Synthesis of N4-(substituted phenyl)-N4-alkyl/ desalkyl-9H-pyrimido[4,5-b]indole-2,4-diamines and identification of new microtubule disrupting compounds that are effective against multidrug resistant cells

Aleem Gangjee; Nilesh Zaware; Ravi Kumar Vyas Devambatla; Sudhir Raghavan; Cara D. Westbrook; Nicholas F. Dybdal-Hargreaves; Ernest Hamel; Susan L. Mooberry

doi:10.1016/j.bmc.2012.12.010

Synthesis of N⁴-(substituted phenyl)-N⁴-alkyl/ desalkyl-9H-pyrimido[4,5-b]indole-2,4-diamines and identification of new microtubule disrupting compounds that are effective against multidrug resistant cells

Aleem Gangjee, Nilesh Zaware, Ravi Kumar Vyas Devambatla, Sudhir Raghavan, Cara D. Westbrook, Nicholas F. Dybdal-Hargreaves, Ernest Hamel, Susan L. Mooberry

Academic Institute

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

18 Scopus citations

Abstract

A series of fourteen N⁴-(substituted phenyl)-N ⁴-alkyl/desalkyl-9H-pyrimido[4,5-b]indole-2,4-diamines was synthesized as potential microtubule targeting agents. The synthesis involved a Fisher indole cyclization of 2-amino-6-hydrazinylpyrimidin-4(3H)-one with cyclohexanone, followed by oxidation, chlorination and displacement with appropriate anilines. Compounds 6, 14 and 15 had low nanomolar potency against MDA-MB-435 tumor cells and depolymerized microtubules. Compound 6 additionally had nanomolar GI₅₀ values against 57 of the NCI 60-tumor panel cell lines. Mechanistic studies showed that 6 inhibited tubulin polymerization and [³H]colchicine binding to tubulin. The most potent compounds were all effective in cells expressing P-glycoprotein or the βIII isotype of tubulin, which have been associated with clinical drug resistance. Modeling studies provided the potential interactions of 6, 14 and 15 within the colchicine site.

Original language	English (US)
Pages (from-to)	891-902
Number of pages	12
Journal	Bioorganic and Medicinal Chemistry
Volume	21
Issue number	4
DOIs	https://doi.org/10.1016/j.bmc.2012.12.010
State	Published - Feb 15 2013

Keywords

Microtubules
Multidrug resistance
Pyrimido[4,5-b]indole-2,4-diamines

ASJC Scopus subject areas

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

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Gangjee, A., Zaware, N., Devambatla, R. K. V., Raghavan, S., Westbrook, C. D., Dybdal-Hargreaves, N. F., Hamel, E., & Mooberry, S. L. (2013). Synthesis of N⁴-(substituted phenyl)-N⁴-alkyl/ desalkyl-9H-pyrimido[4,5-b]indole-2,4-diamines and identification of new microtubule disrupting compounds that are effective against multidrug resistant cells. Bioorganic and Medicinal Chemistry, 21(4), 891-902. https://doi.org/10.1016/j.bmc.2012.12.010

Synthesis of N⁴-(substituted phenyl)-N⁴-alkyl/ desalkyl-9H-pyrimido[4,5-b]indole-2,4-diamines and identification of new microtubule disrupting compounds that are effective against multidrug resistant cells. / Gangjee, Aleem; Zaware, Nilesh; Devambatla, Ravi Kumar Vyas et al.
In: Bioorganic and Medicinal Chemistry, Vol. 21, No. 4, 15.02.2013, p. 891-902.

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

Gangjee, A, Zaware, N, Devambatla, RKV, Raghavan, S, Westbrook, CD, Dybdal-Hargreaves, NF, Hamel, E & Mooberry, SL 2013, 'Synthesis of N⁴-(substituted phenyl)-N⁴-alkyl/ desalkyl-9H-pyrimido[4,5-b]indole-2,4-diamines and identification of new microtubule disrupting compounds that are effective against multidrug resistant cells', Bioorganic and Medicinal Chemistry, vol. 21, no. 4, pp. 891-902. https://doi.org/10.1016/j.bmc.2012.12.010

Gangjee A, Zaware N, Devambatla RKV, Raghavan S, Westbrook CD, Dybdal-Hargreaves NF et al. Synthesis of N⁴-(substituted phenyl)-N⁴-alkyl/ desalkyl-9H-pyrimido[4,5-b]indole-2,4-diamines and identification of new microtubule disrupting compounds that are effective against multidrug resistant cells. Bioorganic and Medicinal Chemistry. 2013 Feb 15;21(4):891-902. doi: 10.1016/j.bmc.2012.12.010

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title = "Synthesis of N4-(substituted phenyl)-N4-alkyl/ desalkyl-9H-pyrimido[4,5-b]indole-2,4-diamines and identification of new microtubule disrupting compounds that are effective against multidrug resistant cells",

abstract = "A series of fourteen N4-(substituted phenyl)-N 4-alkyl/desalkyl-9H-pyrimido[4,5-b]indole-2,4-diamines was synthesized as potential microtubule targeting agents. The synthesis involved a Fisher indole cyclization of 2-amino-6-hydrazinylpyrimidin-4(3H)-one with cyclohexanone, followed by oxidation, chlorination and displacement with appropriate anilines. Compounds 6, 14 and 15 had low nanomolar potency against MDA-MB-435 tumor cells and depolymerized microtubules. Compound 6 additionally had nanomolar GI50 values against 57 of the NCI 60-tumor panel cell lines. Mechanistic studies showed that 6 inhibited tubulin polymerization and [3H]colchicine binding to tubulin. The most potent compounds were all effective in cells expressing P-glycoprotein or the βIII isotype of tubulin, which have been associated with clinical drug resistance. Modeling studies provided the potential interactions of 6, 14 and 15 within the colchicine site.",

keywords = "Microtubules, Multidrug resistance, Pyrimido[4,5-b]indole-2,4-diamines",

author = "Aleem Gangjee and Nilesh Zaware and Devambatla, {Ravi Kumar Vyas} and Sudhir Raghavan and Westbrook, {Cara D.} and Dybdal-Hargreaves, {Nicholas F.} and Ernest Hamel and Mooberry, {Susan L.}",

note = "Funding Information: This work was supported, in part, by the National Institutes of Health and National Cancer Institute Grant CA142868 (A.G. and S.L.M.) and the Duquesne University Adrian Van Kaam Chair in Scholarly Excellence (A.G.). We acknowledge support from the CTRC Cancer Center Support Grant, CCSG ( CA054174 ) (S.L.M.). ",

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AU - Gangjee, Aleem

AU - Zaware, Nilesh

AU - Devambatla, Ravi Kumar Vyas

AU - Raghavan, Sudhir

AU - Westbrook, Cara D.

AU - Dybdal-Hargreaves, Nicholas F.

AU - Hamel, Ernest

AU - Mooberry, Susan L.

N1 - Funding Information: This work was supported, in part, by the National Institutes of Health and National Cancer Institute Grant CA142868 (A.G. and S.L.M.) and the Duquesne University Adrian Van Kaam Chair in Scholarly Excellence (A.G.). We acknowledge support from the CTRC Cancer Center Support Grant, CCSG ( CA054174 ) (S.L.M.).

PY - 2013/2/15

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N2 - A series of fourteen N4-(substituted phenyl)-N 4-alkyl/desalkyl-9H-pyrimido[4,5-b]indole-2,4-diamines was synthesized as potential microtubule targeting agents. The synthesis involved a Fisher indole cyclization of 2-amino-6-hydrazinylpyrimidin-4(3H)-one with cyclohexanone, followed by oxidation, chlorination and displacement with appropriate anilines. Compounds 6, 14 and 15 had low nanomolar potency against MDA-MB-435 tumor cells and depolymerized microtubules. Compound 6 additionally had nanomolar GI50 values against 57 of the NCI 60-tumor panel cell lines. Mechanistic studies showed that 6 inhibited tubulin polymerization and [3H]colchicine binding to tubulin. The most potent compounds were all effective in cells expressing P-glycoprotein or the βIII isotype of tubulin, which have been associated with clinical drug resistance. Modeling studies provided the potential interactions of 6, 14 and 15 within the colchicine site.

AB - A series of fourteen N4-(substituted phenyl)-N 4-alkyl/desalkyl-9H-pyrimido[4,5-b]indole-2,4-diamines was synthesized as potential microtubule targeting agents. The synthesis involved a Fisher indole cyclization of 2-amino-6-hydrazinylpyrimidin-4(3H)-one with cyclohexanone, followed by oxidation, chlorination and displacement with appropriate anilines. Compounds 6, 14 and 15 had low nanomolar potency against MDA-MB-435 tumor cells and depolymerized microtubules. Compound 6 additionally had nanomolar GI50 values against 57 of the NCI 60-tumor panel cell lines. Mechanistic studies showed that 6 inhibited tubulin polymerization and [3H]colchicine binding to tubulin. The most potent compounds were all effective in cells expressing P-glycoprotein or the βIII isotype of tubulin, which have been associated with clinical drug resistance. Modeling studies provided the potential interactions of 6, 14 and 15 within the colchicine site.

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