Mirjana 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.

Synthesis and anti-aromatase activity of some new steroidal D-lactones.

Starting from D-seco derivatives of 5-androstene 1-3, the D-homo lactones, 4 and 5, were synthesized. By the Oppenauer oxidation and/or by dehydration of 4 and 5 with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) or 2,3,5,6-tetrachloro-1,4-benzoquinone (chloranil), the corresponding D-lactones 6-12 were obtained. The structures of 6 and 10 were unambiguously proved by the appropriate X-ray structural analysis. Anti-aromatase assay showed that tested compounds possess inhibition potency, however, two to four times smaller (IC50 from 0.2 to 0.7 microM, respectively) in comparison to aminoglutethimide (AG).

Inclusion complexes of sulfanilamide with β-cyclodextrin and 2-hydroxypropyl-β-cyclodextrin

Sulfanilamide belongs to the group of drugs that have a bacteriostatic effect on different pathogenic microorganisms. This activity originates from the competitive antagonism with p-aminobenzoic acid, which is an integral part of folic acid. The safe use of sulfanilamide is limited due to poor solubility in the aqueous medium. Therefore, the aim of this paper is the synthesis of sulfanilamide, as well as preparing and structural characterization of its inclusion complexes with cyclodextrins. The crude sulfanilamide was obtained in the synthesis between acetanilide and chlorosulfonic acid according to the standard procedure. The synthesized sulfanilamide was recrystallized from water in order to obtain the satisfactory purity of the substance. Sufanilamide was complexed with β-cyclodextrin and 2-hydroxypropyl-β-cyclodextrin by the co-precipitation method. A molecular encapsulation of sulfanilamide was confirmed by using FTIR, 1H-NMR, XRD and DSC methods. Phase-solubility techniques were used to assess the formation of the inclusion complex between sulfanilamide and cyclodextrins. The photostability of sulfanilamide and its inclusion complexes was estimated by UVB irradiation in a photochemical reactor by applying the UV–Vis method. Based on the UV–Vis analysis, sulfanilamide:2-hydroxypropyl-β-cyclodextrin complex was presented as more photostable than sulfanilamide:β-cyclodextrin complex and sulfanilamide. The obtained results enable the potential use of these inclusion complexes for the preparation of oral formulations due to the enhanced solubility of sulfanilamide.

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.

The protection of Nifedipin from photodegradation due to complex formation with β-cyclodextrin

AbstractThe inclusion complex β-cyclodextrin:nifedipin was prepared in solid state by coprecipitation with 1:1 mol ratio. The structure of the obtained complex and nifedipin was characterized by use of X-ray diffraction (XR), infrared spectroscopy (FTIR), nuclear magnetic resonance (NMR), and differential scanning calorimetry (DSC) methods. The photodegradation of nifedipin and the β-cyclodextrin:nifedipin inclusion complex in solid state was monitored under natural daylight by infrared spectroscopy, whereby the free nifedipin degraded four to five times faster than the complexed nifedipin. The photodegradation products of both free and complexed nifedipin, formed during irradiation at 350 nm (with corresponding energy flux of 18 W m−2) were monitored by liquid chromatography during various time intervals. The speed of formation of nitroso- and nitro-phenyl derivatives by nifedipin irradiation was significantly higher than those of complexed nifedipin irradiation, which indicates its increased photostability in the inclusion complex. The effect on this property is significant because it contributes both to the improvement of the therapeutic effect of nifedipin and to the safer application thereof.

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.