Apoptolidin: Induktion von Apoptose durch einen Naturstoff

Daniel, Peter T.; Koert, Ulrich; Schuppan, Julia

doi:10.1002/ange.200502698

Cited by 25 publications

(10 citation statements)

References 201 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Representative examples for the importance of the sugar moiety are the cardiac glycosides (uptake, distribution and binding activity), macrolide antibiotics (ribosome binding) and the anthracyclines (DNA interaction) 2. The ability of apoptolidin A ( 1 ) to selectively induce apoptosis (programmed cell death) in tumor cells also depends on the presence of the glyco residues 3. The apoptolidins (A 1 , B 2 and C 3 ) form a group of 20‐membered ring macrocyclic natural products with 6‐deoxy‐4‐ O ‐methyl‐ L ‐glucose ( 4 ) attached to O‐9 and a disaccharide consisting of L ‐olivomycose ( 5 ) and D ‐oleandrose ( 6 ) linked to O‐27 (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Apoptolidin A: Total Synthesis and Partially Glycosylated Analogues

Wehlan

Dauber

Fernaud

et al. 2006

Chemistry A European J

Self Cite

View full text Add to dashboard Cite

The total synthesis of apoptolidin A is described employing an early glycosylation strategy. Strategic disconnections were chosen between C11-C12 (cross-coupling) and C19O-C1 (macrocyclization). The cis-selective glycosylation at C9-OH was achieved with the new SIBA protective group at O2/O3 of the L-glucose residue. Auxiliary substitutents at the 2-position of the 2-deoxy sugars were applied to form selectively the glycosidic linkages of the C27 disaccharide. The cross-coupling of the glycosylated northern half with the glycosylated southern half was achieved with CuI-thiophene carboxylate. The macrocyclization of a trihydroxy carboxylic acid produced the 20-membered macrolide selectively. H2SiF6 was suitable for the final deprotection of the silyl ethers and the conversion of the C21 methylketal into the hemiketal. The synthetic flexibility of the approach was proven by the synthesis of some glycovariants.

show abstract

Section: Introductionmentioning

confidence: 99%

Apoptolidin A: Total Synthesis and Partially Glycosylated Analogues

Wehlan

Dauber

Fernaud

et al. 2006

Chemistry A European J

Self Cite

View full text Add to dashboard Cite

show abstract

“…Apoptolidins A–E are a family of macrolide natural products that have attracted considerable attention as highly selective apoptosis regulators 1. The critical need for achieving greater selectivity in cancer chemotherapeutics has stimulated efforts to elucidate the mechanistic and structural basis for the apoptolidin’s unique pharmacological profile.…”

Section: Methodsmentioning

confidence: 99%

Catalytic Asymmetric Aldol Equivalents in the Enantioselective Synthesis of the Apoptolidin C Aglycone

2010

View full text Add to dashboard Cite

Apoptolidins A-E are a family of macrolide natural products that have attracted considerable attention as highly selective apoptosis regulators.[1] The critical need for achieving greater selectivity in cancer chemotherapeutics has stimulated efforts to elucidate the mechanistic and structural basis for the apoptolidins unique pharmacological profile. These efforts include several total syntheses of apoptolidin A, each of which has provided invaluable insights into strategies for chemically modifying the natural product for expanded pharmacological profiling.[2] Similar considerations inspired our interest in developing an enantioselective synthesis of the apoptolidins exploring the capacity of catalytic asymmetric aldol reaction surrogates to facilitate the synthesis of these natural products. Toward this goal, we describe herein an enantioselective synthesis of apoptolidinone C (1), the apoptolidin C aglycone, wherein catalytic asymmetric CÀC bond constructions provide the conduit to all ten of the requisite stereogenic centers.Their utility in assembling acetate-or propionate-derived polyketide architecture is among the defining characteristics of modern aldol-based reaction technologies. There exists an array of aldol or aldol equivalents utilizing stoichiometric chiral controllers that provide exceptionally reliable and predictable methods for constructing complex polyacetate and polypropionate arrays.[3] For our purposes, the apoptolidin C aglycone provided a platform for evaluating whether similar levels of operational efficiency and expediency could be achieved in similar synthesis endeavors wherein stereocontrol would derive exclusively from catalyst-based substoichiometric chiral controllers. Specifically, catalytic asymmetric acyl halide-aldehyde cyclocondensation (AAC) reactions provide highly stereoselective acetate or propionate aldol equivalents using Al III -based Lewis acid or cinchona alkaloid Lewis base catalysts, respectively.[4] Complex polyketide assemblage predicated on the AAC methodology follows a reiterative pattern of catalyst controlled CÀC bond construction followed by b-lactone refunctionalization to the b-alkoxy aldehyde required for continued chain homologation in a sequence reminiscent of the iterative homologation-refunctionalization sequence observed in biosynthetic polyketide assembly.A synthesis of apoptolidinone C (1) emerges from the preceding analysis by disconnecting 1 across the C1ÀO and C11ÀC12 bonds to reveal the mixed acetate/propionatederived C12-C28 fragment 2 and the extensively dehydrated polypropionate C1-C11 fragment 3 (Scheme 1). The synthesis of lower fragment 2 highlights the iterative assembly of stereodefined polyketide units enabled by the AAC methodology. Thus, Al III -triamine (4)-catalyzed cyclocondensation of acetyl bromide with methoxyacetaldehyde provided b-lactone 5 as an acetate aldol equivalent (91 %, ! 95 % ee) (Scheme 2).[4] Converting lactone 5 to aldehyde 6 required for continued chain elongation involved amine-mediated ring opening (MeO(Me)NH,...

show abstract

“…Some compounds appear to be rather promising with IC 50 values close to 1 mmol L À1 (or even lower), which is a concentration that might well be achieved as a systemically relevant therapeutic dose. [6][7][8][9][10] Many others, however, exhibit IC 50 values that are clearly higher than 10 mmol L À1 and, in some instances, even approach the millimolar range. [11][12][13][14] In the present study a group of seven indoloquinolizidine derivatives was identified on the basis of functional screening of approximately 11 000 natural-product derived and inspired compounds, which with IC 50 values close to 2 mmol L À1 , inhibited proliferation in different cell lines and increased the amount of apoptotic cells by up to 600 % as compared to the control value.…”

Section: Introductionmentioning

confidence: 99%

Indoloquinolizidine Derivatives as Novel and Potent Apoptosis Inducers and Cell‐Cycle Blockers

Wehner¹,

Nören‐Müller²,

Müller³

et al. 2008

ChemBioChem

View full text Add to dashboard Cite

A collection of approximately 11 000 natural-product derived and inspired compounds was screened for potential apoptosis inducers in the human tumour cell lines HepG2 (liver), HeLa (cervix) and MCF-7 (breast) by means of MTT and ATP-luminescence assays, automated cell counting, caspase 3/7 assay as well as by fluorescence activated cell sorting (FACS) analysis. A group of seven indoloquinolizidine derivatives was identified that exhibited IC(50) values for cell proliferation as low as 2 mumol L(-1), with no major necrosis of cells detectable. At the same time, an increase in the rate of apoptosis of up to 600 % relative to the reference level was observed. FACS analysis indicated that these effects are related to an arrest of cells in the G(2)M phase of the cell cycle.

show abstract

Apoptolidin: Induktion von Apoptose durch einen Naturstoff

Cited by 25 publications

References 201 publications

Apoptolidin A: Total Synthesis and Partially Glycosylated Analogues

Apoptolidin A: Total Synthesis and Partially Glycosylated Analogues

Catalytic Asymmetric Aldol Equivalents in the Enantioselective Synthesis of the Apoptolidin C Aglycone

Indoloquinolizidine Derivatives as Novel and Potent Apoptosis Inducers and Cell‐Cycle Blockers

Contact Info

Product

Resources

About