Synthesis and Biological Activities of Simplified Analogs of the Natural PKC Ligands,Bryostatin‐1 and Aplysiatoxin

Protein kinase C (PKC) isozymes play central roles in signal transduction on the cell surface and could serve as promising therapeutic targets of intractable diseases like cancer, Alzheimer's disease, and acquired immunodeficiency syndrome (AIDS). Although natural PKC ligands like phorbol esters, ingenol esters, and teleocidins have the potential to become therapeutic leads, most of them are potent tumor promoters in mouse skin. By contrast, bryostatin‐1 (bryo‐1) isolated from marine bryozoan is a potent PKC activator with little tumor‐promoting activity. Numerous investigations have suggested bryo‐1 to be a promising therapeutic candidate for the above intractable diseases. However, there is a supply problem of bryo‐1 both from natural sources and by organic synthesis. Recent approaches on the synthesis of bryo‐1 have focused on its simplification, without decreasing the ability to activate PKC isozymes, to develop new medicinal leads. Another approach is to use the skeleton of natural PKC ligands to develop bryo‐1 surrogates. We have recently identified 10‐methyl‐aplog‐1 ( 26 ), a simplified analog of tumor‐promoting aplysiatoxin (ATX), as a possible therapeutic lead for cancer. This review summarizes recent investigations on the simplification of natural PKC ligands, bryo‐1 and ATX, to develop potential medicinal leads.     

Synthesis of medium-sized carbocyclic ketones via the intramolecular B-alkyl Liebeskind-Srogl coupling reaction

Synthesis of medium-sized carbocyclic ketones via the intramolecular B-alkyl Liebeskind-Srogl coupling reaction is described. The sequence of hydroboration of ω-alkenyl thiol ester with 9-BBN and the Liebeskind-Srogl reaction results in the formation of medium-sized carbocyclic ketones with good yield.     

Pd(II)-SPRIX catalyzed enantioselective construction of pyrrolizines/pyrroloindoles employing molecular oxygen as the sole oxidant

Pd(II)-SPRIX catalyst coupled with an environmentally benign molecular oxygen as the sole oxidant successfully exploited the construction of pyrrolizines/pyrroloindoles, imperative scaffolds of bio-potent molecules through intramolecular C-N and C-C bond forming reactions in good yields with appreciable enantioselectivities.     

Inter-atomic distance and temperature dependence of correlation effects among thermal displacements

Diffuse neutron scattering from a powder AgCl was measured from 10 to 260 K. The correlation effects among thermal displacements of atoms were obtained from the diffraction data. The values of the correlation effects decrease rapidly with the increase of the inter-atomic distance. The values also decrease with the decrease of temperature. The similar tendency was also obtained in AgBr and CuI. The temperature dependence of the values of correlation effects agrees with the result by a simple Debye model of lattice vibrations.     

Determination of fluoxetine enantiomers in rat plasma by pre-column fluorescence derivatization and column-switching high-performance liquid chromatography

A column-switching HPLC method employing both octadecylsilica (ODS) and chiral columns with fluorescence detection was developed for the determination of enantiomer of fluoxetine (FLX), an antidepressant drug, in rat plasma. Racemic FLX was derivatized with a fluorescent reagent, 4-(N-chloroformylmethyl-N-methyl)amino-7-nitro-2,1,3-benzoxadiazole (NBD-COCl) or 4-(N-chloroformylmethyl-N-methyl)amino-7-N,N-dimethylaminosulfonyl-2,1,3-benzoxadiazole (DBD-COCl) and the enantiomeric separation of the resultant derivatives was examined on an amylose-based chiral column (CHIRALPAK AD-RH) in the reversed-phase mode. The derivative with NBD-COCl (NBD-FLX) showed a sufficient separation factor (a) and resolution (Rs) compared with that with DBD-COCl. Thus, FLX was derivatized with NBD-COCl and the resultant NBD-FLX was first quantified on the ODS column and then introduced to the CHIRALPAK AD-RH column via a six-port switching valve to examine the enantiomeric ratio. The intra- and inter-day accuracy (97.6-112.7%) and precision (1.47-10.60%) were satisfactory in the range 10-1000 nM FLX and the limit of quantification was approximately 10 nM. The absolute recoveries of FLX with hexane from rat plasma were in the range 87.5-92.2% (n = 3). The method was applied to determine FLX enantiomers in the plasma of rats administered FLX orally, and it was shown that the R-isomer was eliminated faster than the S-isomer.     

Sorption and diffusion of water vapor in polyimide films

Sorption and diffusion of water vapor are investigated gravimetrically for polyimide films. The activity dependence of the solubility and diffusion coefficients, S and D, respectively, is classified under four types: (1) constant S and D type, (2) dual-mode sorption and transport type, (3) dual-mode type followed by a deviation due to a plasticization effect at high vapor activity, and (4) constant S and D type followed by a deviation due to water cluster formation at high activity. For the dual-mode type, the Henry's law component is much larger than the Langmuir component except at low activity, and therefore deviation in behavior from the first type is small. S is larger for polyimides with higher content of polar groups such as carbonyl, carboxyl, and sulfonyl. D is larger for polyimides with a higher fraction of free space, with some exceptions. The polyimide from 3,3′,4,4′-biphenyltetracarboxylic dianhydride and dimethyl-3,7-diaminodibenzothiophene-5, 5-dioxide belongs to the third type and displays both large S and large D. The polyimide from 2,2-bis(3,4-dicarboxyphenyl) hexafluoropropane dianhydride and 4,4′-oxydianiline belongs to the fourth type, and has the largest D but rather small S because of the hydrophobic C(CF₃)₂ groups. © 1992 John Wiley & Sons, Inc.