Biomedical subjects

Kenneth I Hardcastle

Publications and source records attributed to Kenneth I Hardcastle.

21 records · Page 2Linked to original sources

PubMed2002

Endo-oxacyclizations of polyepoxides: biomimetic synthesis of fused polycyclic ethers.

Boron trifluoride-etherate promotes the endo-selective oxacyclization of polyepoxides derived from various acyclic terpenoid polyalkenes, including geraniol, farnesol, and geranylgeraniol, providing an efficient and stereoselective synthesis of substituted oxepanes and fused polyoxepanes. The mechanism of the oxacyclization reaction probably involves intramolecular nucleophilic addition of epoxide oxygen to open another epoxide that is activated as an electrophile by the Lewis acid. These oxacyclizations proceed stereospecifically with inversion of configuration upon opening of each epoxide to provide trans-fused polycyclic products. The oxacyclization cascade is terminated by a tethered nucleophile, which may be the carbonyl oxygen of a ketone, ester, or carbonate, or a trisubstituted alkene. The best oxacyclization yields are generally observed with tert-butyl carbonate as the terminating nucleophile, although in some cases the oxacyclization products include formation of tert-butyl ethers as a minor product. The oxacyclization transformations described herein may mimic ring-forming steps in the biosynthesis of trans-syn-trans-fused polycyclic ether marine natural products.

Biological Factors↗

PubMed2002

Molecular dynamics simulation of [Gd(egta)(H(2)O)](-) in aqueous solution: internal motions of the poly(amino carboxylate) and water ligands, and rotational correlation times.

Molecular dynamics simulations of [Gd(egta)(H(2)O)](-) (egta(4-)=3,12-bis(carboxymethyl)-6,9-dioxa-3,12-diazatetradecanedioate(4-)) have been performed without any artificial constraint on the first coordination sphere, such as covalent bonds between the Gd(3+) and the coordination sites. Two new crystallographic structures were determined for this gadolinium chelate and used to start two molecular dynamics simulations. [Gd(egta)(H(2)O)](-) and [Gd(egta)](-) were both observed during the simulations, with a mean volume for the reaction of dissociation [Gd(egta)(H(2)O)](-)-->[Gd(egta)](-)+H(2)O of +7.2 cm(3)mol(-1), which corroborates the previously published experimental value of +10.5 cm(3)mol(-1). Changes in the conformation of the complex with the inversion of several dihedral angles are observed in the simulations independently from the water dissociation. Very fast changes of the third-order rotation axis direction of the Gd(3+) coordination polyhedron (of symmetry D(3h)) are observed during the simulations and are related to the mechanism of electronic relaxation of the complex. Different rotational correlation times (tau(R)) were calculated from the simulations on various observables of the complex. Protons of the inner sphere have different tau(R). The mean tau(R) of the two Gd-HW(HW=hydrogen of water molecule) vectors is 72% lower than tau(R) of the complex, and 75% lower than tau(R) of the vector Gd-OW (OW=oxygen of water molecule). This discrimination of the tumbling rates should be taken into account in future global (17)O NMR, EPR and NMRD (nuclear magnetic relaxation dispersion) data analysis.

Journal Article↗

PubMedDate not supplied

PAMAM dendrimeric conjugates with a Gd-DOTA phosphinate derivative and their adducts with polyaminoacids: the interplay of global motion, internal rotation, and fast water exchange.

A series of dendrimeric conjugates based on a PAMAM (polyamidoamine) backbone with macrocyclic Gd-DO3A-P(ABn) complexes (monophosphinated analogue of DOTA) was prepared. The chelates were covalently attached to the G1-, G2-, and G4-PAMAM dendrimers through a thiourea linker in high loads (>90%). The prepared conjugates G1-(Gd-DO3A-P(BnN{CS}))(8), G2-(Gd-DO3A-P(BnN{CS}))(16), and G4-(Gd-DO3A-P(BnN{CS}))(59) showed relaxivities of 10.1, 14.1, and 18.6 s(-)(1) mM(-)(1) at 20 MHz and 37 degrees C and pH = 7.5, respectively. A variable-pH study (range 2-12) revealed up to 30% increase in the relaxivity at low pH for the G2-(Gd-DO3A-P(BnN{CS}))(16) conjugate. As confirmed by (1)H NMR titration of the unmodified G2 dendrimer, this is due to protonation of core tertiary amines leading to a more open and rigid structure. The variable-temperature (17)O NMR and (1)H NMRD relaxometric studies confirmed that the relaxivity is not controlled by water exchange but by rotational dynamics. A multiparametrical data evaluation using the Lipari-Szabo approach revealed that the water residence lifetime, (298)tau(M), for the conjugates studied was ca. 45-70 ns, which is longer than the value found for the monomeric model compound Gd-DO3A-P(ABn) (16 ns) but short enough so as not to limit the relaxivity. The global rotational correlation time, (298)tau(Rg), varied from 1.5 to 3.1 ns and seemed to indicate a sufficiently slow molecular tumbling to achieve the high relaxivities measured; however, the rigidity factor S(2) (approximately 0.26), describing the internal flexibility, was far from optimum. The overall relaxivity was significantly increased (e.g. by a factor of 1.8 for the G1-(Gd-DO3A-P(BnN{CS}))(8) conjugate) when a positively charged polyaminoacid like poly(Arg) or poly(Lys) was added to the conjugate solutions. The electrostatic interactions partially "freeze" the internal mobility of the conjugate and also slow down global motion. This assumption was confirmed by an evaluation of (1)H relaxometric data obtained for the G2-(Gd-DO3A-P(BnN{CS}))(16)-poly(Lys)(59) adduct. Importantly, it was proved that the adduct formation did not hamper the water exchange process.

Amino Acids↗