TY - JOUR

T1 - Enzyme-Assisted Total Synthesis of the Optical Antipodes D-myo-Inositol3,4,5-Trisphosphate and D-myo-Inositol 1,5,6-Trisphosphate

T2 - Aspects of Their Structure-Activity Relationship to Biologically Active Inositol Phosphates

AU - Adelt, Stephan

AU - Plettenburg, Oliver

AU - Stricker, Rolf

AU - Reiser, Georg

AU - Altenbach, Hans Josef

AU - Vogel, Günter

N1 - Funding Information: This work was supported by theDeutsche Forschungsgemeinschaft (Grant VO 348/2-2and Sonderforschungsbereich 426/Reiser) and the Fondsder Chemischen Industrie

PY - 1999/4/1

Y1 - 1999/4/1

N2 - Unambiguous total syntheses of both optical antipodes of the enantiomeric pair D-myo-inositol 3,4,5-trisphosphate (Ins(3,4,5)P3) and D- myo-inositol 1,5,6-trisphosphate (Ins(1,5,6)P3) are described. The ring system characteristic of myo-inositol was constructed de novo from p- benzoquinone. X-ray data for the enzymatically resolved (1S,2R,3R,4S)-1,4- diacetoxy-2,3-dibromocyclohex-5-ene enabled the unequivocal assignment of the absolute configuration. Subsequent transformations under stereocontrolled conditions led to enantiopure C2-symmetrical 1,4-(di-O- benzyldiphospho)conduritol B derivatives. Their synthetic potential was exploited to prepare Ins(3,4,5,6)P4 and Ins(1,4,5,6)P4 in three steps. With a recently identified and partially purified InsP5/InsP4 phosphohydrolase from Dictyostelium discoideum, these enantiomers could be converted to the target compounds, Ins(3,4,5)P3 and Ins(1,5,6)P3, on a preparative scale. An HPLC system employed for both purification of the inositol phosphates and analytical runs ensured that the products were isomerically homogeneous. The sensitivity of detection achieved by a complexometric postcolumn derivatization method indicates that the complexation properties of Ins(3,4,5)P3/Ins(1,5,6)P3 resemble those of Ins(1,2,3)P3, a compound with antioxidant potential. The set of inositol phosphates synthesized was used to clarify structural motifs important for molecular recognition by p42(IP4), a high-affinity Ins(1,3,4,5)P4/PtdIns(3,4,5)P3-specific binding protein from pig cerebellum.

AB - Unambiguous total syntheses of both optical antipodes of the enantiomeric pair D-myo-inositol 3,4,5-trisphosphate (Ins(3,4,5)P3) and D- myo-inositol 1,5,6-trisphosphate (Ins(1,5,6)P3) are described. The ring system characteristic of myo-inositol was constructed de novo from p- benzoquinone. X-ray data for the enzymatically resolved (1S,2R,3R,4S)-1,4- diacetoxy-2,3-dibromocyclohex-5-ene enabled the unequivocal assignment of the absolute configuration. Subsequent transformations under stereocontrolled conditions led to enantiopure C2-symmetrical 1,4-(di-O- benzyldiphospho)conduritol B derivatives. Their synthetic potential was exploited to prepare Ins(3,4,5,6)P4 and Ins(1,4,5,6)P4 in three steps. With a recently identified and partially purified InsP5/InsP4 phosphohydrolase from Dictyostelium discoideum, these enantiomers could be converted to the target compounds, Ins(3,4,5)P3 and Ins(1,5,6)P3, on a preparative scale. An HPLC system employed for both purification of the inositol phosphates and analytical runs ensured that the products were isomerically homogeneous. The sensitivity of detection achieved by a complexometric postcolumn derivatization method indicates that the complexation properties of Ins(3,4,5)P3/Ins(1,5,6)P3 resemble those of Ins(1,2,3)P3, a compound with antioxidant potential. The set of inositol phosphates synthesized was used to clarify structural motifs important for molecular recognition by p42(IP4), a high-affinity Ins(1,3,4,5)P4/PtdIns(3,4,5)P3-specific binding protein from pig cerebellum.

UR - http://www.scopus.com/inward/record.url?scp=0033535534&partnerID=8YFLogxK

U2 - 10.1021/jm981113k

DO - 10.1021/jm981113k

M3 - Article

C2 - 10197969

AN - SCOPUS:0033535534

VL - 42

SP - 1262

EP - 1273

JO - Journal of medicinal chemistry

JF - Journal of medicinal chemistry

SN - 0022-2623

IS - 7

ER -