Total Synthesis of Archazolid A

Menche, Dirk; Hassfeld, Jorma; Li, Jun; Rudolph, Sven

doi:10.1021/ja071461o

Cited by 92 publications

(76 citation statements)

References 12 publications

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“…These were found by AM1 to be 5.2/2.0 kcal mol À1 higher in energy than the global minimum as obtained from a non-restrained conformational search under the same conditions. The resulting MMFFs/AM1 conformation of archazolid A with the correct stereochemistry is shown in Figure 24 Subsequently, this stereochemical proposal was confirmed by the present authors group, using a convergent and modular total synthesis of archazolid A [14]. This detailed understanding of the solution structure of the archazolids also proved beneficial in the design of a simplified, but essentially equipotent, analog of this promising V-ATPase inhibitor [15].…”

Section: J-based Configurational Methods and Molecular Mechanics Studiessupporting

confidence: 72%

Modeling of Complex Polyketides: Stereochemical Determination by a Combination of Computational and NMR Methods

Menche

Dreisigacker

2011

Modeling of Molecular Properties

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In structural terms, the polyketides are a diverse class of natural metabolites characterized by a broad range of biological activities. Indeed, polyketide antibiotics, antifungals, cytostatics, antiparasitics and natural insecticides are currently widely used on a commercial basis. Biosynthetically, the polyketides are derived by iterative condensations of acetyl and propionyl subunits, giving rise to diverse assemblies of methyl-and hydroxyl-bearing stereogenic centers that enable large numbers of stereochemical permutations. Unfortunately, this diversity -together with a high degree of spectral complexity and conformational flexibility -causes the stereochemical assignment of polyketides to become a major challenge.The myxobacteria are a particularly rich source of novel polyketides [1,2], and over the past three decades -based on the results of pioneering investigations conducted by the groups of Professors H€ ofle and Reichenbach at the Helmholtz-Zentrum f€ ur Infektionsforschung (Center for Infection Research in Braunschweig, HZI) -an impressive range of structurally unique and biosynthetically diverse polyketides has been isolated from these soil-living organisms. In total, these materials span a range of approximately 60 structurally new polyketide classes, and many structural variants thereof. Most prominently, the epothilones are natural antiproliferative agents from the myxobacterium Sorangium cellulosum (Figure 24.1), that have been developed and approved as anticancer drugs for the treatment of metastatic and advanced breast cancer. Extensive biological studies, as well as computational and NMR-based analyses of these microtubule-stabilizing agents, have been reported for these metabolites, and detailed processes for their fermentative and synthetic production have subsequently been developed [3].In contrast to the macrolides, many other polyketides are much less advanced in their development, despite having similarly promising biological profiles that include antiproliferative, antibiotic, antifungal, or antiplasmodial activities. Likewise, in many cases targets are specifically addressed on a molecular level, ranging from the cytoskeleton, nucleic acid polymerases, the respiratory chain, nuclear transport, Modeling of Molecular Properties, First Edition. Edited by Peter Comba.

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Section: J-based Configurational Methods and Molecular Mechanics Studiessupporting

confidence: 72%

Modeling of Complex Polyketides: Stereochemical Determination by a Combination of Computational and NMR Methods

Menche

Dreisigacker

2011

Modeling of Molecular Properties

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“…Journal of Natural Products ARTICLE molecular modeling and derivatization 23 and subsequently confirmed by total syntheses of archazolids A (1) 24,25 and B (2). 26 So far only a limited number of SAR studies on synthetic 27 and natural analogues 21,22 have been reported; this will be critical in advancing these macrolide antibiotics and may help in deriving a better molecular understanding of the function of the V-ATPase enzyme.…”

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confidence: 71%

Archazolid A-15-O-β-d-glucopyranoside and iso-Archazolid B: Potent V-ATPase Inhibitory Polyketides from the Myxobacteria Cystobacter violaceus and Archangium gephyra

et al. 2011

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“…In 2003 Sasse et al (16) isolated the macrolactone archazolid from the myxobacteria Archangium gephyra and Cystobacter violaceus, which exhibited high cytotoxicity in mouse fibroblasts. Recently, the three-dimensional structure and stereochemistry was assigned by extensive high-field NMR studies in combination with molecular modeling and confirmed by total synthesis (17,18). Archazolid was assumed to be a novel V-ATPase inhibitor because it induced the same morphological changes in mammalian cells as the approved plecomacrolide inhibitors bafilomycin and concanamycin (16,19).…”

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confidence: 99%

Archazolid A Binds to the Equatorial Region of the c-Ring of the Vacuolar H+-ATPase

Bockelmann

Menche

Rudolph

et al. 2010

Journal of Biological Chemistry

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The macrolactone archazolid is a novel, highly specific V-ATPase inhibitor with an IC 50 Vacuolar ATPases (V-ATPases)3 are heteromultimeric proteins that use the energy of ATP hydrolysis to translocate protons from the cytoplasm into intracellular compartments or across the plasma membrane of eukaryotic cells. This transport of protons is mediated by the membrane-integral V O complex, whereas the cleavage of ATP occurs at the cytoplasmatic V 1 complex (1). The V O complex is composed of single copies of subunits a, d, and e, and the ring-forming proteolipid subunits c, cЉ, and in fungi subunit cЈ also (2). Based on the crystal structure from the V O ring of K subunits, a homologue of the H ϩ -translocating subunit c in the V-type Na ϩ -ATPase from Enterococcus hirae, and a cryoelectron microscopy structure from the V-ATPase of Manduca sexta, an arrangement of 10 subunits is proposed for the V O ring (3, 4). The subunits c and cЈ are predicted to have four transmembrane helices (TM 1 to 4), whereas subunit cЉ contains an additional fifth transmembrane helix. All proteolipid subunits contain a conserved glutamate residue, subunits c and cЈ in TM4 and subunit cЉ in TM3, which are essential for proton transport across the membrane (2). This glutamate is a target for the covalent binding inhibitor N,NЈ-dicyclohexylcarbodiimide (DCCD) and its derivatives (5-8).By regulating the pH homeostasis and membrane energization of cells, V-ATPases are involved in a variety of fundamental processes like vesicular trafficking or secondary transport. In addition, plasma membrane V-ATPases are responsible for extracellular acidification, e.g. in osteoclasts or metastasing tumor cells, and therefore play an important role in severe diseases such as osteoporosis or cancer (7). For these reasons the V-ATPase is a promising therapeutic target, and inhibitors of this enzyme are the focus of biomedical research. A variety of such compounds has been discovered of which the plecomacrolide inhibitors bafilomycin and concanamycin are the best studied examples (9). With IC 50 values at low nanomolar concentrations these compounds are highly specific inhibitors of the V-ATPase (10). Throughout the past years the binding site and inhibition mechanism of the plecomacrolides has been studied in more detail. In 2002 Bowman et al. (11) identified via mutagenesis studies in Neurospora crassa amino acids in V O subunit c that contribute to the binding of bafilomycin. In the same year photoaffinity labeling studies with the radioactive concanamycin derivative 125 I-concanolid A also resulted in the *

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Total Synthesis of Archazolid A

Cited by 92 publications

References 12 publications

Modeling of Complex Polyketides: Stereochemical Determination by a Combination of Computational and NMR Methods

Modeling of Complex Polyketides: Stereochemical Determination by a Combination of Computational and NMR Methods

Archazolid A-15-O-β-d-glucopyranoside and iso-Archazolid B: Potent V-ATPase Inhibitory Polyketides from the Myxobacteria Cystobacter violaceus and Archangium gephyra

Archazolid A Binds to the Equatorial Region of the c-Ring of the Vacuolar H+-ATPase

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