Total synthesis of balanol: a potent protein kinase C inhibitor of fungal origin

Adams, Christopher; Fairway, S. M.; Hardy, Christopher J.; Hibbs, David E.; Hursthouse, Michael B.; Morley, Andrew D.; Sharp, B. W.; Vicker, Nigel; Warner, I.

doi:10.1039/p19950002355

Cited by 55 publications

(27 citation statements)

References 13 publications

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“…[42] Ring expansion of piperidin-4-ones into azepane ring systems and further modification to give 1 a has also been reported. [41] A radical cyclization approach to the hexahydroazepine ring and a biomimetic route to the benzophenone fragment of 1 a have been described by Naitos group. [46] Apart from these, syntheses of the 3-amino-hexahydro-azepin-4-ol ring of balanol and suitable analogues have also been reported, because of its potent PKC inhibitory properties.…”

Section: Introductionmentioning

confidence: 98%

Total Synthesis of (−)‐Balanol, All Stereoisomers, Their N‐Tosyl Analogues, and Fully Protected Ophiocordin: An Easy Route to Hexahydroazepine Cores from Garner Aldehydes

Srivastava

Panda

2008

Chemistry A European J

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Total syntheses of (-)-balanol and all of its stereoisomers starting from easily available Garner aldehydes are described. Diastereoselective Grignard reactions on Garner aldehydes and ring-closing metatheses are the key steps for the construction of hexahydroazepine subunits. The benzophenone subunits were constructed through coupling of suitably functionalized aromatic aldehyde and bromo components. The synthetic route constitutes a convenient and scalable reaction sequence to generate all of the stereoisomers of balanol. The methodology is explored further for the synthesis of N-tosyl analogues of balanol and of fully protected ophiocordin.

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Section: Introductionmentioning

confidence: 98%

Total Synthesis of (−)‐Balanol, All Stereoisomers, Their N‐Tosyl Analogues, and Fully Protected Ophiocordin: An Easy Route to Hexahydroazepine Cores from Garner Aldehydes

Srivastava

Panda

2008

Chemistry A European J

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“…As a hybrid polyketide-nonribosomal peptide (PK-NRP) compound, balanol consists of a benzophenone, an azepine, and a p -hydroxybenzamide unit, and thus, balanol is unlikely to be synthesized by commonly integrated PKS-NRPS enzymes. Since the yield of balanol is very low when extracted from the fungus under laboratory conditions, many studies have focused on the chemical synthesis of balanol and its analogues. − The chemical synthesis and structural modification of balanol are complex and challenging, and the biosynthetic pathway of balanol has not yet been reported.…”

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confidence: 99%

“…To characterize the new compound produced by the blnROE strain, large-scale fermentation was carried out. Nine metabolites were isolated and identified (Figure 3), including two nonribosomal peptides (1, 2), five polyketide compounds (3,5,7,8,9), and two compounds containing both polyketide and amino acid derived moieties (4,6). Among these compounds, compound 7 has not been reported to date, and 1, 2, 3, and 6 were isolated from nature for the first time.…”

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confidence: 99%

Revelation of the Balanol Biosynthetic Pathway in Tolypocladium ophioglossoides

et al. 2018

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A cryptic gene cluster, bln, was activated by genome mining in Tolypocladium ophioglossoides. This activation led to the production of balanol and eight other metabolites. Gene disruption and metabolite profile analysis showed that the biosynthesis of balanol involved the convergence of independent PKS and NRPS pathways, and a biosynthetic pathway for balanol was proposed.Letter pubs.acs.org/OrgLett

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“…The total synthesis of balanol (86)(87)(88)(89)(90) and preparation of balanol derivatives now enable dissection of features underlying balanol's high affinity and selectivity for serine and threonine specific protein kinases. Recent studies indicate that balanol potently inhibits cAPK, most PKC isoforms, PKG, and Ca 2+ -calmodulin-dependent protein kinase (91)(92)(93)(94)(95).…”

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confidence: 99%

Crystal Structure of the Potent Natural Product Inhibitor Balanol in Complex with the Catalytic Subunit of cAMP-Dependent Protein Kinase

et al. 1999

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Endogenous protein kinase inhibitors are essential for a wide range of physiological functions. These endogenous inhibitors may mimic peptide substrates as in the case of the heat-stable protein kinase inhibitor (PKI), or they may mimic nucleotide triphosphates. Natural product inhibitors, endogenous to the unique organisms producing them, can be potent exogenous inhibitors against foreign protein kinases. Balanol is a natural product inhibitor exhibiting low nanomolar K i values against serine and threonine specific kinases, while being ineffective against protein tyrosine kinases. To elucidate balanol's specific inhibitory effects and provide a basis for understanding inhibition-regulated biological processes, a 2.1 Å resolution crystal structure of balanol in complex with cAMP-dependent protein kinase (cAPK) was determined. The structure reveals conserved binding regions and displays extensive complementary interactions between balanol and conserved cAPK residues. This report describes the structure of a protein kinase crystallized with a natural ATP mimetic in the absence of metal ions and peptide inhibitor.Protein kinases, of which the human genome is predicted to encode several thousand, reversibly phosphorylate diverse molecular targets and are critical enzymes in the initiation, regulation, and abrogation of both normal and abnormal cellular functions (reviewed in refs 1-6). These often exquisitely specific kinases play essential roles in apoptosis, cell proliferation, gene expression, glycogen metabolism, immune response, neurotransmission, oncogenesis, and secondary messenger signal transduction (7-18). This biological pervasiveness underscores the importance of more explicitly characterizing kinase activation and inhibition. Additionally, there is significant therapeutic value in achieving selective pharmacological control of members of this important class of enzymes, since unregulated or otherwise defective protein kinase activities to date have been implicated in asthma, cancer, cardiovascular disorders, central nervous system (CNS) 1 diseases, diabetes, human immunodeficiency virus (HIV) infections, inflammation, psoriasis, and rheumatoid arthritis (19)(20)(21)(22)(23)(24).To more explicitly characterize protein kinase activation and inhibition, cAMP-dependent protein kinase, the most completely characterized and mechanistically simplest protein kinase (25, reviewed in refs 26-31), is a logical singular choice for biochemical and structural research focusing on cellular phosphorylation events at the molecular level. The inactive cAPK holoenzyme consists of two regulatory (R) and two catalytic (C) subunits that dissociate in response to elevated levels of intracellular cAMP. The triply phosphorylated, active C subunit then phosphorylates serine or threonine residues of peptide substrates containing the consensus sequence Arg-Arg-X-Ser[Thr]-Hyd, where X is variable and Hyd is any hydrophobic residue (3,14,32,33). The C subunit of cAPK shares with other kinase family members a conserved cat...

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Total synthesis of balanol: a potent protein kinase C inhibitor of fungal origin

Cited by 55 publications

References 13 publications

Total Synthesis of (−)‐Balanol, All Stereoisomers, Their N‐Tosyl Analogues, and Fully Protected Ophiocordin: An Easy Route to Hexahydroazepine Cores from Garner Aldehydes

Total Synthesis of (−)‐Balanol, All Stereoisomers, Their N‐Tosyl Analogues, and Fully Protected Ophiocordin: An Easy Route to Hexahydroazepine Cores from Garner Aldehydes

Revelation of the Balanol Biosynthetic Pathway in Tolypocladium ophioglossoides

Crystal Structure of the Potent Natural Product Inhibitor Balanol in Complex with the Catalytic Subunit of cAMP-Dependent Protein Kinase

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