Oxazole and thiazole analogs of sulindac for cancer prevention

TY - JOUR

T1 - Oxazole and thiazole analogs of sulindac for cancer prevention

AU - Mathew, Bini

AU - Hobrath, Judith V.

AU - Connelly, Michele C.

AU - Guy, R. Kiplin

AU - Reynolds, Robert C.

N1 - 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)

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 - cancer

KW - heterocycles

KW - NSAIDs

KW - oxazole

KW - sulindac

KW - thiazole

U2 - 10.4155/fmc-2017-0182

DO - 10.4155/fmc-2017-0182

M3 - Article

C2 - 29671617

SN - 1756-8919

VL - 10

SP - 743

EP - 753

JO - Future Medicinal Chemistry

JF - Future Medicinal Chemistry

IS - 7

ER -