Synthesis and biological activity of aminophthalazines and aminopyridazines as novel inhibitors of PGE2 production in cells

Federico Medda; Earlphia Sells; Hui Hua Chang; Justin Dietrich; Shashi Chappeta; Breland Smith; Vijay Gokhale; Emmanuelle J. Meuillet; Christopher Hulme

doi:10.1016/j.bmcl.2012.11.030

Synthesis and biological activity of aminophthalazines and aminopyridazines as novel inhibitors of PGE₂ production in cells

Federico Medda
, Earlphia Sells
, Hui Hua Chang
, Justin Dietrich
, Shashi Chappeta
, Breland Smith
, Vijay Gokhale
, Emmanuelle J. Meuillet
, Christopher Hulme

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

12 Scopus citations

Abstract

This Letter reports the synthesis and biological evaluation of a collection of aminophthalazines as a novel class of compounds capable of reducing production of PGE₂ in HCA-7 human adenocarcinoma cells. A total of 28 analogs were synthesized, assayed for PGE₂ reduction, and selected active compounds were evaluated for inhibitory activity against COX-2 in a cell free assay. Compound 2xxiv (R¹ = H, R² = p-CH ₃O) exhibited the most potent activity in cells (EC₅₀ = 0.02 μM) and minimal inhibition of COX-2 activity (3% at 5 μM). Furthermore, the anti-tumor activity of analog 2vii was analyzed in xenograft mouse models exhibiting good anti-cancer activity.

Original language	English (US)
Pages (from-to)	528-531
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	23
Issue number	2
DOIs	https://doi.org/10.1016/j.bmcl.2012.11.030
State	Published - Jan 15 2013

Keywords

Aminophthalazines
COX-2
Cancer
PGE

ASJC Scopus subject areas

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

Access to Document

10.1016/j.bmcl.2012.11.030

Cite this

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title = "Synthesis and biological activity of aminophthalazines and aminopyridazines as novel inhibitors of PGE2 production in cells",

abstract = "This Letter reports the synthesis and biological evaluation of a collection of aminophthalazines as a novel class of compounds capable of reducing production of PGE2 in HCA-7 human adenocarcinoma cells. A total of 28 analogs were synthesized, assayed for PGE2 reduction, and selected active compounds were evaluated for inhibitory activity against COX-2 in a cell free assay. Compound 2xxiv (R1 = H, R2 = p-CH 3O) exhibited the most potent activity in cells (EC50 = 0.02 μM) and minimal inhibition of COX-2 activity (3\% at 5 μM). Furthermore, the anti-tumor activity of analog 2vii was analyzed in xenograft mouse models exhibiting good anti-cancer activity.",

keywords = "Aminophthalazines, COX-2, Cancer, PGE",

author = "Federico Medda and Earlphia Sells and Chang, \{Hui Hua\} and Justin Dietrich and Shashi Chappeta and Breland Smith and Vijay Gokhale and Meuillet, \{Emmanuelle J.\} and Christopher Hulme",

note = "Funding Information: The Authors would like to thank financial support provided by NIH training Grant research fellowship (BCP fellowship grant, \#5T32GM008804-09 and BMCB grant \#T32GM08659 ), the University of Arizona College of Pharmacy for start up funds to CH and the NCI CA138702 grant to EJM. ",

year = "2013",

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doi = "10.1016/j.bmcl.2012.11.030",

language = "English (US)",

volume = "23",

pages = "528--531",

journal = "Bioorganic and Medicinal Chemistry Letters",

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T1 - Synthesis and biological activity of aminophthalazines and aminopyridazines as novel inhibitors of PGE2 production in cells

AU - Medda, Federico

AU - Sells, Earlphia

AU - Chang, Hui Hua

AU - Dietrich, Justin

AU - Chappeta, Shashi

AU - Smith, Breland

AU - Gokhale, Vijay

AU - Meuillet, Emmanuelle J.

AU - Hulme, Christopher

N1 - Funding Information: The Authors would like to thank financial support provided by NIH training Grant research fellowship (BCP fellowship grant, #5T32GM008804-09 and BMCB grant #T32GM08659 ), the University of Arizona College of Pharmacy for start up funds to CH and the NCI CA138702 grant to EJM.

PY - 2013/1/15

Y1 - 2013/1/15

N2 - This Letter reports the synthesis and biological evaluation of a collection of aminophthalazines as a novel class of compounds capable of reducing production of PGE2 in HCA-7 human adenocarcinoma cells. A total of 28 analogs were synthesized, assayed for PGE2 reduction, and selected active compounds were evaluated for inhibitory activity against COX-2 in a cell free assay. Compound 2xxiv (R1 = H, R2 = p-CH 3O) exhibited the most potent activity in cells (EC50 = 0.02 μM) and minimal inhibition of COX-2 activity (3% at 5 μM). Furthermore, the anti-tumor activity of analog 2vii was analyzed in xenograft mouse models exhibiting good anti-cancer activity.

AB - This Letter reports the synthesis and biological evaluation of a collection of aminophthalazines as a novel class of compounds capable of reducing production of PGE2 in HCA-7 human adenocarcinoma cells. A total of 28 analogs were synthesized, assayed for PGE2 reduction, and selected active compounds were evaluated for inhibitory activity against COX-2 in a cell free assay. Compound 2xxiv (R1 = H, R2 = p-CH 3O) exhibited the most potent activity in cells (EC50 = 0.02 μM) and minimal inhibition of COX-2 activity (3% at 5 μM). Furthermore, the anti-tumor activity of analog 2vii was analyzed in xenograft mouse models exhibiting good anti-cancer activity.

KW - Aminophthalazines

KW - COX-2

KW - Cancer

KW - PGE

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