Velimir Popsavin

Synthesis and biological evaluation of new pyrazole- and tetrazole-related C-nucleosides with modified sugar moieties

Abstract 3(5)-Carboxamido-4-(β- d -ribofuranosyl)pyrazoles bearing 2′-benzamido ( 15 ) and 3′-mesyloxy ( 29 ) isosteric groups, as well as the tetrazole C -nucleosides with 2-benzamido-2-deoxy-β- d -ribofuranose ( 19 ) and 3-azido-3-deoxy-β- d -xylofuranose ( 36 ) as sugar segments, have been synthesized starting from d -glucose, by utilizing the 2,5-anhydro- d -glucose ethylene acetal derivatives 1 and 20 as divergent intermediates. The C -nucleosides 15 and 36 were shown to be moderate inhibitors of the in vitro growth of both N2a and BHK 21 tumour cell lines, whereas 29 showed a selective, although not potent cytotoxic activity against N2a cells. Compound 29 also showed a moderate in vitro antiviral activity towards the rabies virus.

Enantiodivergent synthesis of cytotoxic styryl lactones from d-xylose. The first total synthesis of (+)- and (−)-crassalactone C

Abstract Enantiodivergent total syntheses of both (+)- and (−)-enantiomers of goniofufurone, 7- epi -goniofufurone and crassalactone C have been accomplished starting from d -xylose. The key steps of the synthesis of 7- epi -(+)-goniofufurone were a stereo-selective addition of phenyl magnesium bromide to a protected dialdose, and a stereospecific furano–lactone ring formation by reaction of a related hemiacetal derivative with Meldrums acid. Synthesis of both (+)-goniofufurone and (+)-crassalactone C required a configurational inversion at C-5 in the common intermediate that was efficiently achieved under the standard Mitsunobu conditions, or alternatively through a sequential oxidation of the benzylic hydroxyl group followed by a stereo-selective reduction with borohydride. A similar approach was then applied to the synthesis of the unnatural (−)-enantiomers of goniofufurone, 7- epi -goniofufurone and crassalactone C, as well as two novel, conformationally constrained analogues of both (+)- and (−)-goniofufurone. Their in vitro antiproliferative activities against a number of human tumour cell lines were recorded and compared with those observed for the parent natural products.

Design, synthesis and antiproliferative activity of styryl lactones related to (+)-goniofufurone.

This paper describes a straightforward divergent synthesis of (+)-goniofufurone mimics (4, 5 and 6) starting from d-xylose. In a preliminary bioassay, analogues 4 and 5 exhibited a submicromolar antiproliferative activity towards HL-60 cells, while the corresponding parent compound 1 was completely inactive against this cell line. At the same time, these molecules showed approximately 10-fold stronger cytotoxicity in the same cell line when compared to the standard anticancer drug doxorubicin (DOX). Analogue 6 displayed 18- and 3-fold higher potency in Raji cell line when compared to control compounds 1 and DOX, respectively. A new divergent route for the preparation of (+)-goniofufurone (1) and (+)-crassalactone C (3) from d-xylose is also disclosed.

Synthesis and in vitro antitumour screening of 2-(β-D-xylofuranosyl)thiazole-4-carboxamide and two novel tiazofurin analogues with substituted tetrahydrofurodioxol moiety as a sugar mimic.

2-(β-D-xylofuranosyl)thiazole-4-carboxamide (2) and two new tiazofurin analogues with 5-hydroxymethyl-2-methyl-tetrahydro-furo[2,3-d][1,3]dioxol-6-ol moiety as a sugar mimic (27 and 28) have been synthesized and evaluated for their in vitro antitumour activity against a panel of human tumour cell lines (K562, HL 60, Jurkat, Raji and HeLa). In contrast to previous literature reports, a metabolic MTT assay revealed remarkable cytotoxicity of 2 against K562 (IC(50)=0.15 μM) and HL-60 (IC(50)=0.13 μM) cells. Flow cytometry data suggest that cytotoxic effects of analogue 2 in the culture of K562 cells might be mediated by apoptosis, in opposite to tiazofurin, which did not induce apoptosis of K562 cells after 24h, thus suggesting a different mechanism of action. All three analogues 2, 27 and 28 were also active against Jurkat, Raji and HeLa cells, with IC(50) values in the range from 0.06 to 5.61 μM, but were completely inactive against the normal foetal lung fibroblasts (MRC-5).

De Novo Synthesis of Two New Cytotoxic Tiazofurin Analogues with Modified Sugar Moieties

A divergent synthesis of two novel tiazofurin analogues, 2-(3-deoxy-3-fluoro-beta-D-xylofuranosyl)thiazole-4-carboxamide (2) and 2-(3-acetamido-3-deoxy-beta-D-xylofuranosyl)thiazole-4-carboxamide (3), has been achieved starting from D-glucose. Both nucleoside analogues were evaluated for their in vitro cytotoxicity against several human leukaemia and solid tumour cell lines.

A Divergent Synthesis of (+)-Muscarine and (+)-epi-Muscarine from d-Glucose

Abstract A novel stereospecific synthesis of (+)-muscarine and (+)-epi-muscarine has been achieved by utilizing d -glucose as a chiral precursor. The key steps of the synthesis involved stereospecific cyclization of 3,5-di-O-sulfonyl- d -glucofuranose derivatives into the corresponding 2,5-anhydrides, and stereospecific hydrogenation of 2,5-anhydro- l -threo-hex-2-enose ethylene acetal derivatives, thus providing an access to divergent intermediates for the preparation of both target molecules in a fully stereospecific manner.

Conformationally constrained goniofufurone mimics as inhibitors of tumour cells growth: Design, synthesis and SAR study.

Synthesis of conformationally restricted (+)-goniofufurone (1) and 7-epi-(+)-goniofufurone (2) analogues, with embedded O-isopropylidene, O-methylidene or cyclic carbonate functions is disclosed starting from d-glucose. A number of potential bioisosteres of 1 and 2 bearing both 5,7-O-methylidene and 4-substituted cinnamoyloxy functions at the C-7 position have also been synthesized. In vitro cytotoxicity of target molecules against a number of human tumour cell lines were recorded and compared with those observed for the parent molecules 1 and 2. Some of the analogues displayed powerful antiproliferative effects on selected human tumour cell lines, but all of them were devoid of any cytotoxicity towards the normal foetal lung fibroblasts (MRC-5). A SAR study reveals the structural features of these lactones that may increase their antiproliferative activity.

Stereospecific synthesis of two novel cytotoxic pyrazole C-nucleosides from d-glucose

Abstract A multistep stereospecific synthesis of two novel pyrazole C -nucleosides 12 and 21 has been achieved starting from d -glucose, by utilizing the 2,5-anhydro- d -glucose ethylene acetal derivative 1 as a divergent intermediate. The C -nucleoside 12 was shown to be a moderate inhibitor of the in vitro growth of N2a and BHK 21 tumor cell lines, whereas 21 showed a moderate cytotoxic activity only against N2a cells.

Synthesis and antiproliferative activity of unnatural enantiomers of 7-epi-goniofufurone and crassalactone C.

A facile synthesis of 7-epi-(-)-goniofufurone as well as the first synthesis of (-)-crassalactone C was achieved starting from D-xylose. A comparison of their in vitro antitumour activities with those observed for the corresponding naturally occurring enantiomers was provided.

Conversion of d-xylose to protected d-lyxose derivatives and to d-lyxose, via the corresponding 1,2-anhydride

Abstract Acid hydrolysis of 3,5-di- O -benzyl-1,2- O -cyclohexylidene-α- d -xylofuranose gave the corresponding lactol, which was subsequently converted to the 3,5-di- O -benzyl-2- O -mesyl- d -xylofuranose. This compound readily reacted with sodium methoxide, sodium benzylate or sodium hydroxide (presumably via the corresponding 1,2-anhydride) to give the protected d -lyxofuranosides. These compounds were finally converted to methyl α- d -lyxopyranoside or to d -lyxose.