Discovery of the Antitumor Effects of a Porphyrazine Diol (Pz 285) in MDA-MB-231 Breast Tumor Xenograft Models in Mice

Irawati K. Kandela; Katherine J. McAuliffe; Lauren E. Cochran; Anthony G.M. Barrett; Brian M. Hoffman; Andrew P. Mazar; Evan R. Trivedi

doi:10.1021/acsmedchemlett.7b00063

Discovery of the Antitumor Effects of a Porphyrazine Diol (Pz 285) in MDA-MB-231 Breast Tumor Xenograft Models in Mice

Irawati K. Kandela, Katherine J. McAuliffe, Lauren E. Cochran, Anthony G.M. Barrett, Brian M. Hoffman, Andrew P. Mazar, Evan R. Trivedi^*

^*Corresponding author for this work

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

4 Scopus citations

Abstract

A series of porphyrazines (Pzs) with chiral bis-acetal moieties in the β-pyrrole positions ((2R,3R)-2,3-dimethyl-2,3-dimethoxy-1,4-diox-2-ene) have been synthesized and screened as antitumor agents in MDA-MB-231 breast tumor cells in vitro. The lead Pz 285 was further tested in a mouse tumor xenograft model with Td-tomato-luc2 fluorescent breast tumor cells (MDA-MB-231 LM24 Her2+) that are highly metastatic to the lungs. Pz 285 shows marked antitumor effects in vivo, with treated mice exhibiting longer median survival that we attribute to smaller primary tumor regrowth after resection and less occurrence of metastasis when compared to vehicle control groups. Pz 285 is further compared to the clinically approved chemotherapeutic doxorubicin (Dox). This report lays the groundwork for development of an understudied class of compounds for classical chemotherapy.

Original language	English (US)
Pages (from-to)	705-709
Number of pages	5
Journal	ACS Medicinal Chemistry Letters
Volume	8
Issue number	7
DOIs	https://doi.org/10.1021/acsmedchemlett.7b00063
State	Published - Jul 13 2017

Funding

This work was supported in part by Baxter Healthcare Corporation through the Baxter/Northwestern Alliance (to B.M.H.), the Michigan Space Grant Consortium Research Seed Grant (to E.R.T.), and the Oakland University Office of the Provost and Vice President for Academic Affairs (to K.J.M). Animal models were set up in the Tumor Biology Core of Northwestern University, which benefits from philanthropic support of the Robert H. Lurie Cancer Center and the Chemistry of Life Processes Institute. Animal studies were approved by the Institutional Animal Care and Use Committee at Northwestern University. Imaging was performed at the Northwestern University Center for Advanced Molecular Imaging generously supported by NCI CCSG P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center.

Keywords

MDA-MB-231 LM24 Her2+
Porphyrazine
antitumor

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1021/acsmedchemlett.7b00063

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title = "Discovery of the Antitumor Effects of a Porphyrazine Diol (Pz 285) in MDA-MB-231 Breast Tumor Xenograft Models in Mice",

abstract = "A series of porphyrazines (Pzs) with chiral bis-acetal moieties in the β-pyrrole positions ((2R,3R)-2,3-dimethyl-2,3-dimethoxy-1,4-diox-2-ene) have been synthesized and screened as antitumor agents in MDA-MB-231 breast tumor cells in vitro. The lead Pz 285 was further tested in a mouse tumor xenograft model with Td-tomato-luc2 fluorescent breast tumor cells (MDA-MB-231 LM24 Her2+) that are highly metastatic to the lungs. Pz 285 shows marked antitumor effects in vivo, with treated mice exhibiting longer median survival that we attribute to smaller primary tumor regrowth after resection and less occurrence of metastasis when compared to vehicle control groups. Pz 285 is further compared to the clinically approved chemotherapeutic doxorubicin (Dox). This report lays the groundwork for development of an understudied class of compounds for classical chemotherapy.",

keywords = "MDA-MB-231 LM24 Her2+, Porphyrazine, antitumor",

author = "Kandela, {Irawati K.} and McAuliffe, {Katherine J.} and Cochran, {Lauren E.} and Barrett, {Anthony G.M.} and Hoffman, {Brian M.} and Mazar, {Andrew P.} and Trivedi, {Evan R.}",

note = "Funding Information: This work was supported in part by Baxter Healthcare Corporation through the Baxter/Northwestern Alliance (to B.M.H.), the Michigan Space Grant Consortium Research Seed Grant (to E.R.T.), and the Oakland University Office of the Provost and Vice President for Academic Affairs (to K.J.M). Animal models were set up in the Tumor Biology Core of Northwestern University, which benefits from philanthropic support of the Robert H. Lurie Cancer Center and the Chemistry of Life Processes Institute. Animal studies were approved by the Institutional Animal Care and Use Committee at Northwestern University. Imaging was performed at the Northwestern University Center for Advanced Molecular Imaging generously supported by NCI CCSG P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. Publisher Copyright: {\textcopyright} 2017 American Chemical Society.",

year = "2017",

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doi = "10.1021/acsmedchemlett.7b00063",

language = "English (US)",

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AU - Cochran, Lauren E.

AU - Barrett, Anthony G.M.

AU - Hoffman, Brian M.

AU - Mazar, Andrew P.

AU - Trivedi, Evan R.

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N2 - A series of porphyrazines (Pzs) with chiral bis-acetal moieties in the β-pyrrole positions ((2R,3R)-2,3-dimethyl-2,3-dimethoxy-1,4-diox-2-ene) have been synthesized and screened as antitumor agents in MDA-MB-231 breast tumor cells in vitro. The lead Pz 285 was further tested in a mouse tumor xenograft model with Td-tomato-luc2 fluorescent breast tumor cells (MDA-MB-231 LM24 Her2+) that are highly metastatic to the lungs. Pz 285 shows marked antitumor effects in vivo, with treated mice exhibiting longer median survival that we attribute to smaller primary tumor regrowth after resection and less occurrence of metastasis when compared to vehicle control groups. Pz 285 is further compared to the clinically approved chemotherapeutic doxorubicin (Dox). This report lays the groundwork for development of an understudied class of compounds for classical chemotherapy.

AB - A series of porphyrazines (Pzs) with chiral bis-acetal moieties in the β-pyrrole positions ((2R,3R)-2,3-dimethyl-2,3-dimethoxy-1,4-diox-2-ene) have been synthesized and screened as antitumor agents in MDA-MB-231 breast tumor cells in vitro. The lead Pz 285 was further tested in a mouse tumor xenograft model with Td-tomato-luc2 fluorescent breast tumor cells (MDA-MB-231 LM24 Her2+) that are highly metastatic to the lungs. Pz 285 shows marked antitumor effects in vivo, with treated mice exhibiting longer median survival that we attribute to smaller primary tumor regrowth after resection and less occurrence of metastasis when compared to vehicle control groups. Pz 285 is further compared to the clinically approved chemotherapeutic doxorubicin (Dox). This report lays the groundwork for development of an understudied class of compounds for classical chemotherapy.

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Discovery of the Antitumor Effects of a Porphyrazine Diol (Pz 285) in MDA-MB-231 Breast Tumor Xenograft Models in Mice

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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