Development of second-generation indole-based dynamin GTPase inhibitors

Christopher P. Gordon; Barbara Venn-Brown; Mark J. Robertson; Kelly A. Young; Ngoc Chau; Anna Mariana; Ainslie Whiting; Megan Chircop; Phillip J. Robinson; Adam McCluskey

doi:10.1021/jm300844m

Development of second-generation indole-based dynamin GTPase inhibitors

Christopher P. Gordon, Barbara Venn-Brown, Mark J. Robertson, Kelly A. Young, Ngoc Chau, Anna Mariana, Ainslie Whiting, Megan Chircop, Phillip J. Robinson, Adam McCluskey

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

43 Citations (Scopus)

Abstract

Focused library development of our lead 2-cyano-3-(1-(3-(dimethylamino) propyl)-2-methyl-1H-indol-3-yl)-N-octylacrylamide (2) confirmed the tertiary dimethylamino-propyl moiety as critical for inhibition of dynamin GTPase. The cyanoamide moiety could be replaced with a thiazole-4(5H)-one isostere (19, IC50(dyn I) = 7.7 Î¼M), reduced under flow chemistry conditions (20, IC50(dyn I) = 5.2 Î¼M) or replaced by a simple amine. The latter provided a basis for a high yield library of compounds via a reductive amination by flow hydrogenation. Two compounds, 24 (IC50 (dyn I) = 0.56 Î¼M) and 25 (IC50(dyn I) = 0.76 Î¼M), stood out. Indole 24 is nontoxic and showed increased potency against dynamin I and II in vitro and in cells (IC50(CME) = 1.9 Î¼M). It also showed 4.4-fold selectivity for dynamin I. The indole 24 compound has improved isoform selectivity and is the most active in-cell inhibitor of clathrin-mediated endocytosis reported to date.

Original language	English
Pages (from-to)	46-59
Number of pages	14
Journal	Journal of Medicinal Chemistry
Volume	56
Issue number	1
DOIs	https://doi.org/10.1021/jm300844m
Publication status	Published - 2013

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@article{81f8d80196ee4722a6c1797a96f68223,

title = "Development of second-generation indole-based dynamin GTPase inhibitors",

abstract = "Focused library development of our lead 2-cyano-3-(1-(3-(dimethylamino) propyl)-2-methyl-1H-indol-3-yl)-N-octylacrylamide (2) confirmed the tertiary dimethylamino-propyl moiety as critical for inhibition of dynamin GTPase. The cyanoamide moiety could be replaced with a thiazole-4(5H)-one isostere (19, IC50(dyn I) = 7.7 {\^I}¼M), reduced under flow chemistry conditions (20, IC50(dyn I) = 5.2 {\^I}¼M) or replaced by a simple amine. The latter provided a basis for a high yield library of compounds via a reductive amination by flow hydrogenation. Two compounds, 24 (IC50 (dyn I) = 0.56 {\^I}¼M) and 25 (IC50(dyn I) = 0.76 {\^I}¼M), stood out. Indole 24 is nontoxic and showed increased potency against dynamin I and II in vitro and in cells (IC50(CME) = 1.9 {\^I}¼M). It also showed 4.4-fold selectivity for dynamin I. The indole 24 compound has improved isoform selectivity and is the most active in-cell inhibitor of clathrin-mediated endocytosis reported to date.",

author = "Gordon, {Christopher P.} and Barbara Venn-Brown and Robertson, {Mark J.} and Young, {Kelly A.} and Ngoc Chau and Anna Mariana and Ainslie Whiting and Megan Chircop and Robinson, {Phillip J.} and Adam McCluskey",

year = "2013",

doi = "10.1021/jm300844m",

language = "English",

volume = "56",

pages = "46--59",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "1",

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TY - JOUR

T1 - Development of second-generation indole-based dynamin GTPase inhibitors

AU - Gordon, Christopher P.

AU - Venn-Brown, Barbara

AU - Robertson, Mark J.

AU - Young, Kelly A.

AU - Chau, Ngoc

AU - Mariana, Anna

AU - Whiting, Ainslie

AU - Chircop, Megan

AU - Robinson, Phillip J.

AU - McCluskey, Adam

PY - 2013

Y1 - 2013

N2 - Focused library development of our lead 2-cyano-3-(1-(3-(dimethylamino) propyl)-2-methyl-1H-indol-3-yl)-N-octylacrylamide (2) confirmed the tertiary dimethylamino-propyl moiety as critical for inhibition of dynamin GTPase. The cyanoamide moiety could be replaced with a thiazole-4(5H)-one isostere (19, IC50(dyn I) = 7.7 Î¼M), reduced under flow chemistry conditions (20, IC50(dyn I) = 5.2 Î¼M) or replaced by a simple amine. The latter provided a basis for a high yield library of compounds via a reductive amination by flow hydrogenation. Two compounds, 24 (IC50 (dyn I) = 0.56 Î¼M) and 25 (IC50(dyn I) = 0.76 Î¼M), stood out. Indole 24 is nontoxic and showed increased potency against dynamin I and II in vitro and in cells (IC50(CME) = 1.9 Î¼M). It also showed 4.4-fold selectivity for dynamin I. The indole 24 compound has improved isoform selectivity and is the most active in-cell inhibitor of clathrin-mediated endocytosis reported to date.

AB - Focused library development of our lead 2-cyano-3-(1-(3-(dimethylamino) propyl)-2-methyl-1H-indol-3-yl)-N-octylacrylamide (2) confirmed the tertiary dimethylamino-propyl moiety as critical for inhibition of dynamin GTPase. The cyanoamide moiety could be replaced with a thiazole-4(5H)-one isostere (19, IC50(dyn I) = 7.7 Î¼M), reduced under flow chemistry conditions (20, IC50(dyn I) = 5.2 Î¼M) or replaced by a simple amine. The latter provided a basis for a high yield library of compounds via a reductive amination by flow hydrogenation. Two compounds, 24 (IC50 (dyn I) = 0.56 Î¼M) and 25 (IC50(dyn I) = 0.76 Î¼M), stood out. Indole 24 is nontoxic and showed increased potency against dynamin I and II in vitro and in cells (IC50(CME) = 1.9 Î¼M). It also showed 4.4-fold selectivity for dynamin I. The indole 24 compound has improved isoform selectivity and is the most active in-cell inhibitor of clathrin-mediated endocytosis reported to date.

UR - http://handle.uws.edu.au:8081/1959.7/549419

U2 - 10.1021/jm300844m

DO - 10.1021/jm300844m

M3 - Article

SN - 0022-2623

VL - 56

SP - 46

EP - 59

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 1

ER -

Development of second-generation indole-based dynamin GTPase inhibitors

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