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

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 Rotella, James C. Kauer, John P. Mallamo, Robert L. Hudkins, Chikara Murakata

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Abstract

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 C, 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.

Original languageEnglish
Pages (from-to)1863-1869
Number of pages7
JournalJournal of Medicinal Chemistry
Volume40
Issue number12
DOIs
StatePublished - 6 Jun 1997

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Phosphotransferases
Motor Neurons
Neurological Models
Basal Nucleus of Meynert
Myosin-Light-Chain Kinase
Cholinergic Neurons
Choline O-Acetyltransferase
Nerve Growth Factor
Cyclic AMP-Dependent Protein Kinases
Spinal Cord
Cell Death
Research
staurosporine aglycone
In Vitro Techniques
3,9-bis((ethylthio)methyl)-K-252a
Basal Forebrain
protein kinase C kinase

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Kaneko, M., Saito, Y., Saito, H., Matsumoto, T., Matsuda, Y., Vaught, J. L., ... Murakata, C. (1997). Neurotrophic 3,9-bis[(alkylthio)methyl]-and-bis(alkoxymethyl)-K-252a derivatives. Journal of Medicinal Chemistry, 40(12), 1863-1869. https://doi.org/10.1021/jm970031d
Kaneko, Masami ; Saito, Yutaka ; Saito, Hiromitsu ; Matsumoto, Tadashi ; Matsuda, Yuzuru ; Vaught, Jeffry L. ; Dionne, Craig A. ; Angeles, Thelma S. ; Glicksman, Marcie A. ; Neff, Nicola T. ; Rotella, David ; Kauer, James C. ; Mallamo, John P. ; Hudkins, Robert L. ; Murakata, Chikara. / Neurotrophic 3,9-bis[(alkylthio)methyl]-and-bis(alkoxymethyl)-K-252a derivatives. In: Journal of Medicinal Chemistry. 1997 ; Vol. 40, No. 12. pp. 1863-1869.
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title = "Neurotrophic 3,9-bis[(alkylthio)methyl]-and-bis(alkoxymethyl)-K-252a derivatives",
abstract = "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 C, 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.",
author = "Masami Kaneko and Yutaka Saito and Hiromitsu Saito and Tadashi Matsumoto and Yuzuru Matsuda and Vaught, {Jeffry L.} and Dionne, {Craig A.} and Angeles, {Thelma S.} and Glicksman, {Marcie A.} and Neff, {Nicola T.} and David Rotella and Kauer, {James C.} and Mallamo, {John P.} and Hudkins, {Robert L.} and Chikara Murakata",
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Kaneko, M, Saito, Y, Saito, H, Matsumoto, T, Matsuda, Y, Vaught, JL, Dionne, CA, Angeles, TS, Glicksman, MA, Neff, NT, Rotella, D, Kauer, JC, Mallamo, JP, Hudkins, RL & Murakata, C 1997, 'Neurotrophic 3,9-bis[(alkylthio)methyl]-and-bis(alkoxymethyl)-K-252a derivatives', Journal of Medicinal Chemistry, vol. 40, no. 12, pp. 1863-1869. https://doi.org/10.1021/jm970031d

Neurotrophic 3,9-bis[(alkylthio)methyl]-and-bis(alkoxymethyl)-K-252a derivatives. / Kaneko, Masami; Saito, Yutaka; Saito, Hiromitsu; Matsumoto, Tadashi; Matsuda, Yuzuru; Vaught, Jeffry L.; Dionne, Craig A.; Angeles, Thelma S.; Glicksman, Marcie A.; Neff, Nicola T.; Rotella, David; Kauer, James C.; Mallamo, John P.; Hudkins, Robert L.; Murakata, Chikara.

In: Journal of Medicinal Chemistry, Vol. 40, No. 12, 06.06.1997, p. 1863-1869.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Neurotrophic 3,9-bis[(alkylthio)methyl]-and-bis(alkoxymethyl)-K-252a derivatives

AU - Kaneko, Masami

AU - Saito, Yutaka

AU - Saito, Hiromitsu

AU - Matsumoto, Tadashi

AU - Matsuda, Yuzuru

AU - Vaught, Jeffry L.

AU - Dionne, Craig A.

AU - Angeles, Thelma S.

AU - Glicksman, Marcie A.

AU - Neff, Nicola T.

AU - Rotella, David

AU - Kauer, James C.

AU - Mallamo, John P.

AU - Hudkins, Robert L.

AU - Murakata, Chikara

PY - 1997/6/6

Y1 - 1997/6/6

N2 - 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 C, 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.

AB - 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 C, 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.

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U2 - 10.1021/jm970031d

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Kaneko M, Saito Y, Saito H, Matsumoto T, Matsuda Y, Vaught JL et al. Neurotrophic 3,9-bis[(alkylthio)methyl]-and-bis(alkoxymethyl)-K-252a derivatives. Journal of Medicinal Chemistry. 1997 Jun 6;40(12):1863-1869. https://doi.org/10.1021/jm970031d