Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 12 de 12
Filter
Add more filters










Publication year range
1.
J Nat Prod ; 83(11): 3381-3386, 2020 11 25.
Article in English | MEDLINE | ID: mdl-33151675

ABSTRACT

Callyspongiolide is a marine-derived macrolide that kills cells in a caspase-independent manner. NCI COMPARE analysis of human tumor cell line toxicity data for synthetic callyspongiolide indicated that its pattern of cytotoxicity correlated with that seen for concanamycin A, an inhibitor of the vacuolar-type H+-ATPase (V-ATPase). Using yeast as a model system, we report that treatment with synthetic callyspongiolide phenocopied a loss of V-ATPase activity including (1) inability to grow on a nonfermentable carbon source, (2) rescue of cell growth via supplementation with Fe2+, (3) pH-sensitive growth, and (4) a vacuolar acidification defect visualized using the fluorescent dye quinacrine. Crucially, in an in vitro assay, callyspongiolide was found to dose-dependently inhibit yeast V-ATPase (IC50 = 10 nM). Together, these data identify callyspongiolide as a new and highly potent V-ATPase inhibitor. Notably, callyspongiolide is the first V-ATPase inhibitor known to be expelled by Pdr5p.


Subject(s)
Enzyme Inhibitors/pharmacology , Macrolides/pharmacology , Vacuolar Proton-Translocating ATPases/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Fluorescent Dyes/chemistry , Humans , Hydrogen-Ion Concentration , Macrolides/chemistry , Molecular Structure , Saccharomyces cerevisiae/growth & development , Saccharomyces cerevisiae/metabolism
2.
J Org Chem ; 83(6): 3090-3108, 2018 03 16.
Article in English | MEDLINE | ID: mdl-29494773

ABSTRACT

We describe the asymmetric synthesis of a highly substituted ω-octynoic acid derivative and demonstrate its utility for generating complex macrocycles from unprotected peptides. The molecule harbors an isolated quaternary center that displays four uniquely functionalized arms, each of which can be reacted orthogonally in sequence as the molecule is integrated into peptide structure. These processing sequences entail (1) scaffold ligation, (2) macrocyclization via internal aromatic alkylations or catalyzed etherifications, (3) acyliminium ion mediated embedding of condensed heterocycles, and (4) terminal alkyne derivatization or dimerization reactions. Numerous polycycles are prepared and fully characterized in this study. Factors that influence reaction efficiencies and selectivity are also probed. We construct a novel mimic of the second mitochondria derived activator of caspase using these techniques, wherein subtle variations in macrocycle connectivity have a marked impact on performance. In general, the chemistry is an important step toward facile, systematic access to complex peptidomimetics synthesized by directly altering the structure and properties of machine-made oligomers.


Subject(s)
Macrocyclic Compounds/chemistry , Peptides/chemistry , Cyclization
3.
J Am Chem Soc ; 140(4): 1280-1284, 2018 01 31.
Article in English | MEDLINE | ID: mdl-29332397

ABSTRACT

An asymmetric synthesis of (-)-callyspongiolide is described. The route builds the macrolide domain atypically from a disaccharide and a monoterpene without passing through a seco-acid. Chiral iridium catalysis selectively joins fragments. Subsequent degradation of an imbedded butyrolactone via perhemiketal fragmentation affords a stereo- and regio-defined homoallylic alcohol that is engaged directly in a carbonylative macrolactonization. Further elaboration of the polyunsaturated appendage provides the natural product in a particularly direct and flexible manner.

4.
Chem Rev ; 117(18): 11994-12051, 2017 Sep 27.
Article in English | MEDLINE | ID: mdl-28603978

ABSTRACT

This review examines the state of the art in synthesis as it relates to the building of complex architectures on scales sufficient to drive human drug trials. We focus on the relatively few instances in which a natural-product-based development candidate has been manufactured de novo, rather than semisynthetically. This summary provides a view of the strengths and weaknesses of current technologies, provides perspective on what one might consider a practical contribution, and hints at directions the field might take in the future.


Subject(s)
Biological Products/chemical synthesis , Pharmaceutical Preparations/chemical synthesis , Biological Products/chemistry , Drug Design , Humans , Molecular Structure , Pharmaceutical Preparations/chemistry
5.
Org Biomol Chem ; 15(6): 1463-1474, 2017 Feb 07.
Article in English | MEDLINE | ID: mdl-28112763

ABSTRACT

The first examples of asymmetric Tamura cycloaddition reactions involving singly activated alkenes are reported. Homophthalic anhydride reacts with α-methyl nitrosytrenes in the presence of an alkaloid-based catalyst to generate fused bicyclic aromatic ketone products with three new stereocentres (which are susceptible to subsequent equilibration) in 12-99% ee. An unusual equilibration process which occurs in methanolic medium in the absence of a recognisable base via proton transfer at the α-carbon of an ester was investigated experimentally and computationally.

6.
Org Biomol Chem ; 14(29): 6955-9, 2016 Aug 07.
Article in English | MEDLINE | ID: mdl-27381361

ABSTRACT

The first catalytic, asymmetric reactions of imines with homophthalic anhydride to form disubstituted 3,4-dihydroisoquinolones are reported. The use of N-mesyl aldimines is key, as more basic imines undergo rapid uncatalysed reactions, while imines possessing larger N-sulphonyl substituents form lactams with lower ee.


Subject(s)
Anhydrides/chemistry , Imines/chemistry , Isoquinolines/chemical synthesis , Catalysis , Cycloaddition Reaction , Isoquinolines/chemistry , Molecular Structure
7.
Org Biomol Chem ; 14(11): 3040-6, 2016 Mar 21.
Article in English | MEDLINE | ID: mdl-26891029

ABSTRACT

It has been shown for the first time that enolisable anhydrides can participate in highly efficient and diastereo/enantioselective additions to activated ketones. In these reactions the anhydride component formally acts (initially) as the nucleophilic component. These processes are promoted by novel, readily prepared urea-substituted cinchona alkaloid-derived catalysts at low loadings under mild conditions. Three classes of enolisable anhydride and three different types of activated ketone were shown to be compatible with the process - generating a diverse range of structurally distinct and densely functionalised lactone products with the formation of two new stereocentres, one of which is quaternary. In one example, a product incorporating two contiguous quaternary stereocentres (one all carbon) was formed with outstanding enantiocontrol. It has been shown in the case of glutaconic anhydride derivatives that the cycloaddtion process is reversible, and can be accompanied by decarboxylation and olefin isomerisation. Reaction conditions can be modified to give access to three types of product with good-excellent ee.

8.
Angew Chem Int Ed Engl ; 54(3): 813-7, 2015 Jan 12.
Article in English | MEDLINE | ID: mdl-25425156

ABSTRACT

The first strategy for bringing about enantioselective azlactone dynamic kinetic resolution to generate orthogonally protected amino acids has been developed. In the presence of a C2-symmetric squaramide-based catalyst, benzyl alcohol reacts with novel yet readily prepared tetrachloroisopropoxycarbonyl-substituted azlactones to generate trapped phthalimide products of significant synthetic interest with excellent enantiocontrol. These materials are masked amino acids which are demonstrably orthogonally protected: cleavage of the phthalimide can be achieved in the presence of the ester and vice versa. This process could be utilized to bring about a highly stereoselective ligation-type coupling of protected serines (at stoichiometric loadings) with racemic azlactones derived from both natural and abiotic amino acids. After deprotection, a subsequent base-mediated O→N acyl transfer occurs to form a dipeptide.


Subject(s)
Lactones/chemistry , Amides/chemistry , Benzyl Alcohol/chemistry , Catalysis , Esters , Kinetics , Phthalimides/chemical synthesis , Phthalimides/chemistry , Stereoisomerism
9.
Angew Chem Int Ed Engl ; 53(10): 2628-32, 2014 Mar 03.
Article in English | MEDLINE | ID: mdl-24573916

ABSTRACT

In the presence of a novel, tert-butyl-substituted squaramide-based catalyst, enolizable anhydrides react with alkylidene oxindoles to generate spirooxindole products of significant synthetic interest with excellent enantio- and diastereocontrol. The methodology is of wide scope and encompasses both homophthalic and glutaconic anhydride derivatives, which lead to structurally diverse products. Glutaconic acid-derived anhydrides undergo a clean post-cyclization decarboxylation process which is not a feature of reactions involving homophthalic acid-derived anhydrides. The unusual influence of reaction temperature on diastereocontrol has been probed, with reactions occurring at 30 °C and -30 °C delivering products epimeric at one stereocenter only, in near optical purity.


Subject(s)
Amides/chemistry , Indoles/chemical synthesis , Spiro Compounds/chemical synthesis , Catalysis , Cyclization , Indoles/chemistry , Models, Molecular , Molecular Structure , Spiro Compounds/chemistry
10.
Chem Commun (Camb) ; 48(52): 6502-4, 2012 Jul 04.
Article in English | MEDLINE | ID: mdl-22622626

ABSTRACT

A new, highly enantio- and diastereoselective catalytic asymmetric formal cycloaddition of aryl succinic anhydrides and aldehydes which generates paraconic acid (γ-butyrolactone) derivatives is reported.


Subject(s)
4-Butyrolactone/chemical synthesis , 4-Butyrolactone/chemistry , Aldehydes/chemistry , Catalysis , Stereoisomerism , Succinic Anhydrides/chemistry
11.
Org Lett ; 14(7): 1850-3, 2012 Apr 06.
Article in English | MEDLINE | ID: mdl-22449206

ABSTRACT

In the presence of a highly efficient novel bifunctional organocatalyst at low loadings under mild conditions, enolizable homophthalic anhydrides can be added to a range of aromatic and aliphatic aldehydes to give dihydroisocoumarins, with excellent yields and diastereo- and enantiocontrol (up to 99% ee).


Subject(s)
Aldehydes/chemistry , Anhydrides/chemistry , Isocoumarins/chemical synthesis , Catalysis , Cinchona Alkaloids/chemistry , Combinatorial Chemistry Techniques , Isocoumarins/chemistry , Molecular Structure , Stereoisomerism
SELECTION OF CITATIONS
SEARCH DETAIL
...