A camptothecin derivative has been prepared wherein the A-ring is fused to an oxazole ring. The compound was prepared via a Friedlander condensation involving benzoxazole 8 and tricyclic ketone 9. This derivative displays potent topoisomerase I inhibition (IC50 150 nM) when assayed in the 'cleavable complex' assay.

Enzymatic activity mediated by recombinant human DNA ligase I (hLI), in conjunction with tannin removal procedures, has been applied to a natural-product screen involving approximately 1000 plant extracts and various pure compounds. The primary hLI activity assay involved the measurement of the amount of radiolabelled phosphate in a synthetic nucleic acid hybrid that becomes resistant to alkaline phosphatase as a result of ligation. A bioactivity-guided fractionation scheme resulted in the isolation of ursolic [IC50=100 micrograms/ml (216 microM)] and oleanolic [IC50=100 micrograms/ml (216 microM)] acids from Tricalysia niamniamensis Hiern (Rubiaceae), which demonstrated similar DNA ligase inhibition profiles to other triterpenes such as aleuritolic acid. Protolichesterinic acid [IC50=6 micrograms/ml (20 microM)], swertifrancheside [IC50 = 8 micrograms/ml(11)microM)] and fulvoplumierin [IC50=87 micrograms/ml (357 microM)] represent three additional natural-product structural classes that inhibit hLI. Fagaronine chloride [IC50=10 micrograms/ml (27 micronM] and certain flavonoids are also among the pure natural products that were found to disrupt the activity of the enzyme, consistent with their nucleic acid intercalative properties. Further analyses revealed that some of the hLI-inhibitory compounds interfered with the initial adenylation step of the ligation reaction, indicating a direct interaction with the enzyme protein. However, in all cases, this enzyme-inhibitor interaction did not disrupt the DNA relaxation activity mediated by hLI. These results indicate that, although the same enzyme active site may be involved in both enzyme adenylation and DNA relaxation, inhibitors may exert allosteric effects by inducing conformational changes that disrupt only one of these activities. Studies with inhibitors are important for the assignment of specific cellular functions to these enzymes, as well as for their development into clinically useful antitumour agents.

Substituted 8-ethyl-2-(2-oxo-1,2-dihydroindol-3-ylidene)-8-hydroxy-2,3,5,8-tetrahydro-6-oxa-3a-azacyclopenta[b]naphthalene-1,4,7-triones were synthesized and evaluated as topoisomerase I inhibitors in an in vitro cleavable complex assay. The activity of these compounds may be attributed to their rigid, planar geometry, and an attempt was made to correlate the SAR in this series to known attributes of camptothecin.

A large number of camptothecin (CPT) analogs have been prepared in the 20S, 20RS, and 20R configurations with a number of ring A substituents. Topoisomerase I (T-I) inhibition data (IC50) have been obtained by standard procedures. In general, substitution at the 9 or 10 positions with amino, halogeno, or hydroxyl groups in compounds with 20S configuration results in compounds with enhanced T-I inhibition. Compounds in the 20RS configuration were less active in vitro and in vivo and those in the 20R configuration were inactive. Compounds with 10,11-methylenedioxy substitution on ring A displayed a marked increase in potency in the T-I inhibition assay. The activities of some of the analogs as determined in a variety of in vivo assays including the L-1210 mouse leukemia assay were, in general, in accord with T-I inhibition. A number of water-soluble analogs such as 20-glycinate esters, 9-glycinamides, or hydrolyzed lactone salts were prepared and tested in in vitro and in vivo assays. In general, these compounds were less active than CPT both in terms of T-I inhibition and life prolongation in the L-1210 assay. However, certain 20-glycinate esters showed good in vivo activity after iv administration.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

The electrochemical behaviour of 1,2,3-tritellura[3]ferrocenophane, [Fe(C5H4Te)2Te), and 1,3-ditellura[3]ferrocenophanes, [Fe(C5H4Te)2E′] (E′= S, Se, or CH2), has been examined and compared to that of the known tri- and di-chalcogena[3]ferrocenophanes. All the complexes undergo a chemically reversible one-electron oxidation. 1,2,3-Tritellura[3]ferrocenophane also exhibits a clean reduction step, even if complicated by subsequent chemical reactions. Discrete variational (DV-Xα) calculations relative to the model compounds [Fe(C5H4Te)2Te], [Fe(C5H4Se)2Se], and [Fe(C5H4S)2S] allow an unambiguous assignment of the molecular orbitals involved in the oxidation and reduction processes. They suggest that the all-tellura[3]ferrocenophane complex, [Fe(C5H4Te)2Te], is the most accessible both to one-electron addition and removal steps.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Dilithium 1,1′-ferroceneditellurolate, Fe(C5H4TeLi)2, has been used to prepare a series of 1,3-ditellura[3]ferrocenophanes, Fe(C5H4Te)2E (E = S, Se, Te, CH2), which have been characterized by 1H NMR and mass spectroscopy.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

The missing tellurium member of the 1,2,3-trichalcogena-[3]ferrocenophanes, Fe(C5H4Te)2Te, was synthesized and structurally characterized. The shiny needles are composed of alternating layers of tellurium and parallel ferrocene units. The molecules Fe(C5H4Te)2Te contain eclipsed cyclopentadienyl rings which are connected by a Te3 bridge.

AbstractThe title complexes (IV) and (VI) are prepared, in which the chalcogen and the acyl group are systematically varied.

A series of nine ferrocene chalcogenol derivatives of the type Fe(C5H5)-(C5H4EC(O)R) and of nine 1,1′-ferrocene dichalcogenol derivatives of the type Fe(C5H4EC(O)R)2 has been prepared in whic the chalcogen (E = S, Se, Te) and the acyl group (C(O)R = benzoyl, 2-thenoyl, ferrocenoyl) were systematically varied. The crucial step of the synthesis includes insertion of the chalcogen E into the LiC bond of the lithioferrocene to give the chalcogenolate intermediate Fe(C5H5)-(C5H4ELi) or Fe(C5H4ELi)2, respectively, to be subsequently treated with the acyl chloride, RC(O)Cl. The 1H and 13C NMR spectra of the new compounds are discussed11Abkürzungen: Cp = η5-C5H5, Cyclopentadienyl; Fc = CpFe(C5H4), Ferrocenyl; Ph = C6H5, Phenyl; pTol = pCH3C6H4-, p-Tolyl; Th = SC4H4-, 2-Thienyl; TMEDA = Tetramethylethylendiamin..

AbstractTreatment of ferrocenyllithium (I) with sulfur, selenium, or tellurium (II), followed by oxidation with air gives the diferrocenyl dichalcogenides (III) which react with ferrocenyllithium (I) to produce the diferrocenyl chalcogenides (IV).

The very first examples of ferrocenyltellurium compounds are described. Inser-tion of tellurium into ferrocenyllithium led to an intermediate {FcTeLi}, which, upon oxidation in air, gave diferrocenylditelluride, Te2Fc2, in 50% yield 11Abkürzungen: Fc = Ferrocenyl, C5H5FeC5H4-; Ph = Phenyl, C6H5-; nBu = n-Butyl, C4H9-.. The reaction of Te2Fc2 with organolithium compounds, RLi, was used to prepare ferrocenyltellurides FcTeR (R = Fc, nBu, o- and p-Anisyl). Bis(ferrocenyltelluro)-methane, FcTe(CH2)TeFc, was also obtained. The ferrocenyltellurium compounds were characterized by their 1H and 13C NMR spectra, and the influence of the chalcogen atom upon the chemical shifts was demonstrated for the EFc2, E2Fc2 and FcE(CH2)EFc(E = S, Se, Te) series.