Synthesis and biological evaluation of novel cryptophycin analogs with modification in the beta-alanine region.

Structure modification of the beta-alanine region (fragment C) of the potent antimitotic agent cryptophycin was investigated. This includes: (1) introduction of substituents at the previously unsubstituted C7 position of the macrolide ring and (2) replacement of the (2R)-3-amino-2-methyl-propanoic acid (beta-alanine) with various (1)-amino acids to give the corresponding 15-membered unnatural cryptophycin analogs.

An artificial neural network simulating performance of normal subjects and schizophrenics on the Wisconsin Card Sorting Test.

Mental diseases such as schizophrenia are being modeled by artificial neural networks in an attempt to understand the underlying neuropathological processes. We studied hospitalized psychiatric patients that met the DSM-IIIR criteria for schizophrenia (N=19), and normal subjects with no psychiatric history (N=18). Performance on the Wisconsin Card Sorting Test (WCST) by schizophrenic patients was poorer than normal subjects as estimated by various scoring measurements. We then modeled an artificial neural network, motivated by biological considerations, that is able to simulate performance of normals and schizophrenics on the WCST. In order to model the complex nature of the WCST, we designed novel learning rules based on non-associative learning paradigms. We found that there must be a minimum amount of noise, or inherent synaptic instability, for our model to perform similar to schizophrenics.

Maintenance of training effects on the Wisconsin Card Sorting Test by patients with schizophrenia or affective disorders.

The authors used the Wisconsin Card Sorting Test to study 50 hospitalized psychiatric patients: 28 with schizophrenia, 17 with affective disorders, and five with schizoaffective disorder. The schizophrenic patients performed significantly more poorly than the patients with affective disorders. Both groups of patients improved when given additional instructions. The schizophrenic patients maintained their improvement when retested approximately 6 weeks later. The results suggest that factors other than frontal cortex dysfunction are involved in schizophrenic patients' performance on the Wisconsin Card Sorting Test.

Assignments of 31P NMR resonances in oligodeoxyribonucleotides: origin of sequence-specific variations in the deoxyribose phosphate backbone conformation and the 31P chemical shifts of double-helical nucleic acids.

It is now possible to unambiguously assign all 31P resonances in the 31P NMR spectra of oligonucleotides by either two-dimensional NMR techniques or site-specific 17O labeling of the phosphoryl groups. Assignment of 31P signals in tetradecamer duplexes, (dTGTGAGCGCTCACA)2, (dTAT-GAGCGCTCATA)2, (dTCTGAGCGCTCAGA)2, and (dTGTGTGCGCACACA)2, and the dodecamer duplex d(CGTGAATTCGCG)2 containing one base-pair mismatch, combined with additional assignments in the literature, has allowed an analysis of the origin of the sequence-specific variation in 31P chemical shifts of DNA. The 31P chemical shifts of duplex B-DNA phosphates correlate reasonably well with some aspects of the Dickerson/Calladine sum function for variation in the helical twist of the oligonucleotides. Correlations between experimentally measured P-O and C-O torsional angles and results from molecular mechanics energy minimization calculations show that these results are consistent with the hypothesis that sequence-specific variations in 31P chemical shifts are attributable to sequence-specific changes in the deoxyribose phosphate backbone. The major structural variation responsible for these 31P shift perturbations appears to be P-O and C-O backbone torsional angles which respond to changes in the local helical structure. Furthermore, 31P chemical shifts and JH3'-P coupling constants both indicate that these backbone torsional angle variations are more permissive at the ends of the double helix than in the middle. Thus 31P NMR spectroscopy and molecular mechanics energy minimization calculations appear to be able to support sequence-specific structural variations along the backbone of the DNA in solution.

Effect of 5-hydroxytryptophan on H-reflex recovery curves in normal subjects and patients with affective disorders.

The effect of the serotonin precursor DL-5-hydroxytryptophan (5-HTP) on the Hoffmann reflex recovery curve (HRRC) was studied in normal subjects and patients with affective illness. 5-HTP significantly decreased the HRRC in normal controls and in depressed and manic patients receiving treatment with lithium or antidepressants. 5-HTP increased the HRRC in unmedicated depressed and manic patients. These results provide further evidence for a serotonergic abnormality in the affective disorders.

Theory and modeling of stereoselective organic reactions.

Theoretical investigations of the transition structures of additions and cycloadditions reveal details about the geometries of bond-forming processes that are not directly accessible by experiment. The conformational analysis of transition states has been developed from theoretical generalizations about the preferred angle of attack by reagents on multiple bonds and predictions of conformations with respect to partially formed bonds. Qualitative rules for the prediction of the stereochemistries of organic reactions have been devised, and semi-empirical computational models have also been developed to predict the stereoselectivities of reactions of large organic molecules, such as nucleophilic additions to carbonyls, electrophilic hydroborations and cycloadditions, and intramolecular radical additions and cycloadditions.