Rational design, synthesis, and biological evaluation of rigid pyrrolidone analogues as potential inhibitors of prostate cancer cell growth

Lixin Qiao; Lian Yun Zhao; Suo Bao Rong; Xiong Wu Wu; Shaomeng Wang; Teruhiko Fujii; Marcelo G. Kazanietz; Laura Rauser; Jason Savage; Bryan L. Roth; Judith Flippen-Anderson; Alan P. Kozikowski

doi:10.1016/S0960-894X(01)00097-X

Rational design, synthesis, and biological evaluation of rigid pyrrolidone analogues as potential inhibitors of prostate cancer cell growth

Lixin Qiao, Lian Yun Zhao, Suo Bao Rong, Xiong Wu Wu, Shaomeng Wang, Teruhiko Fujii, Marcelo G. Kazanietz, Laura Rauser, Jason Savage, Bryan L. Roth, Judith Flippen-Anderson, Alan P. Kozikowski

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31 Scopus citations

Abstract

In view of its role in tumor promotion and signal transduction, protein kinase C (PKC) has proven to be an exciting target for cancer therapy. With the aid of molecular modeling, we rationally designed and stereoselectively synthesized a new class of rigidified pyrrolidone-based PKC activators. Pyrrolidone 15 was found to exhibit reasonable affinity for PKCδ, with lower affinity for the other isozymes tested. Pyrrolidone 2 causes the dose-dependent induction of apoptosis in LNCaP prostate cancer cells. This apoptotic effect could be markedly potentiated by the use of LNCaP cells overexpressing the PKCα or δ isozymes.

Original language	English (US)
Pages (from-to)	955-959
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	11
Issue number	8
DOIs	https://doi.org/10.1016/S0960-894X(01)00097-X
State	Published - Apr 23 2001
Externally published	Yes

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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10.1016/S0960-894X(01)00097-X

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Qiao, L., Zhao, L. Y., Rong, S. B., Wu, X. W., Wang, S., Fujii, T., Kazanietz, M. G., Rauser, L., Savage, J., Roth, B. L., Flippen-Anderson, J., & Kozikowski, A. P. (2001). Rational design, synthesis, and biological evaluation of rigid pyrrolidone analogues as potential inhibitors of prostate cancer cell growth. Bioorganic and Medicinal Chemistry Letters, 11(8), 955-959. https://doi.org/10.1016/S0960-894X(01)00097-X

Qiao, L, Zhao, LY, Rong, SB, Wu, XW, Wang, S, Fujii, T, Kazanietz, MG, Rauser, L, Savage, J, Roth, BL, Flippen-Anderson, J & Kozikowski, AP 2001, 'Rational design, synthesis, and biological evaluation of rigid pyrrolidone analogues as potential inhibitors of prostate cancer cell growth', Bioorganic and Medicinal Chemistry Letters, vol. 11, no. 8, pp. 955-959. https://doi.org/10.1016/S0960-894X(01)00097-X

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title = "Rational design, synthesis, and biological evaluation of rigid pyrrolidone analogues as potential inhibitors of prostate cancer cell growth",

abstract = "In view of its role in tumor promotion and signal transduction, protein kinase C (PKC) has proven to be an exciting target for cancer therapy. With the aid of molecular modeling, we rationally designed and stereoselectively synthesized a new class of rigidified pyrrolidone-based PKC activators. Pyrrolidone 15 was found to exhibit reasonable affinity for PKCδ, with lower affinity for the other isozymes tested. Pyrrolidone 2 causes the dose-dependent induction of apoptosis in LNCaP prostate cancer cells. This apoptotic effect could be markedly potentiated by the use of LNCaP cells overexpressing the PKCα or δ isozymes.",

author = "Lixin Qiao and Zhao, {Lian Yun} and Rong, {Suo Bao} and Wu, {Xiong Wu} and Shaomeng Wang and Teruhiko Fujii and Kazanietz, {Marcelo G.} and Laura Rauser and Jason Savage and Roth, {Bryan L.} and Judith Flippen-Anderson and Kozikowski, {Alan P.}",

note = "Funding Information: This work was supported by NIH grant CA79601 (to A. P.K.), the Department of Defense DMAD 17-93-V-3018 (to A.P.K.), the NIMH Psychoactive Drug Screening Program (MH 01366 to B.L.R.), the Department of Defense Prostate Cancer Research Program (to M.G.K.), and in part by NIDA and the Office of Naval Research (to J.F.-A.).",

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doi = "10.1016/S0960-894X(01)00097-X",

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T1 - Rational design, synthesis, and biological evaluation of rigid pyrrolidone analogues as potential inhibitors of prostate cancer cell growth

AU - Qiao, Lixin

AU - Zhao, Lian Yun

AU - Rong, Suo Bao

AU - Wu, Xiong Wu

AU - Wang, Shaomeng

AU - Fujii, Teruhiko

AU - Kazanietz, Marcelo G.

AU - Rauser, Laura

AU - Savage, Jason

AU - Roth, Bryan L.

AU - Flippen-Anderson, Judith

AU - Kozikowski, Alan P.

N1 - Funding Information: This work was supported by NIH grant CA79601 (to A. P.K.), the Department of Defense DMAD 17-93-V-3018 (to A.P.K.), the NIMH Psychoactive Drug Screening Program (MH 01366 to B.L.R.), the Department of Defense Prostate Cancer Research Program (to M.G.K.), and in part by NIDA and the Office of Naval Research (to J.F.-A.).

PY - 2001/4/23

Y1 - 2001/4/23

N2 - In view of its role in tumor promotion and signal transduction, protein kinase C (PKC) has proven to be an exciting target for cancer therapy. With the aid of molecular modeling, we rationally designed and stereoselectively synthesized a new class of rigidified pyrrolidone-based PKC activators. Pyrrolidone 15 was found to exhibit reasonable affinity for PKCδ, with lower affinity for the other isozymes tested. Pyrrolidone 2 causes the dose-dependent induction of apoptosis in LNCaP prostate cancer cells. This apoptotic effect could be markedly potentiated by the use of LNCaP cells overexpressing the PKCα or δ isozymes.

AB - In view of its role in tumor promotion and signal transduction, protein kinase C (PKC) has proven to be an exciting target for cancer therapy. With the aid of molecular modeling, we rationally designed and stereoselectively synthesized a new class of rigidified pyrrolidone-based PKC activators. Pyrrolidone 15 was found to exhibit reasonable affinity for PKCδ, with lower affinity for the other isozymes tested. Pyrrolidone 2 causes the dose-dependent induction of apoptosis in LNCaP prostate cancer cells. This apoptotic effect could be markedly potentiated by the use of LNCaP cells overexpressing the PKCα or δ isozymes.

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IS - 8

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Rational design, synthesis, and biological evaluation of rigid pyrrolidone analogues as potential inhibitors of prostate cancer cell growth

Abstract

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