Biomedical subjects

A C Morgan

Publications and source records attributed to A C Morgan.

75 records · Page 5Linked to original sources

PubMedDate not supplied

Synthesis and nca-radioiodination of arylstannyl-cobalamin conjugates. Evaluation of aryliodo-cobalamin conjugate binding to transcobalamin II and biodistribution in mice.

A new method of preparing radiolabeled cobalamin derivatives has been developed. The method involves the use of cobalamin-tri-n-butylstannyl hippurate conjugates as intermediates to obtain radioiodinated cobalamin-iodohippurate conjugates. The arylstannyl functionality was used as an exchangeable group to obtain high specific activity radioiodinations and to circumvent some deleterious side reactions common to cobalamins under electrophilic iodination conditions. The first step in the synthesis of tri-n--butylstannyl hippurate conjugates was to obtain free carboxylate groups on the cobalamin moiety. This was accomplished by mild acid hydrolysis of the b-, d-, or e-propionamide side chains on the corrin ring, followed by careful separation of the isomeric products. The second step was to couple a linking molecule (diaminododecane) to the carboxylate. The final step was to conjugate p-tri-n-butylstannyl hippurate to the cobalamin-diaminododecane adduct. All three isomeric cobalamin-p-tri-n-butylstannyl hippurate conjugates were prepared, as were the corresponding cobalamin-p-iodohippurate conjugates (HPLC standards). Radioiodination reactions were conducted with N-chlorosuccinimide and Na[*I]I in Me OH using conditions previously developed for arylstannylations. However, unlike the previous reactions, a key factor in obtaining the desired radioiodinated cobalamins was that the reaction be conducted under neutral conditions. Isolated yields of 40-65% were obtained for all three cobalamin isomers. Specific activities of 10-33% theoretical were obtained for the radioiodinated cobalamins. Evaluation of competitive binding of (nonradioactive) cobalamin-iodohippurate conjugates with recombinant human transcobalamin II showed that the e-isomer bound nearly as well as [57Co]cyanocobalamin (50%), whereas the b-isomer had decreased binding (6%) and the d-isomer was significantly decreased in its binding (0.7%). Two biodistributions of the radioiodinated e-isomer were conducted in athymic mice. One biodistribution investigated tissue localization in mice bearing a renal cell carcinoma xenograft, and the other biodistribution investigated tissue localization when the radioiodinated cyanocobalamin was mixed with 1% BSA prior to injection. A comparison of the results of the two biodistributions and a discussion of how they relate to previous [57/60Co]cyanocobalamin biodistributions are provided.

Animals↗

PubMedDate not supplied

Synthesis of cobalamin dimers using isophthalate cross-linking of corrin ring carboxylates and evaluation of their binding to transcobalamin II.

Several cobalamin (Cbl) dimers have been prepared for evaluation as potential antiproliferative agents in the treatment of AIDS-related lymphoma. The Cbl dimers were synthesized by cross-linking Cbl carboxylates, produced by acid hydrolysis of the b-, d-, and e-propionamide side chains of cyanocobalamin (CN-Cbl), through an isophthalate molecule. Linking molecules were used between the Cbl carboxylates and the isophthalate moiety. The linkers were incorporated to provide a distance between the two Cbl molecules such that the dimeric Cbls might bind two molecules of transcobalamin II (TCII), the Cbl transport protein in plasma. Initially, the linking moiety used was 1,12-diaminododecane, but the resulting dimers had low aqueous solubility. To improve the solubility of the dimers, 4,7,10-trioxa-1,13-tridecanediamine was employed as the linking moiety. This improved the water solubility of the dimers considerably, while retaining the distance between the Cbl molecules at 41-42 A (fully extended). To introduce additional substitution on Cbl dimers, 5-aminoisophthalic acid was used as the cross-linking reagent. p-Iodobenzoyl and p-(tri-n-butylstannyl)benzoyl conjugates of 5-aminoisophthalate were synthesized and used to prepare Cbl dimers. The stannylbenzoyl-conjugated Cbl dimers were prepared as precursors to be used in radioiodination reactions, and the iodobenzoyl-conjugated Cbl dimers were prepared as HPLC standards for the radioiodinated product. Attempts to iodinate/radioiodinate the stannylbenzoyl Cbl dimers were unsuccessful. Although an explanation for this is not readily apparent, the failure to react may be due to the lipophilicity of the linker used and the steric environment of the two Cbl moieties. A biotinylated derivative of 5-aminoisophthalate was also synthesized and used to prepare biotinylated-Cbl dimers. In a competitive rhTCII binding assay with [57Co]CN-Cbl, Cbl dimers containing the lipophilic diaminododecane linking moiety had decreased binding avidities compared to those of Cbl monomers substituted at the same corrin ring carboxylate. However, Cbl dimers containing the water-solubilizing trioxadiamine linker appeared to have avidities similar to those of the Cbl monomers.

Antineoplastic Agents↗

PubMedDate not supplied

[The role of implicit knowledge in therapeutic change. Some implications of developmental observations for adult psychotherapy].

Several aspects of development change that are dependent on interactions between parent and infant are examined for their value in casting light on the process of change in adult psychotherapies. First, the domain of implicit knowledge (where changes necessarily occur in nonverbal infants) is identified. The vast majority of therapeutic change is found to occur in this domain. We then examine the improvised, largely unpredictable, nonlinear environments toward mutual goals that characterize the process of parent-infant and therapist-patient interactions. Finally, we provide a microdescription of these processes and provide a terminology for the "moments" that make up their flow. Of particular importance is the "moment of meeting", in which the participants interact in a way that created a new implicit, intersubjective understanding of their relationship and permits a new "way-of-being-with-the-other". We view "moments of meeting" as the key element in bringing about change in implicit knowledge, just as interpretations are thought to be the key element in bringing about change in explicit knowledge.

Humans↗