Doing the methylene shuffle - further insights into the inhibition of mitotic kinesin Eg5 with S-trityl L-cysteine

Murad N. Abualhasan; James A. D. Good; Kitiyaporn Wittayanarakul; Nahoum G. Anthony; Giacomo Berretta; Oliver Rath; Frank Kozielski; Oliver B. Sutcliffe; Simon P. Mackay

doi:10.1016/j.ejmech.2012.05.034

Doing the methylene shuffle - further insights into the inhibition of mitotic kinesin Eg5 with S-trityl L-cysteine

Murad N. Abualhasan, James A. D. Good, Kitiyaporn Wittayanarakul, Nahoum G. Anthony, Giacomo Berretta, Oliver Rath, Frank Kozielski, Oliver B. Sutcliffe, Simon P. Mackay

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

20 Citations (Scopus)

Abstract

S-Trityl L-cysteine (STLC) is an inhibitor of the mitotic kinesin Eg5 with potential as an antimitotic chemotherapeutic agent. We previously reported the crystal structure of the ligand protein complex, and now for the first time, have quantified the interactions using a molecular dynamics based approach. Based on these data, we have explored the SAR of the trityl head group using the methylene shuffle strategy to expand the occupation of one of the hydrophobic pockets. The most potent compounds exhibit strong (<100 nM) inhibition of Eg5 in the basal ATPase assay and inhibit growth in a variety of tumour-derived cell lines. (C) 2012 Elsevier Masson SAS. All rights reserved.

Original language	English
Pages (from-to)	483-498
Number of pages	16
Journal	European Journal of Medicinal Chemistry
Volume	54
DOIs	https://doi.org/10.1016/j.ejmech.2012.05.034
Publication status	Published - Aug 2012

Keywords

methylene shuffle
insights
inhibition
mitotic kinesin Eg5 with S-trityl L-cysteine

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10.1016/j.ejmech.2012.05.034

Cite this

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title = "Doing the methylene shuffle - further insights into the inhibition of mitotic kinesin Eg5 with S-trityl L-cysteine",

abstract = "S-Trityl L-cysteine (STLC) is an inhibitor of the mitotic kinesin Eg5 with potential as an antimitotic chemotherapeutic agent. We previously reported the crystal structure of the ligand protein complex, and now for the first time, have quantified the interactions using a molecular dynamics based approach. Based on these data, we have explored the SAR of the trityl head group using the methylene shuffle strategy to expand the occupation of one of the hydrophobic pockets. The most potent compounds exhibit strong (<100 nM) inhibition of Eg5 in the basal ATPase assay and inhibit growth in a variety of tumour-derived cell lines. (C) 2012 Elsevier Masson SAS. All rights reserved.",

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author = "Abualhasan, {Murad N.} and Good, {James A. D.} and Kitiyaporn Wittayanarakul and Anthony, {Nahoum G.} and Giacomo Berretta and Oliver Rath and Frank Kozielski and Sutcliffe, {Oliver B.} and Mackay, {Simon P.}",

year = "2012",

month = aug,

doi = "10.1016/j.ejmech.2012.05.034",

language = "English",

volume = "54",

pages = "483--498",

journal = "European Journal of Medicinal Chemistry",

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AU - Abualhasan, Murad N.

AU - Good, James A. D.

AU - Wittayanarakul, Kitiyaporn

AU - Anthony, Nahoum G.

AU - Berretta, Giacomo

AU - Rath, Oliver

AU - Kozielski, Frank

AU - Sutcliffe, Oliver B.

AU - Mackay, Simon P.

PY - 2012/8

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N2 - S-Trityl L-cysteine (STLC) is an inhibitor of the mitotic kinesin Eg5 with potential as an antimitotic chemotherapeutic agent. We previously reported the crystal structure of the ligand protein complex, and now for the first time, have quantified the interactions using a molecular dynamics based approach. Based on these data, we have explored the SAR of the trityl head group using the methylene shuffle strategy to expand the occupation of one of the hydrophobic pockets. The most potent compounds exhibit strong (<100 nM) inhibition of Eg5 in the basal ATPase assay and inhibit growth in a variety of tumour-derived cell lines. (C) 2012 Elsevier Masson SAS. All rights reserved.

AB - S-Trityl L-cysteine (STLC) is an inhibitor of the mitotic kinesin Eg5 with potential as an antimitotic chemotherapeutic agent. We previously reported the crystal structure of the ligand protein complex, and now for the first time, have quantified the interactions using a molecular dynamics based approach. Based on these data, we have explored the SAR of the trityl head group using the methylene shuffle strategy to expand the occupation of one of the hydrophobic pockets. The most potent compounds exhibit strong (<100 nM) inhibition of Eg5 in the basal ATPase assay and inhibit growth in a variety of tumour-derived cell lines. (C) 2012 Elsevier Masson SAS. All rights reserved.

KW - methylene shuffle

KW - insights

KW - inhibition

KW - mitotic kinesin Eg5 with S-trityl L-cysteine

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U2 - 10.1016/j.ejmech.2012.05.034

DO - 10.1016/j.ejmech.2012.05.034

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JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

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Doing the methylene shuffle - further insights into the inhibition of mitotic kinesin Eg5 with S-trityl L-cysteine

Abstract

Keywords

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SMSdrug.net: Alignment Of Synthesis, Medicinal Chemistry And Strucrural Genomics To Accelerate Uk Drug Discovery: Network SMS-Drug

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Doing the methylene shuffle - further insights into the inhibition of mitotic kinesin Eg5 with S-trityl L-cysteine

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Projects

SMSdrug.net: Alignment Of Synthesis, Medicinal Chemistry And Strucrural Genomics To Accelerate Uk Drug Discovery: Network SMS-Drug

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