Quinolone-1-(2H)-ones as hedgehog signalling pathway inhibitors

Trieu N. Trinh, Eileen A. McLaughlin, Mohammed K. Abdel-Hamid, Christopher P. Gordon, Ilana R. Bernstein, Victoria Pye, Peter Cossar, Jennette A. Sakoff, Adam McCluskey

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

A series of quinolone-2-(1H)-ones derived from the Ugi-Knoevenagel three- and four-component reaction were prepared exhibiting low micromolar cytotoxicity against a panel of eight human cancer cell lines known to possess the Hedgehog Signalling Pathway (HSP) components, as well as the seminoma TCAM-2 cell line. A focused SAR study was conducted and revealed core characteristics of the quinolone-2-(1H)-ones required for cytotoxicity. These requirements included a C3-tethered indole moiety, an indole C5-methyl moiety, an aliphatic tail or an ester, as well as an additional aromatic moiety. Further investigation in the SAG-activated Shh-LIGHT2 cell line with the most active analogues: 2-(3-cyano-2-oxo-4-phenylquinolin-1(2H)-yl)-2-(1-methyl-1H-indol-3-yl)-N-(pentan-2-yl)acetamide (5), 2-(3-cyano-2-oxo-4-phenylquinolin-1(2H)-yl)-2-(5-methyl-1H-indol-3-yl)-N-(pentan-2-yl)acetamide (23) and ethyl (2-(3-cyano-2-oxo-4-phenylquinolin-1(2H)-yl)-2-(5-methyl-1H-indol-3-yl)acetyl)glycinate (24) demonstrated a down regulation of the HSP via a reduction in Gli expression, and in the mRNA levels of Ptch1 and Gli2. Analogues 5, 23 and 24 returned in cell inhibition values of 11.6, 2.9 and 3.1 μM, respectively, making this new HSP-inhibitor pharmacophore amongst the most potent non-Smo targeted inhibitors thus far reported.

Original languageEnglish
Pages (from-to)6304-6315
Number of pages12
JournalOrganic and Biomolecular Chemistry
Volume14
Issue number26
DOIs
Publication statusPublished - 24 May 2016
Externally publishedYes

Fingerprint

Quinolones
cultured cells
inhibitors
Cells
indoles
Cytotoxicity
Cell Line
analogs
Seminoma
Tail
esters
Esters
Down-Regulation
cancer
Messenger RNA
requirements
cells
Neoplasms
carbostyril
acetamide

Cite this

Trinh, T. N., McLaughlin, E. A., Abdel-Hamid, M. K., Gordon, C. P., Bernstein, I. R., Pye, V., ... McCluskey, A. (2016). Quinolone-1-(2H)-ones as hedgehog signalling pathway inhibitors. Organic and Biomolecular Chemistry, 14(26), 6304-6315. https://doi.org/10.1039/c6ob00606j
Trinh, Trieu N. ; McLaughlin, Eileen A. ; Abdel-Hamid, Mohammed K. ; Gordon, Christopher P. ; Bernstein, Ilana R. ; Pye, Victoria ; Cossar, Peter ; Sakoff, Jennette A. ; McCluskey, Adam. / Quinolone-1-(2H)-ones as hedgehog signalling pathway inhibitors. In: Organic and Biomolecular Chemistry. 2016 ; Vol. 14, No. 26. pp. 6304-6315.
@article{73b61119522b471ab552f4ea2fd8cbac,
title = "Quinolone-1-(2H)-ones as hedgehog signalling pathway inhibitors",
abstract = "A series of quinolone-2-(1H)-ones derived from the Ugi-Knoevenagel three- and four-component reaction were prepared exhibiting low micromolar cytotoxicity against a panel of eight human cancer cell lines known to possess the Hedgehog Signalling Pathway (HSP) components, as well as the seminoma TCAM-2 cell line. A focused SAR study was conducted and revealed core characteristics of the quinolone-2-(1H)-ones required for cytotoxicity. These requirements included a C3-tethered indole moiety, an indole C5-methyl moiety, an aliphatic tail or an ester, as well as an additional aromatic moiety. Further investigation in the SAG-activated Shh-LIGHT2 cell line with the most active analogues: 2-(3-cyano-2-oxo-4-phenylquinolin-1(2H)-yl)-2-(1-methyl-1H-indol-3-yl)-N-(pentan-2-yl)acetamide (5), 2-(3-cyano-2-oxo-4-phenylquinolin-1(2H)-yl)-2-(5-methyl-1H-indol-3-yl)-N-(pentan-2-yl)acetamide (23) and ethyl (2-(3-cyano-2-oxo-4-phenylquinolin-1(2H)-yl)-2-(5-methyl-1H-indol-3-yl)acetyl)glycinate (24) demonstrated a down regulation of the HSP via a reduction in Gli expression, and in the mRNA levels of Ptch1 and Gli2. Analogues 5, 23 and 24 returned in cell inhibition values of 11.6, 2.9 and 3.1 μM, respectively, making this new HSP-inhibitor pharmacophore amongst the most potent non-Smo targeted inhibitors thus far reported.",
keywords = "Hedgehogs, Hedgehog Proteins, hedgehog pathway",
author = "Trinh, {Trieu N.} and McLaughlin, {Eileen A.} and Abdel-Hamid, {Mohammed K.} and Gordon, {Christopher P.} and Bernstein, {Ilana R.} and Victoria Pye and Peter Cossar and Sakoff, {Jennette A.} and Adam McCluskey",
year = "2016",
month = "5",
day = "24",
doi = "10.1039/c6ob00606j",
language = "English",
volume = "14",
pages = "6304--6315",
journal = "Organic Molecular Chemistry",
issn = "1477-0520",
publisher = "Royal Society of Chemistry",
number = "26",

}

Trinh, TN, McLaughlin, EA, Abdel-Hamid, MK, Gordon, CP, Bernstein, IR, Pye, V, Cossar, P, Sakoff, JA & McCluskey, A 2016, 'Quinolone-1-(2H)-ones as hedgehog signalling pathway inhibitors', Organic and Biomolecular Chemistry, vol. 14, no. 26, pp. 6304-6315. https://doi.org/10.1039/c6ob00606j

Quinolone-1-(2H)-ones as hedgehog signalling pathway inhibitors. / Trinh, Trieu N.; McLaughlin, Eileen A.; Abdel-Hamid, Mohammed K.; Gordon, Christopher P.; Bernstein, Ilana R.; Pye, Victoria; Cossar, Peter; Sakoff, Jennette A.; McCluskey, Adam.

In: Organic and Biomolecular Chemistry, Vol. 14, No. 26, 24.05.2016, p. 6304-6315.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Quinolone-1-(2H)-ones as hedgehog signalling pathway inhibitors

AU - Trinh, Trieu N.

AU - McLaughlin, Eileen A.

AU - Abdel-Hamid, Mohammed K.

AU - Gordon, Christopher P.

AU - Bernstein, Ilana R.

AU - Pye, Victoria

AU - Cossar, Peter

AU - Sakoff, Jennette A.

AU - McCluskey, Adam

PY - 2016/5/24

Y1 - 2016/5/24

N2 - A series of quinolone-2-(1H)-ones derived from the Ugi-Knoevenagel three- and four-component reaction were prepared exhibiting low micromolar cytotoxicity against a panel of eight human cancer cell lines known to possess the Hedgehog Signalling Pathway (HSP) components, as well as the seminoma TCAM-2 cell line. A focused SAR study was conducted and revealed core characteristics of the quinolone-2-(1H)-ones required for cytotoxicity. These requirements included a C3-tethered indole moiety, an indole C5-methyl moiety, an aliphatic tail or an ester, as well as an additional aromatic moiety. Further investigation in the SAG-activated Shh-LIGHT2 cell line with the most active analogues: 2-(3-cyano-2-oxo-4-phenylquinolin-1(2H)-yl)-2-(1-methyl-1H-indol-3-yl)-N-(pentan-2-yl)acetamide (5), 2-(3-cyano-2-oxo-4-phenylquinolin-1(2H)-yl)-2-(5-methyl-1H-indol-3-yl)-N-(pentan-2-yl)acetamide (23) and ethyl (2-(3-cyano-2-oxo-4-phenylquinolin-1(2H)-yl)-2-(5-methyl-1H-indol-3-yl)acetyl)glycinate (24) demonstrated a down regulation of the HSP via a reduction in Gli expression, and in the mRNA levels of Ptch1 and Gli2. Analogues 5, 23 and 24 returned in cell inhibition values of 11.6, 2.9 and 3.1 μM, respectively, making this new HSP-inhibitor pharmacophore amongst the most potent non-Smo targeted inhibitors thus far reported.

AB - A series of quinolone-2-(1H)-ones derived from the Ugi-Knoevenagel three- and four-component reaction were prepared exhibiting low micromolar cytotoxicity against a panel of eight human cancer cell lines known to possess the Hedgehog Signalling Pathway (HSP) components, as well as the seminoma TCAM-2 cell line. A focused SAR study was conducted and revealed core characteristics of the quinolone-2-(1H)-ones required for cytotoxicity. These requirements included a C3-tethered indole moiety, an indole C5-methyl moiety, an aliphatic tail or an ester, as well as an additional aromatic moiety. Further investigation in the SAG-activated Shh-LIGHT2 cell line with the most active analogues: 2-(3-cyano-2-oxo-4-phenylquinolin-1(2H)-yl)-2-(1-methyl-1H-indol-3-yl)-N-(pentan-2-yl)acetamide (5), 2-(3-cyano-2-oxo-4-phenylquinolin-1(2H)-yl)-2-(5-methyl-1H-indol-3-yl)-N-(pentan-2-yl)acetamide (23) and ethyl (2-(3-cyano-2-oxo-4-phenylquinolin-1(2H)-yl)-2-(5-methyl-1H-indol-3-yl)acetyl)glycinate (24) demonstrated a down regulation of the HSP via a reduction in Gli expression, and in the mRNA levels of Ptch1 and Gli2. Analogues 5, 23 and 24 returned in cell inhibition values of 11.6, 2.9 and 3.1 μM, respectively, making this new HSP-inhibitor pharmacophore amongst the most potent non-Smo targeted inhibitors thus far reported.

KW - Hedgehogs

KW - Hedgehog Proteins

KW - hedgehog pathway

UR - http://www.scopus.com/inward/record.url?scp=84976885416&partnerID=8YFLogxK

UR - http://www.mendeley.com/research/quinolone12-hones-hedgehog-signalling-pathway-inhibitors

U2 - 10.1039/c6ob00606j

DO - 10.1039/c6ob00606j

M3 - Article

VL - 14

SP - 6304

EP - 6315

JO - Organic Molecular Chemistry

JF - Organic Molecular Chemistry

SN - 1477-0520

IS - 26

ER -

Trinh TN, McLaughlin EA, Abdel-Hamid MK, Gordon CP, Bernstein IR, Pye V et al. Quinolone-1-(2H)-ones as hedgehog signalling pathway inhibitors. Organic and Biomolecular Chemistry. 2016 May 24;14(26):6304-6315. https://doi.org/10.1039/c6ob00606j