Divergolide congeners illuminate alternative reaction channels for ansamycin diversification

2015 ◽  
Vol 13 (6) ◽  
pp. 1618-1623 ◽  
Author(s):  
Ling Ding ◽  
Jakob Franke ◽  
Christian Hertweck
Keyword(s):  
Structure Elucidation ◽  
Polyketide Synthase ◽  
Ring Closure ◽  
Side Chain ◽  
Neighboring Group ◽  
Ring Contraction ◽  
Reaction Channels ◽  
Extender Unit

Isolation and structure elucidation of six new divergolides reveal unusual ansamycin diversification reactions including formation of the unusual isobutenyl side chain from a branched polyketide synthase extender unit, azepinone ring closure, macrolide ring contraction and formation of a seco variant by a neighboring group-assisted decarboxylation.

scholarly journals Dihydroquinolines, Dihydronaphthyridines and Quinolones by Domino Reactions of Morita-Baylis-Hillman Acetates

Molecules ◽  
2021 ◽  
Vol 26 (4) ◽  
pp. 890
Author(s):  
Joel K. Annor-Gyamfi ◽  
Ebenezer Ametsetor ◽  
Kevin Meraz ◽  
Richard A. Bunce
Keyword(s):  
Aromatic Ring ◽  
Aromatic Amines ◽  
Control Experiment ◽  
Ring Closure ◽  
Domino Reaction ◽  
Side Chain ◽  
Initial Reaction ◽  
Dual Reactivity ◽  
Michael Acceptor ◽  
Nitrogen Nucleophile

An efficient synthetic route to highly substituted dihydroquinolines and dihydronaphthyridines has been developed using a domino reaction of Morita-Baylis-Hillman (MBH) acetates with primary aliphatic and aromatic amines in DMF at 50–90 °C. The MBH substrates incorporate a side chain acetate positioned adjacent to an acrylate or acrylonitrile aza-Michael acceptor as well as an aromatic ring activated toward SNAr ring closure. A control experiment established that the initial reaction was an SN2′-type displacement of the side chain acetate by the amine to generate the alkene product with the added nitrogen nucleophile positioned trans to the SNAr aromatic ring acceptor. Thus, equilibration of the initial alkene geometry is required prior to cyclization. A further double bond migration was observed for several reactions targeting dihydronaphthyridines from substrates with a side chain acrylonitrile moiety. MBH acetates incorporating a 2,5-difluorophenyl moiety were found to have dual reactivity in these annulations. In the absence of O2, the expected dihydroquinolines were formed, while in the presence of O2, quinolones were produced. All of the products were isolated in good to excellent yields (72–93%). Numerous cases (42) are reported, and mechanisms are discussed.

scholarly journals On the Importance of the Thiazole Nitrogen in Epothilones: Semisynthesis and Microtubule-Binding Affinity of Deaza-Epothilone C

Chemistry ◽  
2020 ◽  
Vol 2 (2) ◽  
pp. 499-509
Author(s):  
Adriana Edenharter ◽  
Lucie Ryckewaert ◽  
Daniela Cintulová ◽  
Juan Estévez-Gallego ◽  
José Fernando Díaz ◽  
...  
Keyword(s):  
Decisive Role ◽  
Ring Closure ◽  
Side Chain ◽  
Microtubule Binding ◽  
Acid Fragment ◽  
Epothilone A ◽  
Thiophene Moiety ◽  
Free Energy Of Binding

Deaza-epothilone C, which incorporates a thiophene moiety in place of the thiazole heterocycle in the natural epothilone side chain, has been prepared by semisynthesis from epothilone A, in order to assess the contribution of the thiazole nitrogen to microtubule binding. The synthesis was based on the esterification of a known epothilone A-derived carboxylic acid fragment and a fully synthetic alcohol building block incorporating the modified side chain segment and subsequent ring-closure by ring-closing olefin metathesis. The latter proceeded with unfavorable selectivity and in low yield. Distinct differences in chemical behavior were unveiled between the thiophene-derived advanced intermediates and what has been reported for the corresponding thiazole-based congeners. Compared to natural epothilone C, the free energy of binding of deaza-epothilone C to microtubules was reduced by ca. 1 kcal/mol or less, thus indicating a distinct but non-decisive role of the thiazole nitrogen in the interaction of epothilones with the tubulin/microtubule system. In contrast to natural epothilone C, deaza-epothilone C was devoid of antiproliferative activity in vitro up to a concentration of 10 μM, presumably due to an insufficient stability in the cell culture medium.

scholarly journals Engineering Anthracycline Biosynthesis toward Angucyclines

2003 ◽  
Vol 47 (4) ◽  
pp. 1291-1296 ◽  
Author(s):  
Mikko Metsä-Ketelä ◽  
Kaisa Palmu ◽  
Tero Kunnari ◽  
Kristiina Ylihonko ◽  
Pekka Mäntsälä
Keyword(s):  
Gene Cluster ◽  
Polyketide Synthase ◽  
Gene Cassette ◽  
Side Chain ◽  
Antibiotic Biosynthesis ◽  
Biosynthesis Gene Cluster ◽  
Biosynthesis Gene ◽  
Starter Unit

ABSTRACT The biosynthesis pathways of two anthracyclines, nogalamycin and aclacinomycin, were directed toward angucyclines by using an angucycline-specific cyclase, pgaF, isolated from a silent antibiotic biosynthesis gene cluster. Addition of pgaF to a gene cassette that harbored the early biosynthesis genes of nogalamycin resulted in the production of two known angucyclinone metabolites, rabelomycin and its precursor, UWM6. Substrate flexibility of pgaF was demonstrated by replacement of the nogalamycin minimal polyketide synthase genes in the gene cassette with the equivalent aclacinomycin genes together with aknE2 and aknF, which specify the unusual propionate starter unit in aclacinomycin biosynthesis. This modification led to the production of a novel angucyclinone, MM2002, in which the expected ethyl side chain was incorporated into the fourth ring.

scholarly journals FT-ICR-MS Characterization of Intermediates in the Biosynthesis of the α-Methylbutyrate Side Chain of Lovastatin by the 277 kDa Polyketide Synthase LovF

Biochemistry ◽  
2011 ◽  
Vol 50 (2) ◽  
pp. 287-299 ◽  
Author(s):  
Michael J. Meehan ◽  
Xinkai Xie ◽  
Xiling Zhao ◽  
Wei Xu ◽  
Yi Tang ◽  
...  
Keyword(s):  
Polyketide Synthase ◽  
Side Chain ◽  
Ft Icr Ms ◽  
Ft Icr

scholarly journals Complete Reconstitution and Deorphanization of the 3 MDa NOCAP (NOCardiosis-Associated Polyketide) Synthase

2020 ◽  
Author(s):  
Kai P. Yuet ◽  
Corey W. Liu ◽  
Stephen R. Lynch ◽  
James Kuo ◽  
Wesley Michaels ◽  
...  
Keyword(s):  
Structure Elucidation ◽  
Assembly Line ◽  
Polyketide Synthase ◽  
Spectroscopic Analysis ◽  
Hydroxyl Group ◽  
E Coli ◽  
Life Threatening ◽  
Tailoring Enzymes ◽  
Protein Components

ABSTRACTSeveral Nocardia strains associated with nocardiosis, a potentially life-threatening disease, house a nonamodular assembly-line polyketide synthase (PKS) that presumably synthesizes an unknown natural product. Here, we report the discovery and structure elucidation of the NOCAP (NOCardiosis-Associated Polyketide) aglycone by first fully reconstituting the NOCAP synthase in vitro from purified protein components followed by heterologous expression in E. coli and spectroscopic analysis of the purified products. The NOCAP aglycone has an unprecedented structure comprised of a substituted resorcylaldehyde headgroup linked to a 15-carbon tail that harbors two conjugated all-trans trienes separated by a stereogenic hydroxyl group. This report is the first example of reconstituting a trans-acyltransferase assembly-line PKS either in vitro or in E. coli, and of using these approaches to “deorphanize” a complete assembly-line PKS identified via genomic sequencing. With the NOCAP aglycone in hand, the stage is set for understanding how this PKS and associated tailoring enzymes confer an advantage to their native hosts during human Nocardia infections.

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