Synthesis and biological evaluation of C-ring truncated deguelin derivatives as heat shock protein 90 (HSP90) inhibitors

Ho Shin Kim; Mannkyu Hong; Jihyae Ann; Suyoung Yoon; Cong Truong Nguyen; Su Chan Lee; Ho Young Lee; Young Ger Suh; Ji Hae Seo; Hoon Choi; Jun Yong Kim; Kyu Won Kim; Joohwan Kim; Young Myeong Kim; So Jung Park; Hyun Ju Park; Jeewoo Lee

doi:10.1016/j.bmc.2016.09.067

Synthesis and biological evaluation of C-ring truncated deguelin derivatives as heat shock protein 90 (HSP90) inhibitors

Ho Shin Kim, Mannkyu Hong, Jihyae Ann, Suyoung Yoon, Cong Truong Nguyen, Su Chan Lee, Ho Young Lee, Young Ger Suh, Ji Hae Seo, Hoon Choi, Jun Yong Kim, Kyu Won Kim, Joohwan Kim, Young Myeong Kim, So Jung Park, Hyun Ju Park, Jeewoo Lee

Department of Pharmacy

Research output: Contribution to journal › Article › peer-review

29 Scopus citations

Abstract

Based on the lead compound L-80 (compound 2), a potent heat shock protein 90 (HSP90) inhibitor, a series of C-ring truncated deguelin analogs were designed, synthesized and evaluated for Hypoxia Inducible Factor-1α (HIF-1α) inhibition as a primary screening method. Their structure–activity relationship was investigated in a systematic manner by varying the A/B ring, linker and D/E ring, respectively. Among the synthesized inhibitors, compound 5 exhibited potent HIF-1α inhibition in a dose-dependent manner and significant antitumor activity in human non-small cell lung carcinoma (H1299), with better activities than L-80. It also inhibited in vitro hypoxia-mediated angiogenic processes in human retinal microvascular endothelial cells (HRMEC). The docking study of 5 showed a similar binding mode as L-80: it occupied the C-terminal ATP-binding pocket of HSP90, indicating that the anticancer and antiangiogenic activities of 5 were derived from HIF-1α destabilization by inhibiting the C-terminal ATP-binding site of hHSP90.

Original language	English
Pages (from-to)	6082-6093
Number of pages	12
Journal	Bioorganic and Medicinal Chemistry
Volume	24
Issue number	22
DOIs	https://doi.org/10.1016/j.bmc.2016.09.067
State	Published - 2016

Keywords

Antitumor
Deguelin
Heat shock protein 90
HIF-1
HSP90
Hypoxia Inducible Factor-1

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bmc.2016.09.067

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Kim, H. S., Hong, M., Ann, J., Yoon, S., Nguyen, C. T., Lee, S. C., Lee, H. Y., Suh, Y. G., Seo, J. H., Choi, H., Kim, J. Y., Kim, K. W., Kim, J., Kim, Y. M., Park, S. J., Park, H. J., & Lee, J. (2016). Synthesis and biological evaluation of C-ring truncated deguelin derivatives as heat shock protein 90 (HSP90) inhibitors. Bioorganic and Medicinal Chemistry, 24(22), 6082-6093. https://doi.org/10.1016/j.bmc.2016.09.067

@article{b17338269e284b5f8fdb63c497ad02d3,

title = "Synthesis and biological evaluation of C-ring truncated deguelin derivatives as heat shock protein 90 (HSP90) inhibitors",

abstract = "Based on the lead compound L-80 (compound 2), a potent heat shock protein 90 (HSP90) inhibitor, a series of C-ring truncated deguelin analogs were designed, synthesized and evaluated for Hypoxia Inducible Factor-1α (HIF-1α) inhibition as a primary screening method. Their structure–activity relationship was investigated in a systematic manner by varying the A/B ring, linker and D/E ring, respectively. Among the synthesized inhibitors, compound 5 exhibited potent HIF-1α inhibition in a dose-dependent manner and significant antitumor activity in human non-small cell lung carcinoma (H1299), with better activities than L-80. It also inhibited in vitro hypoxia-mediated angiogenic processes in human retinal microvascular endothelial cells (HRMEC). The docking study of 5 showed a similar binding mode as L-80: it occupied the C-terminal ATP-binding pocket of HSP90, indicating that the anticancer and antiangiogenic activities of 5 were derived from HIF-1α destabilization by inhibiting the C-terminal ATP-binding site of hHSP90.",

keywords = "Antitumor, Deguelin, Heat shock protein 90, HIF-1, HSP90, Hypoxia Inducible Factor-1",

author = "Kim, \{Ho Shin\} and Mannkyu Hong and Jihyae Ann and Suyoung Yoon and Nguyen, \{Cong Truong\} and Lee, \{Su Chan\} and Lee, \{Ho Young\} and Suh, \{Young Ger\} and Seo, \{Ji Hae\} and Hoon Choi and Kim, \{Jun Yong\} and Kim, \{Kyu Won\} and Joohwan Kim and Kim, \{Young Myeong\} and Park, \{So Jung\} and Park, \{Hyun Ju\} and Jeewoo Lee",

note = "Publisher Copyright: {\textcopyright} 2016 Elsevier Ltd",

year = "2016",

doi = "10.1016/j.bmc.2016.09.067",

language = "English",

volume = "24",

pages = "6082--6093",

journal = "Bioorganic and Medicinal Chemistry",

issn = "0968-0896",

publisher = "Elsevier Ltd",

number = "22",

}

Kim, HS, Hong, M, Ann, J, Yoon, S, Nguyen, CT, Lee, SC, Lee, HY, Suh, YG, Seo, JH, Choi, H, Kim, JY, Kim, KW, Kim, J, Kim, YM, Park, SJ, Park, HJ & Lee, J 2016, 'Synthesis and biological evaluation of C-ring truncated deguelin derivatives as heat shock protein 90 (HSP90) inhibitors', Bioorganic and Medicinal Chemistry, vol. 24, no. 22, pp. 6082-6093. https://doi.org/10.1016/j.bmc.2016.09.067

TY - JOUR

T1 - Synthesis and biological evaluation of C-ring truncated deguelin derivatives as heat shock protein 90 (HSP90) inhibitors

AU - Kim, Ho Shin

AU - Hong, Mannkyu

AU - Ann, Jihyae

AU - Yoon, Suyoung

AU - Nguyen, Cong Truong

AU - Lee, Su Chan

AU - Lee, Ho Young

AU - Suh, Young Ger

AU - Seo, Ji Hae

AU - Choi, Hoon

AU - Kim, Jun Yong

AU - Kim, Kyu Won

AU - Kim, Joohwan

AU - Kim, Young Myeong

AU - Park, So Jung

AU - Park, Hyun Ju

AU - Lee, Jeewoo

PY - 2016

Y1 - 2016

N2 - Based on the lead compound L-80 (compound 2), a potent heat shock protein 90 (HSP90) inhibitor, a series of C-ring truncated deguelin analogs were designed, synthesized and evaluated for Hypoxia Inducible Factor-1α (HIF-1α) inhibition as a primary screening method. Their structure–activity relationship was investigated in a systematic manner by varying the A/B ring, linker and D/E ring, respectively. Among the synthesized inhibitors, compound 5 exhibited potent HIF-1α inhibition in a dose-dependent manner and significant antitumor activity in human non-small cell lung carcinoma (H1299), with better activities than L-80. It also inhibited in vitro hypoxia-mediated angiogenic processes in human retinal microvascular endothelial cells (HRMEC). The docking study of 5 showed a similar binding mode as L-80: it occupied the C-terminal ATP-binding pocket of HSP90, indicating that the anticancer and antiangiogenic activities of 5 were derived from HIF-1α destabilization by inhibiting the C-terminal ATP-binding site of hHSP90.

AB - Based on the lead compound L-80 (compound 2), a potent heat shock protein 90 (HSP90) inhibitor, a series of C-ring truncated deguelin analogs were designed, synthesized and evaluated for Hypoxia Inducible Factor-1α (HIF-1α) inhibition as a primary screening method. Their structure–activity relationship was investigated in a systematic manner by varying the A/B ring, linker and D/E ring, respectively. Among the synthesized inhibitors, compound 5 exhibited potent HIF-1α inhibition in a dose-dependent manner and significant antitumor activity in human non-small cell lung carcinoma (H1299), with better activities than L-80. It also inhibited in vitro hypoxia-mediated angiogenic processes in human retinal microvascular endothelial cells (HRMEC). The docking study of 5 showed a similar binding mode as L-80: it occupied the C-terminal ATP-binding pocket of HSP90, indicating that the anticancer and antiangiogenic activities of 5 were derived from HIF-1α destabilization by inhibiting the C-terminal ATP-binding site of hHSP90.

KW - Antitumor

KW - Deguelin

KW - Heat shock protein 90

KW - HIF-1

KW - HSP90

KW - Hypoxia Inducible Factor-1

UR - https://www.scopus.com/pages/publications/84991235660

U2 - 10.1016/j.bmc.2016.09.067

DO - 10.1016/j.bmc.2016.09.067

M3 - Article

C2 - 27745993

AN - SCOPUS:84991235660

SN - 0968-0896

VL - 24

SP - 6082

EP - 6093

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

IS - 22

ER -

Synthesis and biological evaluation of C-ring truncated deguelin derivatives as heat shock protein 90 (HSP90) inhibitors

Abstract

Keywords

UN SDGs

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