De novo antimicrobial peptides with the sequences: (KLAKKLA)n, (KLAKLAK)n (where n = 1,2,3), (KALKALK)3, (KLGKKLG)n, and (KAAKKAA)n (where n = 2,3), were prepared as the C-terminus amides. These peptides were designed to be perfectly amphipathic in helical conformations. Peptide antibacterial activity was tested against Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus. Peptide cytotoxicity was tested against human erythrocytes and 3T3 mouse fibroblasts. The 3T3 cell testing was a much more sensitive test of cytotoxicity. The peptides were much less lytic toward human erythrocytes than 3T3 cells. Peptide secondary structure in aqueous solution, sodium dodecylsulfate micelles, and phospholipid vesicles was estimated using circular dichroism spectroscopy. The leucine/alanine-containing 21-mers were bacteriostatic at 3-8 microM and cytotoxic to 3T3 cells at about 10 microM concentrations. The leucine/alanine- or leucine/glycine-containing 14-mers and the leucine/glycine 21-mer were bacteriostatic at 6-22 microM but had much lower cytotoxicity toward 3T3 cells and higher selectivities than the natural antimicrobial peptides magainin 2 amide and cecropin B amide. The 7-mer peptides are devoid of biological activity and of secondary structure in membrane mimetic environments. The 14-mer peptides and the glycine-containing 21-mer show modest levels of helicity in model membranes. The leucine/alanine-containing 21-mer peptides have substantial helicity in model membranes. The propensity to alpha-helical conformation of the peptides in amphipathic media is proportional to their 3T3 cell cytotoxicity.

Intramolecular quenching of tryptophan fluorescence by protein functional groups was studied in a series of rigid cyclic hexapeptides containing a single tryptophan. The solution structure of the canonical peptide c[D-PpYTFWF] (pY, phosphotyrosine) was determined in aqueous solution by 1D- and 2D-(1)H NMR techniques. The peptide backbone has a single predominant conformation. The tryptophan side chain has three chi(1) rotamers: a major chi(1) = -60 degrees rotamer with a population of 0.67, and two minor rotamers of equal population. The peptides have three fluorescence lifetimes of about 3.8, 1.8, and 0.3 ns with relative amplitudes that agree with the chi(1) rotamer populations determined by NMR. The major 3.8-ns lifetime component is assigned to the chi(1) = -60 degrees rotamer. The multiple fluorescence lifetimes are attributed to differences among rotamers in the rate of excited-state electron transfer to peptide bonds. Electron-transfer rates were calculated for the six preferred side chain rotamers using Marcus theory. A simple model with reasonable assumptions gives excellent agreement between observed and calculated lifetimes for the 3.8- and 1.8-ns lifetimes and assigns the 1.8-ns lifetime component to the chi(1) = 180 degrees rotamer. Substitution of phenylalanine by lysine on either side of tryptophan has no effect on fluorescence quantum yield or lifetime, indicating that intramolecular excited-state proton transfer catalyzed by the epsilon-ammonium does not occur in these peptides.

Indoles undergo two isotopically sensitive temperature-dependent fluorescence quenching processes: solvent quenching and excited-state proton transfer. Fluorescence quantum yields of simple indoles in protium and deuterium solvents were measured in the absence and presence of glycine. Photochemical H-D exchange was monitored by NMR and mass spectrometry.Although the fluorescence quantum yield and lifetime of 2-methylindole show large deuterium isotope effects in aqueous solutions, photochemical H-D exchange was not detected after extensive irradiation, whereas, H-D exchange is readily observed for 2-and 3-methylindole in solutions containing glycine. Stern-Volmer plots of glycine quenching data give bimolecular rate constants kq from (0.5-3) X 108 M™1 11s™1 for indoles in water. The kq values of 2-and 3-methylindole are faster in protium than in deuterium solvents. The isotope effect on kq implicates excited-state proton transfer in the collisional quenching mechanism.This contrasts with iodide quenching which has no isotope effect on kq. A glycine derivative lacking the ammonium protons, iV,iV,7V-trimethylglycine, does not quench indole fluorescence. The intermolecular excited-state reaction of 2-and 3-methylindole with 0.3 M glycine-d5 in 50% D20/CD30D induces H-D exchange at three ring carbons. In 2-methylindole the exchange is fastest at C3 and occurs with similar rates at C4 and C7 on the indole ring. The temperature dependence of 3-methylindole fluorescence in 0.5 M glycine was also determined. The large difference in temperature dependence for solvent quenching and glycine quenching causes curvature in the Arrhenius plot. The frequency factor A2 = 7.2 X 1010 s™1 and activation energy E2* = 3.6 kcal/mol for glycine quenching are similar to the values for intramolecular excited-state proton transfer in tryptamine.Possible mechanisms for the excited-state proton transfer reaction and the implications of this reaction for tryptophan fluorescence in proteins are discussed.

Targeted alpha-particle therapy (TAT) aims to selectively deliver radionuclides emitting α-particles (cytotoxic payload) to tumors by chelation to monoclonal antibodies, peptides or small molecules that recognize tumor-associated antigens or cell-surface receptors. Because of the high linear energy transfer (LET) and short range of alpha (α) particles in tissue, cancer cells can be significantly damaged while causing minimal toxicity to surrounding healthy cells. Recent clinical studies have demonstrated the remarkable efficacy of TAT in the treatment of metastatic, castration-resistant prostate cancer. In this comprehensive review, we discuss the current consensus regarding the properties of the α-particle-emitting radionuclides that are potentially relevant for use in the clinic; the TAT-mediated mechanisms responsible for cell death; the different classes of targeting moieties and radiometal chelators available for TAT development; current approaches to calculating radiation dosimetry for TATs; and lead optimization via medicinal chemistry to improve the TAT radiopharmaceutical properties. We have also summarized the use of TATs in pre-clinical and clinical studies to date.

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Ring opening metathesis polymerization (ROMP) has been used to prepare conjugated polymers that contain ferrocene moieties as part of their backbones. The conjugated polymer poly-(ferrocenylenedivinylene) (PFDV) and the analogous unconjugated polymer poly(ferrocenylenebutenylene) (PFB) with chain lengths of greater than 10 were found to be insoluble in typical organic solvents. The conductivities of oxidatively doped films of PFDV and PFB were found to be 10™4 and ™5 ™1 cm™1, respectively. Oxidative doping of the monomer 1,4-( 1, -ferrocenediyl)-1-butene was found to yield conductivities on the order of ™5 ™1 cm™1, supporting interchain hopping as the dominant mechanism for charge carrier movement through these films. The ROMP of monomers octamethyl-l,4-(l,l'ferrocenediyl)-!,3-butadiene and l,4-(l,l'-ferrocenediyl)-l-methoxy-l,3-butadiene was also studied. Although soluble polymer was successfully generated from the latter monomer, no conditions were found under which the octamethyl compound could be polymerized.