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15 recordsLinked to original sources
PubMed1977

Inhibition of translation in eukaryotic systems by harringtonine.

The Cephalotaxus alkaloids harringtonine, homoharringtonine and isoharringtonine inhibit protein synthesis in eukaryotic cells. The alkaloids do not inhibit, in model systems, any of the steps of the initiation process but block poly(U)-directed polyphenylalanine synthesis as well as peptide bond formation in the fragment reaction assay, the sparsomycin-induced binding of (C)U-A-C-C-A-[3H]Leu-Ac, and the enzymic and the non-enzymic binding of Phe-tRNA to ribosomes. These results suggest that the Cephalotaxus alkaloids inhibit the elongation phase of translation by preventing substrate binding to the acceptor site on the 60-S ribosome subunit and therefore block aminoacyl-tRNA binding and peptide bond formation. However, the Cephalotaxus alkaloids do not inhibit polypeptide synthesis and peptidyl[3H]puromycin formation in polysomes. Furthermore, these alkaloids strongly inhibit [14C]trichlodermin binding to free ribosomes but hardly affect the interaction of the antibiotic with yeast polysomot interact with polysomes and therefore only inhibit cycles of elongation. This explains the polysome run off that has been observed by some workers in the presence of harringtonine.

Alkaloids↗
PubMed2026

Complete biosynthesis of the anticancer cephalotaxinone and homoerythratine.

Cephalotaxine-type and homoerythrina-type alkaloids are structurally unique and biologically important natural products isolated from endangered species that belong to the genus Cephalotaxus. Among them, homoharringtonine (HHT [1]) is a marketed drug used to treat leukemia. However, the scalable production of HHT is significantly hindered by limited natural resources. Despite intensive investigation over half a century, the complete biosynthetic pathways of these alkaloids remain unknown. Here, we applied a comprehensive multi-omics analysis and used a set of chemically synthesized standard compounds to identify the missing enzymes required for the biosynthesis of cephalotaxinone and homoerythratine. We also uncovered a rare case of divergent oxidation catalyzed by two highly homologous cytochrome P450 enzymes, CfCYP2 and CfCYP3, in the biosynthesis of two structurally distinct alkaloids. We further identified the key residues that significantly affect the divergent oxidation outcomes and ultimately reconstituted the complete biosynthetic pathways for producing these two alkaloids in N. benthamiana.

Cephalotaxus↗
PubMed1978

Binding of [3H]narciclasine to eukaryotic ribosomes. A study on a structure-activity relationship.

[3H]Narciclasine is a specific inhibitor of peptide bond formation on eukaryotic ribosomes and binds to 60-S ribosomal subunits. Binding of [3H]-narciclasine to yeast ribosomes is inhibited by many other inhibitors of peptide bond formation including anisomycin, several sequiterpene antibiotics (trichodermin, trichothecin, fusarenon X and verrucarin A) several Cephalotaxus alkaloids (harringtonine, homoharringtonine and isoharringtonine), several Amaryllidaceae alkaloids (pretazettine, haemanthamine, lycorine, pseudolycorine and dihydrolycorine) and the narciclasine derivatives trans-dihydronarciclasine, trans-dihydronarciclasine acetonide and isonarciclasine. Binding is also inhibited, although to a very small extent, by methylnarciclasine and cisdihydronarciclasine. In contrast, no inhibition of [3H]narciclasine binding was observed in the presence of certain other inhibitors of peptide bond formation including blasticidin S, gougerotin, sparsomycin and puromycin.

Alkaloids↗
PubMed1975

Preparation and antitumor activity of a rearranged ester of cephalotaxine.

For further evaluation of structure-activity relationships among the Cephalotaxus alkaloids, a "rearranged" ester (2b) of cephalotaxine was prepared, one which is an isomer of deoxyharringtonine (5a). The parent alkaloid, cephalotaxine (1a), was allowed to react with thionyl chloride to replace its hydroxyl group with chlorine. The resulting chloro compound 1b, on treatment with the silver salt of half ester 6, yielded 2b via an allylic rearrangement followed by further double bond migration. The new "rearranged" deoxyharringtonine isomer 2b proved to be inactive in the P-388 lymphocytic leukemia system and thus further delineated the structural requirements for antitumor activity in this series of alkaloids.

Alkaloids↗
PubMed1977

Cytotoxicity and cell cycle specificity of homoharringtonine.

The plant alkaloid, homoharringtonine, isolated from Cephalotaxus harringtonia is cytotoxic to HeLa, KB, and L cells growing in monolayer cell cultures. This effect appears to be cell-cycle specific. In synchronized KB cells, protein synthesis was preferentially inhibited in the G(1) and G(2) phases (70 and 45% inhibition, respectively) as might be expected for a protein-synthesis inhibitor.

Alkaloids↗
PubMedDate not supplied

Experimental antitumor agents from plants, 1974-76.

The published literature in the areas of antitumor agents and cocarcinogens, for the years 1974-6 is reviewed. Some of the chemical classes of compounds discussed include tthe sesquiterpene lactones, diterpenes of the phorbol and simaroubolide types, triterpenes of the withanolide and cucurbitacin types, lignans, monomeric and dimeric indole alkaloids, isoquinoline alkaloids, Cephalotaxus alkaloids, camptothecin and the maytansinoids. Emphasis is placed on the isolation, synthesis, biosynthesis and biological activities of the most promising entities.

Alkaloids↗