Farnesyl diphosphate-based inhibitors of Ras farnesyl protein transferase.

The rational design, synthesis, and biological activity of farnesyl diphosphate (FPP)-based inhibitors of the enzyme Ras farnesyl protein transferase (FPT) is described. Compound 3, wherein a beta-carboxylic phosphonic acid type pyrophosphate (PP) surrogate is connected to the hydrophobic farnesyl group by an amide linker, was found to be a potent (I50(FPT) = 75 nM) and selective inhibitor of FPT, as evidenced by its inferior activity against squalene synthetase (I50(SS) = 516 microM) and mevalonate kinase (I50(MK) = > 200 microM). A systematic structure-activity relationship study involving modifications of the farnesyl group, the amide linker, and the PP surrogate of 3 was undertaken. Both the carboxylic and phosphonic acid groups of the beta-carboxylic phosphonic acid PP surrogate are essential for activity, since deletion of either group results in 50-2600-fold loss in activity (6-9, I50 = 4.6-220 microM). The farnesyl group also displays very stringent requirements and does not tolerate one carbon homologation (12, I50 = 17.7 microM), substitution by a dodecyl fragment (14, I50 = 9 microM), or introduction of an extra methyl group at the allylic position (18, I50 = 55 microM). Modifications around the amide linker group of 3 were more forgiving, as evidenced by the activity of N-methyl analog (21, I50 = 0.53 microM), the one carbon atom shorter farnesoic acid-derived retroamide analog (32, I50 = 250 nM), and the exact retroamide analog (49, I50 = 50 nM). FPP analogs such as 3, 32, and 49 are novel, potent, selective, small-sized, nonpeptidic inhibitors of FPT that may find utility as antitumor agents.

Goal-directed behavior and perception of self-competence in children with spina bifida.

Compared a group of school-age children with spina bifida (n = 15) between the ages of 6 and 12 years with an age- and IQ-matched control group of normal children (n = 15). As predicted, the spina bifida children spent less time using goal-directed behaviors and more time in simple manipulation of the toys compared to the normal children. There were no group differences between the spina bifida and normal children's perceived competence but parents of the spina bifida children rated their children as having lower cognitive and physical competence. Associations were found between goal-directed behaviors and perceived self-competence for children in the spina bifida group but not the normal group.

Roles for Texas physicians in the implementation of Education of Handicapped Act Amendments.

As a result of Public Law 99-457, there are increasing state efforts to provide special education services to handicapped students ages 3 and older, and to develop early intervention for those from birth to age 3 years. Physicians can make significant contributions to these efforts. This paper presents information about PL99-457 and discusses the potential roles for Texas physicians in the implementation of the law and in meeting the needs of developmentally at-risk infants, young children, and their families. Roles are described in the areas of clinical care, research, graduate and continuing education, and policy development.

Neonatal intensive care and pediatric rehabilitation: a joint program for care of chronically ill infants.

A joint program involving a traditional neonatal intensive care unit and a pediatric rehabilitation unit was developed to care for the increasing number of infants with chronic illnesses requiring long-term specialized care. The program emphasizes provision of a more normal, age-appropriate environment, parent education, and opportunities for extended parent-child interaction.