Asynthetic peptide that inhibits the growth of estrogen receptor positive (ER+) human breast cancers, growing as xenografts in mice, has been reported. The cyclic 9-mer peptide, cyclo[EMTOVNOGQ], is derived from alpha-fetoprotein (AFP), a safe, naturally occurring human protein produced during pregnancy, which itself has anti-estrogenic and anti-breast cancer activity. To determine the pharmacophore of the peptide, a series of analogs was prepared using solid-phase peptide synthesis. Analogs were screened in a 1-day bioassay, which assessed their ability to inhibit the estrogen-stimulated growth of uterus in immature mice. Deletion of glutamic acid, Glu1, abolished activity of the peptide, but glutamine (Gln) or asparagine (Asn) could be substituted for Glu1 without loss of activity. Methionine (Met2) was replaced with lysine (Lys) or tyrosine (Tyr) with retention of activity. Substitution of Lys for Met2 in the cyclic molecule resulted in a compound with activity comparable with the Met2-containing cyclic molecule, but with a greater than twofold increase in purity and corresponding increase in yield. This Lys analog demonstrated anti-breast cancer activity equivalent to that of the original Met-containing peptide. Therefore, Met2 is not essential for biologic activity and substitution of Lys is synthetically advantageous. Threonine (Thr3) is a nonessential site, and can be substituted with serine (Ser), valine (Val), or alanine (Ala) without significant loss of activity. Hydroxyproline (Hyp), substituted in place of the naturally occurring prolines (Pro4, Pro7), allowed retention of activity and increased stability of the peptide during storage. Replacement of the first Pro (Pro4) with Ser maintains the activity of the peptide, but substitution of Ser for the second Pro (Pro7) abolishes the activity of the peptide. This suggests that the imino acid at residue 7 is important for conformation of the peptide, and the backbone atoms are part of the pharmacophore, but Pro4 is not essential. Valine (Val5) can be substituted only with branched-chain amino acids (isoleucine, leucine or Thr); replacement by d-valine or Ala resulted in loss of biologic activity. Thus, for this site, the bulky branched side chain is essential. Asparagine (Asn6) is essential for activity. Substitution with Gln or aspartic acid (Asp), resulted in reduction of biologic activity. Removal of glycine (Gly8) resulted in a loss of activity but nonconservative substitutions can be made at this site without a loss of activity indicating that it is not part of the pharmacophore. Cyclization of the peptide is facilitated by addition of Gln9, but this residue does not occur in AFP nor is it necessary for activity. Gln9 can be replaced with Asn, resulting in a molecule with similar activity. These data indicate that the pharmacophore of the peptide includes side chains of Val5 and Asn6 and backbone atoms contributed by Thr3, Val5, Asn6, Hyp7 and Gly8. Met2 and Gln9 can be modified or replaced. Glu1 can be replaced with charged amino acids, and is not l...
Acetylene and ethylene complexes of Cu and Ag atoms were generated in rare-gas matrices and were examined by electron spin resonance spectroscopy. The study revealed that Cu atoms form both mono-and diligand complexes, Cu-(C2H2)"=i.2 and Cu(C2H4)"=i.2, while Ag atoms form a bona fide complex with a diethylene group only, hence Ag(C2H4)2. The g tensors and the hyperfine coupling tensors to the metal and hydrogen nuclei were determined and analyzed. It is shown that all these complexes have -coordinated structures consistent with the Dewar-Chatt-Duncanson scheme. The semifilled orbital of the monoligand complexes is an s-p hybridized orbital of the metal atom pointing away from the ligand moiety. The diligand complexes have £>2/j symmetry; the metal atom is flanked by two ligand molecules oriented parallel to each other. The semifilled orbital of the latter is essentially the p orbital of the metal atom parallel to the ligand molecules. In the case of Ag and acetylene, when allowed to react in the vapor phase, an Ag-acetylene adduct having the vinyl structure was generated.
TiO (and perhaps Ti02), ZrO, and HfO, prepared by vaporization of the solid oxides at ~2500°K., have been trapped in neon and argon matrices at 4 and 20°K. The ^-substituted molecules were also prepared by passing 1802 over the corresponding heated metal. The electronic spectra of these molecules indicate that ZrO and probably HfO have a 1 + ground state as opposed to the known 3 ground state of TiO. For TiO, the a and y triplet-triplet gas transitions are observed, as expected. Only one other transition appears, at 6124 A., corresponding to Coheur's y' system or to one of Rosen's tentatively assigned systems. The triplet systems of ZrO are not observed, but the singlet A bands in the gas, assigned here as 1 + •*-X^+, appear strongly in the matrices. The spectrum of HfO is discussed in relation to that of ZrO, and the energy levels of the three oxides assigned to configurations of a simple molecular orbital scheme. The infrared spectra of TiO, ZrO, and HfO in neon matrices yield ground state frequencies of 1005, 975, and 974 cm.-1, respectively; the gas values are 999.2, 969.7, and 967.6 (?) cm.-1.
Electron spin resonance spectra were observed on Cu, Ag, and Au atoms isolated in Ne, Ar, Kr, and Xe matrices at ∼ 4°K. The hyperfine coupling constants and the g values were determined and examined for the matrix effect. With xenon matrices a superhyperfine structure with magnetic xenon nuclei was partially resolved, and by means of computer simulation, it was shown that these atoms are substitutionally incorporated within the Xe lattice. Also an evidence for atom-vacancy pairing was observed for Cu in Ne matrix.
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