Regioselective acylations of 7-desacetylforskolin

Kosley, Raymond W.; Cherill, Robert J.

doi:10.1021/jo00273a039

Cited by 18 publications

(6 citation statements)

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“…The deacetylation of forskolin has been achieved previously with the use of methanolic potassium carbonate which can provide 7-desacetylforskolin in 65% yield ( Kosley and Cherill, 1989 ). Here, we carried out the deacetylation of forskolin using a solution of methanolic ammonia solution (2M) to afford 7-desacetylforskolin quantitatively.…”

Section: Methodsmentioning

confidence: 99%

Total biosynthesis of the cyclic AMP booster forskolin from Coleus forskohlii

Pateraki

Andersen-Ranberg

Jensen

et al. 2017

eLife

106

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Forskolin is a unique structurally complex labdane-type diterpenoid used in the treatment of glaucoma and heart failure based on its activity as a cyclic AMP booster. Commercial production of forskolin relies exclusively on extraction from its only known natural source, the plant Coleus forskohlii, in which forskolin accumulates in the root cork. Here, we report the discovery of five cytochrome P450s and two acetyltransferases which catalyze a cascade of reactions converting the forskolin precursor 13R-manoyl oxide into forskolin and a diverse array of additional labdane-type diterpenoids. A minimal set of three P450s in combination with a single acetyl transferase was identified that catalyzes the conversion of 13R-manoyl oxide into forskolin as demonstrated by transient expression in Nicotiana benthamiana. The entire pathway for forskolin production from glucose encompassing expression of nine genes was stably integrated into Saccharomyces cerevisiae and afforded forskolin titers of 40 mg/L.DOI: http://dx.doi.org/10.7554/eLife.23001.001

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Section: Methodsmentioning

confidence: 99%

Total biosynthesis of the cyclic AMP booster forskolin from Coleus forskohlii

Pateraki

Andersen-Ranberg

Jensen

et al. 2017

eLife

106

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“…Organic materials were from Aldrich Chemicals and were used without further purification. The starting material, the 1,9-dimethylformamide acetal protected 7-desacetylforskolin (2) , was synthesized by a published procedure . The 1,9-dimethylformamide acetal-protected 7-desacetylforskolin-6,7-carbonate (20) was also prepared by a published procedure …”

Section: Methodsmentioning

confidence: 99%

“…The 6- and 7-hydroxyls of forskolin are relatively insensitive sites on the molecule for derivatization, and a flexible strategy had been previously developed to regioselectively prepare both 6- and 7-carbamate analogs. , The carbamate group was chosen as the linker based on prior successes with the chemistry involved and the hydrolytic and metabolic stability of a carbamate. The amine-containing reactants for subsequent carbamate formation were selected due to their polar or hydrophobic characteristics and a two-carbon span between the reactive amine and the desired terminal moiety in the final derivative.…”

Section: Chemistrymentioning

confidence: 99%

“…The preparation of this series is outlined in Scheme 1. The acetal protected precursor 2 was prepared as previously described 9 and then treated with carbonyldiimidazole (CDI) in CH 2 Cl 2 for 4-6 h at room temperature. The intermediate imidazolide 3 was not isolated, but immediately treated with an excess of the desired amine to form the 1,9-protected-7-carbamate 4.…”

Section: Chemistrymentioning

confidence: 99%

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Forskolin Carbamates: Binding and Activation Studies with Type I Adenylyl Cyclase

Robbins

Boring²,

Tang³

et al. 1996

J. Med. Chem.

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Three series of analogs were regioselectively prepared from a protected forskolin precursor to afford 7-carbamoyl-7-desacetylforskolins (series 1), 6-carbamoyl-7-desacetylforskolins (series 2), and 6-carbamoylforskolins (series 3). The analogs were pharmacologically evaluated for binding (IC50) to and activation (EC50) of type I adenylyl cyclase in membranes from stably transfected Sf9 cell lines expressing a single adenylate cyclase subtype. The following ranges were determined for the IC50's and EC50's of each individual series: series 1, IC50 = 43-1600 nM, EC50 = 0.5-9.6 microM; series 2, IC50 = 65-680 nM, EC50 = 0.63-6.5 microM; series 3, IC50 = 21-271 nM, EC50 = 0.5-8.1 microM (forskolin IC50 = 41 nM and EC50 = 0.5 microM). Activation paralleled binding; however, some analogs exhibited poor binding and good activation whereas others demonstrated good binding but poor activation. Steric bulk tended to diminish binding and activation when at the 6- or 7-position, although bulk was accommodated at the 6-position if the 7-site was reacetylated. Acylation of the 7-position by the carbamoyl linker or acetyl was important for obtaining good binding and activation; however, the effect was more pronounced with binding. For both binding and activation, small, linear, lipophilic substituents (propyl, allyl, isopropyl) are well tolerated at the 7-position but less so in the 6-position, even when the 7-site is reacetylated. Planar aromatic moieties (phenyl and 2-pyridinyl) demonstrated moderate to good potency for binding and activation when located at either the 6- or 7-positions. There is an overall trend toward increasing potency for both binding and activation with polar substituents.

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“…The clerodane 17-carboxylic acids (19)30 and (20)31 have been isolated along with some labdanes and ent-kaurenes from the liverwort, Jungermannia in fusca. Baccharis species have been a rich source of diterpenoids.…”

Section: Clerodanesmentioning

confidence: 99%

Diterpenoids

Hanson¹

1991

Nat. Prod. Rep.

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Regioselective acylations of 7-desacetylforskolin

Cited by 18 publications

References 0 publications

Total biosynthesis of the cyclic AMP booster forskolin from Coleus forskohlii

Total biosynthesis of the cyclic AMP booster forskolin from Coleus forskohlii

Forskolin Carbamates: Binding and Activation Studies with Type I Adenylyl Cyclase

Diterpenoids

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