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A series of novel 1,4-diaryl-2-azetidinones were synthesized and evaluated for antiproliferative activity, cell cycle effects, and apoptosis induction. Strong cytotoxicity was observed with the best compounds (±)-trans-20, (±)-trans-21, and enantiomers (+)-trans-20 and (+)-trans-21, which exhibited IC(50) values of 3-13 nM against duodenal adenocarcinoma cells. They induced inhibition of tubulin polymerization and subsequent G2/M arrest. This effect was accompanied by activation of AMP-activated protein kinase (AMPK), activation of caspase-3, and induction of apoptosis. Additionally, the most potent compounds displayed antiproliferative activity against different colon cancer cell lines, opening the route to a new class of potential therapeutic agents against colon cancer.

A series of macrocyclic Eu, Gd, and Tb complexes has been prepared in which the intramolecular ligation of a beta-arylsulfonamide nitrogen is rendered pH-dependent, giving rise to changes in the hydration state, q, at the lanthanide center. In complexes based on DO3A, variation of the p-substituent in the arylsulfonamide moiety determines the apparent protonation constant log K(MLH) with values of 5.7, 6.4, and 6.7 for the -CF(3), -Me, and -OMe substituents, respectively. Introduction of three beta-carboxyalkyl substituents, alpha to three ring nitrogens, inhibits displacement of the bound water by added protein and also suppresses intermolecular binding by endogenous anions (lactate, HCO(3)(-)). Measurements of the pH dependence of the form and intensity of the Eu complexes revealed that intramolecular carboxylate coordination occurred competitively. This was reduced either by enhancing the electron density at the sulfonamide nitrogen or by enlarging the chelate ring from 7--8. Amplification of the relaxivity changes in the pH range 8--5 occurred on protein binding, and over the pH range 7.4--6.8 a 48% change in relaxivity was defined for [Gd.3a] (298 K, 65.6 MHz) in 50% human serum solution.

A novel ligand based on a pyridine-containing macrocycle bearing two acetic and one methylenephosphonic arms (PCP2A) has been synthesized. An efficient synthesis of PCP2A is based on the macrocyclization reaction between 2,6-bis(chloromethyl)pyridine and a 1,4, 7-triazaheptane derivative bearing a methylenephosphonate group on N-4. The Gd(III) complex of PCP2A displays characteristic properties which make it a very promising contrast agent for improved applications in magnetic resonance imaging. In fact it shows (i) a very high stability constant (log K(GdPCP2A) = 23.4) which should guarantee against the in vivo release of toxic free Gd(III) ions and free ligand molecules and (ii) a relaxivity that is about 2 times higher than the values reported for contrast agents currently used in the clinical practice. Its high relaxivity is the result of the presence of two water molecules in the inner coordination sphere and a significant contribution from water molecule(s) hydrogen bonded to the phosphonate group. Moreover, the inner sphere water molecules are involved in an exchange with the bulk water which is relatively fast. This property is important for the attainment of an even higher relaxivity once the molecular reorientation rate of the [GdPCP2A(H(2)O)(2)](-) moiety is lengthened by means of conjugation to a macromolecular substrate.

The synthesis of three triazamacrocycles containing the pyridine moiety and three acetate pendant arms (PCTA) is reported. The three systems differ due to the number of carbon atoms in the macrocyclic ring forming ligands PCTA-[12], -[13], and -[14], endowed with different coordination capabilities toward lanthanide(III) ions. Microscopic protonation sequences for the three ligands have been investigated by (1)H NMR spectroscopy. Complexes of PCTA-[12], -[13], and -[14] with La(III), Gd(III), and Lu(III) have been prepared. Relaxometric measurements on the aqueous solutions of the paramagnetic Gd(III) complexes in the presence of competitive ligands gave the following stability constants: log K(f) = 20.8 for Gd-PCTA-[12], log K(f) = 19.3 for GdPCTA-[13], and log K(f) = 12.5 for GdPCTA-[14]. The measurement of water relaxation rates indicated a tendency to decrease the degree of hydration upon increasing the ring size. The VT (1)H and (13)C-NMR spectra of the diamagnetic La(III) and Lu(III) complexes exhibit a large variability of the solution structures dictated by the matching of the size of the lanthanide ion and the macrocyclic cavity. This results in noticeable differences in their stereochemical nonrigidity, hydration state, and thermodynamic stability. To some extent the changes observed in continuing from the 12-14-membered ring macrocyclic complexes parallels the behaviors shown by the octacoordinated lanthanide(III) complexes with DOTA and TETA. GdPCTA-[12] and -[13] feature promising properties in view of their possible use as contrast agents for magnetic resonance imaging.