Judith L. Flippen-Anderson

Synthesis of polyazapolycyclic caged polynitramines

Abstract Syntheses of new polyazapolycyclic caged polynitramines are described. Sequentially reacting 4,10-dibenzyl-2,6,8,12-tetraacetyl-2,4,6,8,10,12-hexaazaisowurtzitane (5a) with NOBF4 and NO2BF4 in sulfolane solvent produces 2,4,6,8,10,12-hexanitro-2,4,6,8,10,12-hexaazaisowurtzitane (2,4,6,8,10,12-hexanitro-2,4,6,8,10,12-hexaazatetracyclo-[5.5.0.05,9.03,11]dodecane, 6). Syntheses of two new polyazapolycyclic caged trinitramines, 3,5,12-trinitro-3,5,12-triazawurtzitane (7a) and 2,4,10-trinitro-2,4,10-triazaadamantane (12a), as well as their labile parent secondary amines, are discussed. A new caged polynitrosamine, 3,5,12-trinitroso-3,5,12-triazawurtzitane (7d), has been obtained by ring-cleavage nitrosation of the new hexamine-wurtzitane compound 3,5,7,9-tetraazahexacyclo-[9.3.1.13,7.02,9.04,13.05,10]-hexadecane (10).

Iron(III) complexes of some thiosemicarbazones derived from 2-acetylpyridine, its 6-methyl derivative and itsN-oxide

SummaryA series of iron(III) complexes of thiosemicarbazones derived from 2-acetylpyridine, 6-methyl-2-acetylpyridine and 2-acetylpyridineN-oxide have been prepared from Fe(ClO4)3 and FeCl3. All of the isolated solids have cations involving two monobasic tridentate ligands, and either perchlorate or tetrachloroferrate(III) anions and are 1∶1 electrolytes. Coordinationvia the pyridine nitrogen (or theN-oxide oxygen), the imine nitrogen and the sulphur atom are confirmed by infrared spectra and x-ray diffraction. The presence of two different iron(III) species is indicated by the electron spin resonance spectra of the tetrachloroferrate(III) solids. E.s.r. along with electronic spectra prove the spin-paired configuration of these cationic iron(III) complexes.

Synthesis and biological activity of novel neuroprotective diketopiperazines.

The cyclic dipeptide cyclo[His-Pro] (CHP) is synthesized endogenously de novo and as a breakdown product of thyrotropin-releasing hormone (TRH), a tripeptide with known neuroprotective activity. We synthesized two isomeric compounds based on the structure of CHP, in which the histidine residue was replaced by 3,5-di-tert-butyltyrosine (DBT), a phenolic amino acid that traps reactive oxygen species. These novel diketopiperazines prevented neuronal death in an in vitro model of traumatic injury. In addition, they dose-dependently prevented death caused by the direct induction of free radicals, and by calcium mobilization through an agent that evokes rapid, necrotic death. The drugs showed activity in the latter system at picomolar concentrations. The neuroprotective profile of these compounds suggests that they may be useful as treatments for neuronal degeneration in vivo, potentially through several different mechanisms.

A new role for l-ascorbic acid: michael donor to α,β-unsaturated carbonyl compounds

Abstract In a novel Michael-type reaction L-ascorbic acid ( 1 ) undergoes addition to acrolein to give the tricyclic hemiacetal lactone 3 . The constitution and relative configuration of 3 was studied by a combination of NMR and IR spectroscopy. Ultimately, the structure of 3 was determined by X-ray crystallography. The absolute stereochemistry follows from the known chirality of C-4 and C-5 of L-ascorbic acid. A mechanism for the reaction, including its steric course, is proposed. Methyl vinyl ketone reacts with 1 in a similar fashion to give diketo lactone derivative 4 , Upon the action of methanolic hydrogen chloride on 4 one anomer, the tricyclic methyl ketal lactone 5 , forms. Structure 5 is closely related to 3 . Synthetic and possible biological applications of the new reaction are discussed.

Determining the occurrence of a 3 10 -helix and an α-helix in two different segments of a lipopeptaibol antibiotic using TOAC, a nitroxide spin-labeled C α -tetrasubstituted α-aminoacid

Trichogin GA IV is a 11-residue lipopeptaibol antibiotic exhibiting membrane modifying properties. We synthesized step-by-step by solution methods three trichogin analogues, each with a double Aib (alpha-aminoisobutyric acid)-->TOAC (2,2,6,6-tetramethylpiperidine-1-oxyl-4-amino-4-carboxylic acid) replacement. The strict similarity in the conformational propensities of Aib and TOAC allowed us to exploit these analogues in a detailed investigation of the conformation of this lipopeptaibol in different organic solvents and in a membrane-mimetic environment using in particular the double spin labeling ESR technique. We conclude that the secondary structure in solution remains essentially unchanged if compared to that previously found in the crystal state for trichogin. More specifically, the N-terminal region of the peptide folds in a 3(10)-helix, while the central and C-terminal regions are mainly alpha-helical. An additional, significant proof for the modest plasticity of the trichogin structure was obtained by an X-ray diffraction analysis of the nOct-[TOAC4,8, Leu-OMe11] analogue. For the three analogues permeability measurements revealed membrane-modifying properties comparable to those of natural trichogin.

Crystallographic structure of a helical lipopeptaibol antibiotic analogue

An X-ray diffraction analysis of the [Fmoc0, TOAC4,8, Leu-OMe11]analogue of the lipopeptaibol antibiotic trichogin A Iv shows that the undecapeptide is folded in a right-handed, mixed α/310-helix. The helical molecules are connected in a head-to-tail arrangement along the b-axis through C=O...H-N intermolecular H-bonding. This packing mode generates a hydrophobic cavity where the Fmoc Nα-protecting groups are accommodated. The distances and angles between the nitroxide groups of the two TOAC residues, separated by one turn of the α-helix, have been determined.

Synthesis and crystal structure of methyl 4,6-dideoxy-4-(3-deoxy-l-glycero-tetronamido) - 2-O-methyl-α-d-mannopyranoside, the methyl α-glycoside of the terminal unit, and presumed antigenic determinant, of the O-specific polysaccharide of Vibrio cholerae O:1, serotype Ogawa

Methyl 4-azido-4,6-dideoxy-3-O-benzyl-alpha-D-mannopyranoside and its analogous 3-O-(4-methoxybenzyl) derivative were methylated and the 2-O-methyl derivatives formed were converted into methyl 4-amino-4,6-dideoxy-2-O-methyl-alpha-D- mannopyranoside [sequence: see text]. Reaction of the latter with 3-deoxy-L-glycero-tetronolactone gave the methyl glycoside of 4,6-dideoxy-4-(3-deoxy-L-glycero- tetronamido)-2-methyl-alpha-D-mannopyranose [sequence: see text], the monosaccharide that is reported to be the terminal moiety of the O-specific polysaccharide of Vibrio cholerae O:1, serotype Ogawa. The unit cell packing of the compound, which crystallized as a monohydrate, differs from that of the previously described crystalline compound lacking the 2-O-methyl group. The unmethylated sugar is the terminal moiety of the O-specific polysaccharide of Vibrio cholerae O:1, serotype Inaba. The crystal structure of methyl 4,6-dideoxy-2-O- methyl-4-trifluoroacetamido-alpha-D-mannopyranoside [sequence: see text] is also described.

Rational design, synthesis, and biological evaluation of rigid pyrrolidone analogues as potential inhibitors of prostate cancer cell growth.

In view of its role in tumor promotion and signal transduction, protein kinase C (PKC) has proven to be an exciting target for cancer therapy. With the aid of molecular modeling, we rationally designed and stereoselectively synthesized a new class of rigidified pyrrolidone-based PKC activators. Pyrrolidone 15 was found to exhibit reasonable affinity for PKCdelta, with lower affinity for the other isozymes tested. Pyrrolidone 2 causes the dose-dependent induction of apoptosis in LNCaP prostate cancer cells. This apoptotic effect could be markedly potentiated by the use of LNCaP cells overexpressing the PKCalpha or delta isozymes.

X-ray structures of the ? opioid antagonist TIPP and a protected derivative of the ? opioid antagonist ICI 174,864

The solid state structures of two synthetic opioid peptides have been determined by X-ray single crystal analysis. The first X-ray structure is that of N,N-diallyl-(O-t-butyl)-Tyr-Aib-Aib-Phe-Leu-OMe (RTI02), a protected derivative of the δ-receptor selective antagonist ICI 174,864 (N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH. ICI 174,864 is one of a series of rationally designed Aib-substituted enkephalin analogs which have shown site-specific antagonist properties. The second compound, the tetrapeptide Tyr-Tic-Phe-Phe-OH (TIPP), is one of a family of linear peptides containing the conformationally restricted Tic residue (tetrahydroisoquinoline-3-carboxylic acid). TIPP exhibits high affinity, selectivity and antagonism for the δ-receptor. Crystals of both peptides were obtained by slow evaporation and found to be monoclinic in space group P21. Unit cell dimensions for RTI02 were: a=13.619(4) Å, b=12.467(3) Å, c=13.750(4) Å, β=96.03(4)o and V=2322(1) Å3. The asymmetric unit contained one molecule of RTI02 and one molecule of methanol, giving a calculated density of 1.156 g cm-3. Unit cell dimensions for TIPP were: a=8.879(5) Å, b=20.146(8) Å, c=12.710(6) Å, β=107.89(2)o and V=2164(2) Å3. The asymmetric unit contained one molecule of TIPP and three molecules of acetic acid, giving a calculated density of 1.251 g cm-3. The RTI02 backbone has a double β-bend, stabilized by two intramolecular hydrogen bonds. The TIPP backbone is also folded, but with only a single bend, stabilized by one intramolecular hydrogen bond and several hydrogen bonds to solvent molecules. Both compounds contain aromatic rings in close vicinity (4–6 Å).

2,3:6,7-Bis(2′,3′-quinolino)pentacyclo[6.5.0.04,12.05,10.09,13]tridecane

Abstract The title compound (4) was synthesized by two sequential Friedlaender condensations between pentacyclic bis(ketoester) 2 and o-aminobenzaldehyde. The dihedral angle between the two quinoline rings in 4 is 76.4°; the nonbonded NXXXN interatomic distance in 4 is 4.32 A.