Neurotrophic 3,9-Bis[(alkylthio)methyl]- and -Bis(alkoxymethyl)-K-252a Derivatives

• DOI: 10.1021/jm970031d
• Publication Date: 2002-07-26T05:10:41Z
• Authors: Masami Kaneko; Yutaka Saito; Hiromitsu Saito; Tadashi Matsumoto; Yuzuru Matsuda; Jeffry L. Vaught; Craig A. Dionne; Thelma S. Angeles; Marcie A. Glicksman; Nicola T. Neff; David P. Rotella; James C. Kauer; John P. Mallamo; Robert L. Hudkins; Chikara Murakata
• Keywords: Motor Neurons; Neurons; 0301 basic medicine; Indoles; Carbazoles; Receptor Protein-Tyrosine Kinases; Apoptosis; Chick Embryo; Choline O-Acetyltransferase; Indole Alkaloids; Rats; 3. Good health; 03 medical and health sciences; Prosencephalon; Proto-Oncogene Proteins; Nerve Degeneration; Animals; Humans; Female; Nerve Growth Factors; Enzyme Inhibitors; Receptor, trkA; Protein Kinase C

A series of 3,9 disubstituted [(alkylthio)methyl]- and (alkoxymethyl)-K-252a derivatives was synthesized with the aim of enhancing and separating the neurotrophic properties from the undesirable NGF (trk A kinase) and PKC inhibitory activities of K-252a. Data from this series reveal that substitution in the 3- and 9-positions of K-252a with these groups reduces trk A kinase inhibitory properties approximately 100- to > 500-fold while maintaining or in certain cases enhancing the neurotrophic activity. From this research, 3,9-bis[(ethylthio)methyl]-K-252a (8) was identified as a potent and selective neurotrophic agent in vitro as measured by enhancement of choline acetyltransferase activity in embryonic rat spinal cord and basal forebrain cultures. Compound 8 was found to have weak kinase inhibitory activity for trk A, protein kinase C1 protein kinase A, and myosin light chain kinase. On the basis of the in vitro profile, 8 was evaluated in in vivo models suggestive of neurological diseases. Compound 8 was active in preventing degeneration of cholinergic neurons of the nucleus basalis magnocellularis (NBM) and reduced developmentally programmed cell death (PCD) of female rat spinal nucleus of the bulbocavernosus motoneurons and embryonic chick lumbar motoneurons.