From COX-2 inhibitor nimesulide to potent anti-cancer agent: Synthesis, in vitro, in vivo and pharmacokinetic evaluation

Bo Zhong; Xiaohan Cai; Snigdha Chennamaneni; Xin Yi; Lili Liu; John J. Pink; Afshin Dowlati; Yan Xu; Aimin Zhou; Bin Su

doi:10.1016/j.ejmech.2011.11.012

From COX-2 inhibitor nimesulide to potent anti-cancer agent: Synthesis, in vitro, in vivo and pharmacokinetic evaluation

Bo Zhong, Xiaohan Cai, Snigdha Chennamaneni, Xin Yi, Lili Liu, John J. Pink, Afshin Dowlati, Yan Xu, Aimin Zhou, Bin Su

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

58 Scopus citations

Abstract

Cyclooxygenase-2 (COX-2) inhibitor nimesulide inhibits the proliferation of various types of cancer cells mainly via COX-2 independent mechanisms, which makes it a good lead compound for anti-cancer drug development. In the presented study, a series of new nimesulide analogs were synthesized based on the structure-function analysis generated previously. Some of them displayed very potent anti-cancer activity with IC ₅₀s around 100 nM-200 nM to inhibit SKBR-3 breast cancer cell growth. CSUOH0901 (NSC751382) from the compound library also inhibits the growth of the 60 cancer cell lines used at National Cancer Institute Developmental therapeutics Program (NCIDTP) with IC ₅₀s around 100 nM-500 nM. Intraperitoneal injection with a dosage of 5 mg/kg/d of CSUOH0901 to nude mice suppresses HT29 colorectal xenograft growth. Pharmacokinetic studies demonstrate the good bioavailability of the compound.

Original language	English (US)
Pages (from-to)	432-444
Number of pages	13
Journal	European Journal of Medicinal Chemistry
Volume	47
Issue number	1
DOIs	https://doi.org/10.1016/j.ejmech.2011.11.012
State	Published - Jan 2012

Keywords

Anti-cancer
COX-2 inhibitor
Nimesulide
Pharmacokinetics
Xenograft

ASJC Scopus subject areas

Pharmacology
Drug Discovery
Organic Chemistry

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10.1016/j.ejmech.2011.11.012

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title = "From COX-2 inhibitor nimesulide to potent anti-cancer agent: Synthesis, in vitro, in vivo and pharmacokinetic evaluation",

abstract = "Cyclooxygenase-2 (COX-2) inhibitor nimesulide inhibits the proliferation of various types of cancer cells mainly via COX-2 independent mechanisms, which makes it a good lead compound for anti-cancer drug development. In the presented study, a series of new nimesulide analogs were synthesized based on the structure-function analysis generated previously. Some of them displayed very potent anti-cancer activity with IC 50s around 100 nM-200 nM to inhibit SKBR-3 breast cancer cell growth. CSUOH0901 (NSC751382) from the compound library also inhibits the growth of the 60 cancer cell lines used at National Cancer Institute Developmental therapeutics Program (NCIDTP) with IC 50s around 100 nM-500 nM. Intraperitoneal injection with a dosage of 5 mg/kg/d of CSUOH0901 to nude mice suppresses HT29 colorectal xenograft growth. Pharmacokinetic studies demonstrate the good bioavailability of the compound.",

keywords = "Anti-cancer, COX-2 inhibitor, Nimesulide, Pharmacokinetics, Xenograft",

author = "Bo Zhong and Xiaohan Cai and Snigdha Chennamaneni and Xin Yi and Lili Liu and Pink, {John J.} and Afshin Dowlati and Yan Xu and Aimin Zhou and Bin Su",

note = "Funding Information: This research was supported by a startup fund from Cleveland State University . The research was also supported by the Translational Research Core Facility and Athymic Animal & Xenograft Core Facility of the Case Comprehensive Cancer Center ( P30 CA43703 ). We thank the Developmental Therapeutic Program at the National Cancer Institute for screening the compound against 60 human tumor cell lines and acute toxicity studies. ",

year = "2012",

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doi = "10.1016/j.ejmech.2011.11.012",

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T2 - Synthesis, in vitro, in vivo and pharmacokinetic evaluation

AU - Zhong, Bo

AU - Cai, Xiaohan

AU - Chennamaneni, Snigdha

AU - Yi, Xin

AU - Liu, Lili

AU - Pink, John J.

AU - Dowlati, Afshin

AU - Xu, Yan

AU - Zhou, Aimin

AU - Su, Bin

N1 - Funding Information: This research was supported by a startup fund from Cleveland State University . The research was also supported by the Translational Research Core Facility and Athymic Animal & Xenograft Core Facility of the Case Comprehensive Cancer Center ( P30 CA43703 ). We thank the Developmental Therapeutic Program at the National Cancer Institute for screening the compound against 60 human tumor cell lines and acute toxicity studies.

PY - 2012/1

Y1 - 2012/1

N2 - Cyclooxygenase-2 (COX-2) inhibitor nimesulide inhibits the proliferation of various types of cancer cells mainly via COX-2 independent mechanisms, which makes it a good lead compound for anti-cancer drug development. In the presented study, a series of new nimesulide analogs were synthesized based on the structure-function analysis generated previously. Some of them displayed very potent anti-cancer activity with IC 50s around 100 nM-200 nM to inhibit SKBR-3 breast cancer cell growth. CSUOH0901 (NSC751382) from the compound library also inhibits the growth of the 60 cancer cell lines used at National Cancer Institute Developmental therapeutics Program (NCIDTP) with IC 50s around 100 nM-500 nM. Intraperitoneal injection with a dosage of 5 mg/kg/d of CSUOH0901 to nude mice suppresses HT29 colorectal xenograft growth. Pharmacokinetic studies demonstrate the good bioavailability of the compound.

AB - Cyclooxygenase-2 (COX-2) inhibitor nimesulide inhibits the proliferation of various types of cancer cells mainly via COX-2 independent mechanisms, which makes it a good lead compound for anti-cancer drug development. In the presented study, a series of new nimesulide analogs were synthesized based on the structure-function analysis generated previously. Some of them displayed very potent anti-cancer activity with IC 50s around 100 nM-200 nM to inhibit SKBR-3 breast cancer cell growth. CSUOH0901 (NSC751382) from the compound library also inhibits the growth of the 60 cancer cell lines used at National Cancer Institute Developmental therapeutics Program (NCIDTP) with IC 50s around 100 nM-500 nM. Intraperitoneal injection with a dosage of 5 mg/kg/d of CSUOH0901 to nude mice suppresses HT29 colorectal xenograft growth. Pharmacokinetic studies demonstrate the good bioavailability of the compound.

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KW - Xenograft

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From COX-2 inhibitor nimesulide to potent anti-cancer agent: Synthesis, in vitro, in vivo and pharmacokinetic evaluation

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