8-Epitacrolimus (2), a new l-pipecolic acid macrolide lactone, was obtained by base-catalyzed epi... more 8-Epitacrolimus (2), a new l-pipecolic acid macrolide lactone, was obtained by base-catalyzed epimerization of tacrolimus (FK-506, 1), an important immunosuppressive drug, and its structure determined by a single-crystal X-ray diffraction method. The compound was fully characterized by spectroscopic techniques. The epimer is of importance due to its potential biological effects as well as because of its possible formation during formulation, handling, and use of tacrolimus products.
Transformations of the macrocyclic lactone tacrolimus (1), an important immunosuppressive drug pr... more Transformations of the macrocyclic lactone tacrolimus (1), an important immunosuppressive drug produced by Streptomyces species, are described. These transformation products are primarily of interest as reference substances for drug impurity analyses. Upon action of acid (p-toluenesulfonic acid in toluene), tacrolimus is dehydrated by loss of water from the β-hydroxyketone moiety with partial inversion of configuration at C-8, resulting in formation of 5-deoxy-Δ(5,6)-tacrolimus and 5-deoxy-Δ(5,6)-8-epitacrolimus. The structure of the latter was determined by single-crystal X-ray crystallography. The same products are formed upon action of free radicals (iodine in boiling toluene), along with formation of 8-epitacrolimus. The latter is converted by p-toluenesulfonic acid to 5-deoxy-Δ(5,6)-8-epitacrolimus. Treatment of tacrolimus with weak base (1,5-diazabicyclo[4.3.0]nonene) gives, in addition to 8-epitacrolimus, the open-chain acid corresponding to 5-deoxy-Δ(5,6)-tacrolimus, a rare non-cyclic derivative of tacrolimus. Strong base (t-butoxide) causes pronounced degradation of the molecule. Thermolysis of tacrolimus leads to ring expansion by an apparent [3,3]-sigmatropic rearrangement of the allylic ester moiety with subsequent loss of water from the β-hydroxyketone moiety. (1)H and (13)C NMR spectra of the obtained compounds, complicated by the presence of amide bond rotamers and ketal moiety tautomers, were assigned by extensive use of 2D NMR techniques.
A three-step synthesis of the norneolignan skeleton involving the Carroll rearrangement as the ke... more A three-step synthesis of the norneolignan skeleton involving the Carroll rearrangement as the key step has been developed and used for synthesis of the norneolignan skeleton, 1,3-diphenylpenta-1,4-diene and hinokiresinol.
A systematic change of the substituents and side chain of the norneolignan hinokiresinol afforded... more A systematic change of the substituents and side chain of the norneolignan hinokiresinol afforded a 10 fold improvement of the IC(50) value toward inhibition of the growth of Plasmodium falciparum. The more potent compounds controlled the parasitemia in mice infected with Plasmodium berghei.
The absolute configuration of the norlignan (+)-nyasol was determined to be S by comparison of th... more The absolute configuration of the norlignan (+)-nyasol was determined to be S by comparison of the experimental vibrational circular dichroism data with first-principle calculations taking into account the eight lowest energy conformations. The established absolute configuration of (+)-nyasol enables establishment of the absolute configuration of (-)-hinokiresinol, which is concluded to be S. A total synthesis and resolution of hinokiresinol has been performed to resolve the conflicting reports of the coupling constant of the vinylic protons of the disubstituted double bond in this molecule. Racemic hinokiresinol was resolved. Both enantiomers possess the same antiplasmodial activity.
Removal of each of the acyl groups of thapsigargin at O-3, O-8 and O-10 significant reduces the a... more Removal of each of the acyl groups of thapsigargin at O-3, O-8 and O-10 significant reduces the affinity of the inhibitors to the SERCA1a pump. Replacement of the acyl groups at O-3 and O-10 with flexible residues could be performed with only a minor decrease of the affinity, whereas introduction of voluminous stiff residues caused dramatic reduction of the affinity. The results can be rationalized on the basis of the interactions of thapsigargin with the SERCA1a pump as revealed from 3D X-ray structural models of thapsigargin bound to the SERCA1a. In conclusion the results confirm and elaborate the previously suggested pharmocophore model of thapsigargin.
8-Epitacrolimus (2), a new l-pipecolic acid macrolide lactone, was obtained by base-catalyzed epi... more 8-Epitacrolimus (2), a new l-pipecolic acid macrolide lactone, was obtained by base-catalyzed epimerization of tacrolimus (FK-506, 1), an important immunosuppressive drug, and its structure determined by a single-crystal X-ray diffraction method. The compound was fully characterized by spectroscopic techniques. The epimer is of importance due to its potential biological effects as well as because of its possible formation during formulation, handling, and use of tacrolimus products.
Transformations of the macrocyclic lactone tacrolimus (1), an important immunosuppressive drug pr... more Transformations of the macrocyclic lactone tacrolimus (1), an important immunosuppressive drug produced by Streptomyces species, are described. These transformation products are primarily of interest as reference substances for drug impurity analyses. Upon action of acid (p-toluenesulfonic acid in toluene), tacrolimus is dehydrated by loss of water from the β-hydroxyketone moiety with partial inversion of configuration at C-8, resulting in formation of 5-deoxy-Δ(5,6)-tacrolimus and 5-deoxy-Δ(5,6)-8-epitacrolimus. The structure of the latter was determined by single-crystal X-ray crystallography. The same products are formed upon action of free radicals (iodine in boiling toluene), along with formation of 8-epitacrolimus. The latter is converted by p-toluenesulfonic acid to 5-deoxy-Δ(5,6)-8-epitacrolimus. Treatment of tacrolimus with weak base (1,5-diazabicyclo[4.3.0]nonene) gives, in addition to 8-epitacrolimus, the open-chain acid corresponding to 5-deoxy-Δ(5,6)-tacrolimus, a rare non-cyclic derivative of tacrolimus. Strong base (t-butoxide) causes pronounced degradation of the molecule. Thermolysis of tacrolimus leads to ring expansion by an apparent [3,3]-sigmatropic rearrangement of the allylic ester moiety with subsequent loss of water from the β-hydroxyketone moiety. (1)H and (13)C NMR spectra of the obtained compounds, complicated by the presence of amide bond rotamers and ketal moiety tautomers, were assigned by extensive use of 2D NMR techniques.
A three-step synthesis of the norneolignan skeleton involving the Carroll rearrangement as the ke... more A three-step synthesis of the norneolignan skeleton involving the Carroll rearrangement as the key step has been developed and used for synthesis of the norneolignan skeleton, 1,3-diphenylpenta-1,4-diene and hinokiresinol.
A systematic change of the substituents and side chain of the norneolignan hinokiresinol afforded... more A systematic change of the substituents and side chain of the norneolignan hinokiresinol afforded a 10 fold improvement of the IC(50) value toward inhibition of the growth of Plasmodium falciparum. The more potent compounds controlled the parasitemia in mice infected with Plasmodium berghei.
The absolute configuration of the norlignan (+)-nyasol was determined to be S by comparison of th... more The absolute configuration of the norlignan (+)-nyasol was determined to be S by comparison of the experimental vibrational circular dichroism data with first-principle calculations taking into account the eight lowest energy conformations. The established absolute configuration of (+)-nyasol enables establishment of the absolute configuration of (-)-hinokiresinol, which is concluded to be S. A total synthesis and resolution of hinokiresinol has been performed to resolve the conflicting reports of the coupling constant of the vinylic protons of the disubstituted double bond in this molecule. Racemic hinokiresinol was resolved. Both enantiomers possess the same antiplasmodial activity.
Removal of each of the acyl groups of thapsigargin at O-3, O-8 and O-10 significant reduces the a... more Removal of each of the acyl groups of thapsigargin at O-3, O-8 and O-10 significant reduces the affinity of the inhibitors to the SERCA1a pump. Replacement of the acyl groups at O-3 and O-10 with flexible residues could be performed with only a minor decrease of the affinity, whereas introduction of voluminous stiff residues caused dramatic reduction of the affinity. The results can be rationalized on the basis of the interactions of thapsigargin with the SERCA1a pump as revealed from 3D X-ray structural models of thapsigargin bound to the SERCA1a. In conclusion the results confirm and elaborate the previously suggested pharmocophore model of thapsigargin.
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