ABSTRACT
The fungal metabolite TAN-2483B has a 2,6-trans-relationship across the pyran ring of its furo[3,4-b]pyran-5-one core, which has thwarted previous attempts at its synthesis. We have now developed a chiral pool approach to this core and prepared side-chain analogues of TAN-2483B. The synthesis relies on ring expansion of a reactive furan ring-fused dibromocyclopropane and alkynylation of the resulting pyran. The furan ring is constructed by palladium-catalysed carbonylative lactonisation. Various side-chains are appended through Wittig-type chemistry. The prepared analogues showed micromolar activity towards cancer cell lines HL-60, 1A9 and MCF-7 and certain human disease-relevant kinases, including Bruton's tyrosine kinase (Btk).
Subject(s)
Antineoplastic Agents/chemical synthesis , Lactones/chemistry , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/chemical synthesis , Pyrans/chemistry , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Lactones/chemical synthesis , Lactones/pharmacology , Molecular Structure , Phosphotransferases/antagonists & inhibitors , Phosphotransferases/metabolism , Protein Kinase Inhibitors/pharmacology , Pyrans/chemical synthesis , Pyrans/pharmacology , Structure-Activity RelationshipABSTRACT
A new peloruside congener, peloruside E (5), has been isolated in sub-milligram quantities from a specimen of the New Zealand marine sponge Mycale hentscheli. The structure of 5 differs from the parent compound peloruside A (1) by replacement of the C-10 gem-dimethyl moiety with a monomethyl substituent and represents the first structural deviation in the pelorusane scaffold. Peloruside E (5) is potently antiproliferative (HL-60, IC50 90 nM, cf. 1, 19 nM) and polymerizes purified tubulin, albeit at a rate lower than that of 1.
Subject(s)
Macrolides/isolation & purification , Microtubules/drug effects , Porifera/chemistry , Tubulin Modulators/pharmacology , Animals , HL-60 Cells , Humans , Macrolides/chemistry , Macrolides/pharmacology , Magnetic Resonance SpectroscopyABSTRACT
Type II NADH:quinone oxidoreductase (NDH-2) is a proposed drug-target of major pathogenic microorganisms such as Mycobacterium tuberculosis and Plasmodium falciparum. Many NDH-2 inhibitors have been identified, but rational drug development is impeded by the lack of information regarding their mode of action and associated inhibitor-bound NDH-2 structure. We have determined the crystal structure of NDH-2 complexed with a quinolone inhibitor 2-heptyl-4-hydroxyquinoline-N-oxide (HQNO). HQNO is nested into the slot-shaped tunnel of the Q-site, in which the quinone-head group is clamped by Q317 and I379 residues, and hydrogen-bonds to FAD. The interaction of HQNO with bacterial NDH-2 is very similar to the native substrate ubiquinone (UQ1) interactions in the yeast Ndi1-UQ1 complex structure, suggesting a conserved mechanism for quinone binding. Further, the structural analysis provided insight how modifications of quinolone scaffolds improve potency (e.g. quinolinyl pyrimidine derivatives) and suggests unexplored target space for the rational design of new NDH-2 inhibitors.
Subject(s)
Quinolones/chemistry , Quinone Reductases/antagonists & inhibitors , Quinone Reductases/chemistry , Bacteria/enzymology , Binding Sites , Crystallography , Drug Design , Hydrogen Bonding , Ubiquinone/chemistryABSTRACT
Seven new members of the hamigeran family of diterpenoids have been isolated from the New Zealand marine sponge Hamigera tarangaensis. Among the new additions are hamigeran R (1), considered to be the first benzonitrile-based marine natural product, and hamigeran S (2), the first dimeric structure in the series. The formation of 1 and 2 is thought to occur via the reaction of hamigeran G with a nitrogen source, where the nitrile carbon of 1 is derived from the terpenoid skeleton.
