ml).

Synthesis of new iso-C-nucleoside analogues from 2-(methyl 2-O-benzyl-4,6-O-benzylidene-3-deoxy-alpha-D-altropyranosid-3-yl)ethanal.

Treatment of 2-(methyl 2-O-benzyl-4,6-O-benzylidene-3-deoxy-alpha-D-altropyranosid-3-yl)ethanal with malononitrile, cyanoacetamide and 2-cyano-N-(4-methoxyphenyl)acetamide, respectively, in the presence of aluminium oxide yielded 2-cyano-4-(methyl 2-O-benzyl-4,6-O-benzylidene-3-deoxy-alpha-D-altropyranosid-3-yl)crotonic acid derivatives. Cyclization with sulfur and triethylamine was performed to synthesize the 2-amino-5-(methyl 2-O-benzyl-4,6-O-benzylidene-3-deoxy-alpha-D-altropyranosid-3-yl)thiophene-3-carbonic acid derivatives, which were treated with triethyl orthoformate/ammonia and triethyl orthoformate, respectively, to furnish 6-(methyl 2-O-benzyl-4,6-O-benzylidene-3-deoxy-alpha-D-altropyranosid-3-yl)thieno[2.3-d]pyrimidine derivatives. Deprotection in two steps afforded 2-amino-5-(1,6-anhydro-3-deoxy-beta-D-altropyranos-3-yl)thiophene-3-carbonitrile and 6-(1,6-anhydro-3-deoxy-beta-D-altropyranos-3-yl)thieno[2.3-d]pyrimidine derivatives, respectively.

Pyrimidine acyclo-C-nucleosides by ring transformations of 2-formyl-L-arabinal.

The protected 2-formyl-L-arabinal 2 reacted with thiourea and cyanamide in the presence of sodium hydride to afford via ring transformations the 5-[1R,2S-1,2- bis(benzyloxy)-3-hydroxypropyl]-1,2-dihydropyrimidines 3 and 4, respectively. Similarly, treatment of 2 with 3-amino-2H-1,2,4-triazole yielded 6-[1R,2S-1,2- bis(benzyloxy)-3-hydroxypropyl][1,2,4]-triazolo[1,5-a]pyrimidine (5).

Synthesis of anellated carbasugars from (--)-quinic acid.

(3R,4R,5R)-3-[(tert-Butyl-dimethylsilyl)oxy]-4,5-(isopropylidenedioxy)-1-cyclohexanone (2) reacted with carbon disulfide and methyl iodide in the presence of sodium hydride to furnish (3R,4R,5R)-5-[(tert-butyl-dimethylsilyl)oxy]-3,4-(isopropylidenedioxy)-2-[bis(methylthio)methylene]-1-cyclohexanone (3). 2 and N,N-dimethylformamide dimethyl acetal afforded (2E,3R,4R,5R)-5-[(tert-butyl-dimethylsilyl)oxy]-2-(dimethylaminomethylene)-3,4-(isopropylidenedioxy)-1-cyclohexanone (4). These push-pull activated methylenecyclohexanones 3 and 4 underwent a ring closure reaction with hydrazine hydrate and methylhydrazine, respectively, to give pyrazoloanellated carbasugars. Treatment of 3 with formamidinium, acetamidinium and benzamidinium salts, respectively, in the presence of sodium methanolate yielded three (5R,6R,7R)-7-[(tert-butyl-dimethylsilyl)oxy]-5,6,7,8-tetrahydro-5,6-(isopropylidenedioxy)benzo[d]pyrimidines.