Polyketide-derived macrolactones like zearalenone (1), zearalane (2) or curvularin (3) display a wide range of interesting pharmacological activities. Here, we present a short and efficient approach towards this class of natural products by a combination of the Sonogashira and Mitsunobu reactions. The resulting lactone 9 was tested against human cancer cell lines at the NCI.
2, 5-Dialkylfuran and tetrahydrofuran compounds as structural elements of Annonaceae acetogenins like Asitrocinwere synthesized starting from furfural by Grignard reactions, lithiation of the furan ring and addition of aliphatic aldehydes. Hydrogenation of the furan rings over Pd-catalyst gave the corresponding tetrahydrofurans. All resulting compounds showed no or rather less antimicrobial activity against grampositive, gram-negative bacteria and fungi compared to tetracycline or clotrimazol but high cytotoxic activity against HL 60 cell line determined in the MTT assay.
New phenolic compounds with hydrophilic side chains were prepared from 4‐benzyloxybenzaldehyde and alkenyl magnesium bromides, followed by Sharpless dihydroxylation and hydrogenolytic removal of the benzyl group. The resulting compounds were tested in an agar diffusion assay against gram positive bacteria, gram negative bacteria, and against the fungi Candida glabrata and Aspergillus niger.
Metathesis. -Ring closing metathesis to title compounds (IV) is achieved by using Grubbs' catalyst. The resulting E/Z mixtures are separable by GLC. The lactones (IV) and the ring opening product (VI) show weak cytotoxic activitiy against HL-60 cells.
Acetogeninas anonáceas análogas foram preparadas a partir de 5-iodofurano-2-carbaldeído e ácido undec-10-inoico ou undec-10-inol pela reação de Sonogashira, seguida da reação de Grignard e hidrólise catalizada por mercúrio. A citocidade foi avaliada por ensaios MTT contra células HL e no Instituto Nacional de Câncer (Alemanha).Analogues of annonaceous acetogenins were built up from 5-iodofuran-2-carbaldehyde and undec-10-ynoic acid or undec-10-ynol by a Sonogashira reaction, followed by a Grignard reaction and a mercury catalysed hydratisation. The cytotoxicity was evaluated with MTT assay ((3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide colorimetric assay for measuring cellular proliferation) against HL cells and at the National Cancer Institute (NCI).
.2,5-Dialkylfuran and tetrahydrofuran compounds as structural elements of Annonaceae acetogenins like Asitrocin were synthesized starting from furfural by Grignard reactions, lithiation of the furan ring and addition of aliphatic aldehydes. Hydrogenation of the furan rings over Pd-catalyst gave the corresponding tetrahydrofurans. All resulting compounds showed no or rather less antimicrobial activity against grampositive, gram-negative bacteria and fungi compared to tetracycline or clotrimazol but high cytotoxic activity against HL 60 cell line determined in the MTT assay. . So more simple compounds with the same or even higher potency are interesting for the development of new anticancer drugs. One of the discussed mechanisms of action is a complexation of mitochondrial iron by the dihydroxyalkyltetrahydrofuran core of the acetogenins [1]. So this partial structure of the natural compounds was the target of our synthesis. On the other hand some furancarbinols as 4-ipomeanol are well known cytotoxic compounds. 4-Ipomeanol is after bioactivation in lung tissue (clara cells) by cytochrom P 450 an alkylating agent [7]. It is tested in phase II studies against human lung cancer. So bisalkylfuran compounds might be interesting for the development of new anticancer drugs too. In addition, the products should also be tested for their antimicrobial activity (Scheme 1).
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Scheme 1.
ChemistryCommercially available furan-2-carbaldehyde was reacted in a Grignard reaction with dodecylmagnesium bromide to give the alcohol 1 in good yield [3,4]. The furan ring of 1 was hydrogenated over Pd/C-catalyst under normal pressure to the tetrahydrofuran derivative 2 (mixture of diastereomers). On the other hand the furan ring of 1 was lithiated with n-BuLi, (a second equivalent of n-BuLi was consumed for deprotonation of the hydroxy group) and the resulting dianion was reacted with pent-4-enal to give the dialkylfuran 3 as an inseparable mixture of diastereomers (seperation was impossible by column chromatography). 3 was also hydrogenated with Pd/C in methanol to give the tetrahydrofuran 4 as a diastereomeric mixture. In the course of this hydrogenation the double bond was also reduced (Scheme 2).In the same manner homologues were prepared by reaction of furan-2-carbaldehyde with pent-4-enylmagnesiumbromide to the alcohol 5, followed by lithiation with two equivalents n-BuLi and addition of tridecanal.The diol 6 was obtained only in low yield. Hydrogenation of 6 gave the disubstituted tetrahydrofuran 7 (Scheme 3).It was impossible for us to separate the diastereomeric mixtures by flash column chromatography on silica gel or by preparative high-pressure liquid chromatography.
Pharmacological results and discussionThe compounds described above were tested in the agar diffusion assay against E. coli, S. hominis, P. antimicrobia and the yeasts Y. lipolytica, C. glabrata and the filamentou fungi A. niger. All compounds showed only minor or no antimicrobial activity, only 2, 3, 4, 5 and 6 showed a moderate activity (Table 1). The cytot...
2005 Furan derivatives R 0060 2-(Arylpropionylamino)-and 2-(Arylacryloylamino)benzophenones: Farnesyltransferase Inhibition and Antimalarial Activity. -Title compounds of type (I) (19 examples) are prepared and tested for their farnesyltransferase inhibition and antimalarial activity. (Ic) shows the greatest antimalarial activity and displays no measurable cytotoxicity in the MTT-assay. Cinnamoyl derivatives [cf. (Id,e)] display fair farnesyltransferase activity but their low solubility prevents any relevant antimalarial activity. -(FUCIK, K.; KETTLER, K.; WIESNER, J.; ORTMANN, R.; UNTERREITMEIER, D.; KRAUSS, J.; BRACHER, F.; JOMAA, H.; SCHLITZER*, M.; Pharmazie 59 (2004) 10, 744-752; Inst. Pharm., Zent. Pharmaforsch.,
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