Oxazole and thiazole analogs of sulindac for cancer prevention

Bini Mathew; Judith V. Hobrath; Michele C. Connelly; R. Kiplin Guy; Robert C. Reynolds

doi:10.4155/fmc-2017-0182

Oxazole and thiazole analogs of sulindac for cancer prevention

Bini Mathew, Judith V. Hobrath, Michele C. Connelly, R. Kiplin Guy, Robert C. Reynolds

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

6 Scopus citations

Abstract

Aim: Experimental and epidemiological studies and clinical trials suggest that nonsteroidal anti-inflammatory drugs possess antitumor potential. Sulindac, a widely used nonsteroidal anti-inflammatory drug, can prevent adenomatous colorectal polyps and colon cancer, especially in patients with familial adenomatous polyposis. Sulindac sulfide amide (SSA) is an amide-linked sulindac sulfide analog that showed in vivo antitumor activity in a human colon tumor xenograft model. Results/methodology: A new analog series with heterocyclic rings such as oxazole or thiazole at the C-2 position of sulindac was prepared and screened against prostate, colon and breast cancer cell lines to probe the effect of these novel substitutions on the activity of sulindac analogs. Conclusion: In general, replacement of the amide function of SSA analogs had a negative impact on the cell lines tested. A small number of hits incorporating rigid oxazole or thiazole groups in the sulindac scaffold in place of the amide linkage show comparable activity to our lead agent SSA.

Original language	English
Pages (from-to)	743-753
Number of pages	11
Journal	Future Medicinal Chemistry
Volume	10
Issue number	7
DOIs	https://doi.org/10.4155/fmc-2017-0182
State	Published - Apr 2018

Bibliographical note

Funding Information:
This work was supported by a grant from the National Institutes of Health NCI 1R01CA131378 (RCR PI). We also acknowledge DOD Era of Hope award W81XWH-07–1–0463 (RCR PI) for supporting HTS cancer cell activity profiling. We thank both L White and L Rasmussen for HTS support services. We also gratefully acknowledge contributions by the High Throughput Biology Center in the Department of Chemical Biology and Therapeutics at St Jude Children’s Research Hospital in Memphis, TN for providing BJ and acute lymphoblastic leukemia cell lines for screening. The work at St Jude was supported by American Lebanese Syrian Associated Charities (ALSAC). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Publisher Copyright:
© 2018 2018 Robert C Reynolds.

Keywords

NSAIDs
cancer
heterocycles
oxazole
sulindac
thiazole

ASJC Scopus subject areas

Molecular Medicine
Pharmacology
Drug Discovery

UN SDGs

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

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10.4155/fmc-2017-0182

Cite this

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title = "Oxazole and thiazole analogs of sulindac for cancer prevention",

abstract = "Aim: Experimental and epidemiological studies and clinical trials suggest that nonsteroidal anti-inflammatory drugs possess antitumor potential. Sulindac, a widely used nonsteroidal anti-inflammatory drug, can prevent adenomatous colorectal polyps and colon cancer, especially in patients with familial adenomatous polyposis. Sulindac sulfide amide (SSA) is an amide-linked sulindac sulfide analog that showed in vivo antitumor activity in a human colon tumor xenograft model. Results/methodology: A new analog series with heterocyclic rings such as oxazole or thiazole at the C-2 position of sulindac was prepared and screened against prostate, colon and breast cancer cell lines to probe the effect of these novel substitutions on the activity of sulindac analogs. Conclusion: In general, replacement of the amide function of SSA analogs had a negative impact on the cell lines tested. A small number of hits incorporating rigid oxazole or thiazole groups in the sulindac scaffold in place of the amide linkage show comparable activity to our lead agent SSA.",

keywords = "NSAIDs, cancer, heterocycles, oxazole, sulindac, thiazole",

author = "Bini Mathew and Hobrath, {Judith V.} and Connelly, {Michele C.} and Guy, {R. Kiplin} and Reynolds, {Robert C.}",

note = "Funding Information: This work was supported by a grant from the National Institutes of Health NCI 1R01CA131378 (RCR PI). We also acknowledge DOD Era of Hope award W81XWH-07–1–0463 (RCR PI) for supporting HTS cancer cell activity profiling. We thank both L White and L Rasmussen for HTS support services. We also gratefully acknowledge contributions by the High Throughput Biology Center in the Department of Chemical Biology and Therapeutics at St Jude Children{\textquoteright}s Research Hospital in Memphis, TN for providing BJ and acute lymphoblastic leukemia cell lines for screening. The work at St Jude was supported by American Lebanese Syrian Associated Charities (ALSAC). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. Publisher Copyright: {\textcopyright} 2018 2018 Robert C Reynolds.",

year = "2018",

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doi = "10.4155/fmc-2017-0182",

language = "English",

volume = "10",

pages = "743--753",

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AU - Mathew, Bini

AU - Hobrath, Judith V.

AU - Connelly, Michele C.

AU - Guy, R. Kiplin

AU - Reynolds, Robert C.

N1 - Funding Information: This work was supported by a grant from the National Institutes of Health NCI 1R01CA131378 (RCR PI). We also acknowledge DOD Era of Hope award W81XWH-07–1–0463 (RCR PI) for supporting HTS cancer cell activity profiling. We thank both L White and L Rasmussen for HTS support services. We also gratefully acknowledge contributions by the High Throughput Biology Center in the Department of Chemical Biology and Therapeutics at St Jude Children’s Research Hospital in Memphis, TN for providing BJ and acute lymphoblastic leukemia cell lines for screening. The work at St Jude was supported by American Lebanese Syrian Associated Charities (ALSAC). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. Publisher Copyright: © 2018 2018 Robert C Reynolds.

PY - 2018/4

Y1 - 2018/4

N2 - Aim: Experimental and epidemiological studies and clinical trials suggest that nonsteroidal anti-inflammatory drugs possess antitumor potential. Sulindac, a widely used nonsteroidal anti-inflammatory drug, can prevent adenomatous colorectal polyps and colon cancer, especially in patients with familial adenomatous polyposis. Sulindac sulfide amide (SSA) is an amide-linked sulindac sulfide analog that showed in vivo antitumor activity in a human colon tumor xenograft model. Results/methodology: A new analog series with heterocyclic rings such as oxazole or thiazole at the C-2 position of sulindac was prepared and screened against prostate, colon and breast cancer cell lines to probe the effect of these novel substitutions on the activity of sulindac analogs. Conclusion: In general, replacement of the amide function of SSA analogs had a negative impact on the cell lines tested. A small number of hits incorporating rigid oxazole or thiazole groups in the sulindac scaffold in place of the amide linkage show comparable activity to our lead agent SSA.

AB - Aim: Experimental and epidemiological studies and clinical trials suggest that nonsteroidal anti-inflammatory drugs possess antitumor potential. Sulindac, a widely used nonsteroidal anti-inflammatory drug, can prevent adenomatous colorectal polyps and colon cancer, especially in patients with familial adenomatous polyposis. Sulindac sulfide amide (SSA) is an amide-linked sulindac sulfide analog that showed in vivo antitumor activity in a human colon tumor xenograft model. Results/methodology: A new analog series with heterocyclic rings such as oxazole or thiazole at the C-2 position of sulindac was prepared and screened against prostate, colon and breast cancer cell lines to probe the effect of these novel substitutions on the activity of sulindac analogs. Conclusion: In general, replacement of the amide function of SSA analogs had a negative impact on the cell lines tested. A small number of hits incorporating rigid oxazole or thiazole groups in the sulindac scaffold in place of the amide linkage show comparable activity to our lead agent SSA.

KW - NSAIDs

KW - cancer

KW - heterocycles

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KW - sulindac

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Oxazole and thiazole analogs of sulindac for cancer prevention

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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