Litebamine N-homologues were easily prepared from laurolitsine, generally via three reaction steps (N-alkylation, solvolysis with 1 M NH4OAc under reflux, and the Mannich reaction) in more than 80% overall yield. Among the prepared compounds, N-propyl-, N-isobutyl-, and N-isopropylnorlitebamines exhibited moderate antiacetylcholinesterase activity (IC50 ca. 7.0 microM), while the corresponding N-metho salt of N-propylnorlitebamine showed potent activity (IC50 2.70 microM).

The 1H- and 13C-nmr assignments of territrems A, B, and C [1-3] were made by using nOe and 2D nmr techniques. Following the same methods, the structure of MB2 [4], the major product of territrem B incubated with rat liver microsomal fraction, was determined as a hydroxylation product at the pro S methyl group of C-4 of territrem B.

Permuted isomers of L-R-phosphatidyl-D-myo-inositol trisphosphate (PtdInsP 3 ), including PtdIns-(3,4,5)P 3 , PtdIns(3,4,6)P 3 , PtdIns(3,5,6)P 3 , and PtdIns(4,5,6)P 3 , have been synthesized as part of our effort to understand the underlying principles governing ligand selection for PtdIns(3,4,5)P 3 -specific binding proteins. These PtdInsP 3 isomers are examined by using two PtdIns(3,4,5)P 3 -dependent functional assays: binding to the C-terminal SH2 domain of the p85 regulatory subunit of PI 3-kinase and platelet aggregation. Our data show that all these isomers bind to the SH2 domain with comparable affinity despite variation in the regioisomeric distribution of phosphate functions. Moreover, all these phospholipids are capable of triggering platelet aggregation with the relative potency of PtdIns(3,4,5)P 3 > PtdIns(3,5,6)P 3 > PtdIns(4,5,6)P 3 > PtdIns(3,4,6)P 3 . Evidence suggests that these PtdInsP 3 's facilitate cell aggregation by activating Ca 2+ influx across the plasma membrane. In contrast, other inositol lipids examined including PtdIns(3,4)P 2 , PtdIns-(4,5)P 2 , PtdIns(3)P, and PtdIns(4)P are ineffective in eliciting the aggregation even at much higher concentrations. Taken together, the present data suggest that the charge density on the phosphorylated inositol ring represents a key factor in determining the phosphoinositide binding specificity of target proteins. It is conceivable that the interaction with the PtdIns(3,4,5)P 3 -binding motif requires the participation of all three phosphates on the headgroup of PtdIns(3,4,5)P 3 . Consequently, other membrane phosphoinositides (e.g., the bis-and monophosphates) become thermodynamically unfavorable for the binding to these PtdIns(3,4,5)P 3 targets.

No abstract

The N-homologues and optical isomers of thaliporphine (5a), a potent antiarrhythmic agent, were prepared starting from laurolitsine (1), an abundant aporphine present in Phoebe formosana. Treating N-propylnorglaucine with 90% H2SO4 yielded one additional product, an 11-sulfonyl-1,11-anhydroaporphine. Reaction of N-formylnorglaucine (3a) with 90% H2SO4, however, yielded the 9-sulfonyl-seco product as a major product. Treatment of 3a with 98% H2SO4 yielded pancordine (10), which, upon catalytic hydrogenation, yielded (±)-wilsonirine. (1)H NMR spectroscopic analysis was applied successfully to monitor the optical purity of the crystalline salt while undertaking optical resolution. Thaliporphine (5a) was demonstrated to possess better positive inotropic and less negative chronotropic effects than the left-hand optical isomer and showed the best activity on rat cardiac tissue among the N-homologues prepared.