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FROM NON-STEROIDAL ANTI-INFLAMMATORY DRUG (NSIAD) INDOMETHACIN TO ANTI-CANCER AGENTS: DESIGN, SYNTHESIS, BIOLOGICAL EVALUATION AND MECHANISM INVESTIGATION

Chennamaneni, Snigdha

Abstract Details

2014, Doctor of Philosophy in Clinical-Bioanalytical Chemistry, Cleveland State University, College of Sciences and Health Professions.

According to American Cancer Society 2014 Statistics, colorectal cancer is the third most diagnosed cancer and also a leading cause of death in both men and women in the United States. About 25% of all cancers are related to chronic infection and other types of unresolved inflammation. Non-Steriodal Anti-inflammatory Drugs (NSAIDs) are widely used to inhibit inflmmation and inflammation-associated symptoms. Indomethacin (INDO) is a NSAID well known for the inhibition of cyclooxygensae (COX) enzyme that is responsible for the prostaglandin (PG) synthesis. PG also contributes to cellular processes like cell proliferation, apoptosis and angiogenesis. Recent advances have identified different biological properties of INDO, like chemoprevention of cancer, additional to anti-inflammatory activities. But it has various side effects associated with gastrointestinal and cardiovascular toxicities. The objective of this dissertation is to modify the INDO structure in order to enhance the anti-colorectal cancer activity that is independent of COX inhibition.

Initially a series of INDO derivatives were synthesized by systematic modification of carboxylic acid moiety, benzoyl ring followed by 5-methoxy group. First, keeping the 4-chlorobenzoyl group, the carboxyl group was coupled with various amines including substituted anilinies, aliphatic monoamines and diamines, resulting the first generation of derivatives. Secondly, holding the favorable amide moiety, various substitutions or additional phenyl ring on benzoyl groups, the methoxy group on the 5-position of INDO was converted to various amide derivatives. The small molecule library was then assessed in vitro for cell growth inhibition against multiple cancer cell lines; one of the INDO analogs displayed the most potent antiproliferative activity against HT29 colon cancer cell lines with an IC 50 of 1.73 μM, which is 1000 times more potent than the lead compound, INDO (IC 50 = 1052 μM). In-vitro tubulin polymerization assay indicated this compound interferes with the process of tubulin polymerization. The binding mode of this compound in tubulin was predicted using the molecular docking simulation.

Bin Su, PhD (Committee Chair)
Aimin Zhou, PhD (Committee Member)
Girish Shukla, PhD (Committee Member)
John Masnovi, PhD (Committee Member)
Xue-Long Sun, PhD (Committee Member)
144 p.

Recommended Citations

Citations

  • Chennamaneni, S. (2014). FROM NON-STEROIDAL ANTI-INFLAMMATORY DRUG (NSIAD) INDOMETHACIN TO ANTI-CANCER AGENTS: DESIGN, SYNTHESIS, BIOLOGICAL EVALUATION AND MECHANISM INVESTIGATION [Doctoral dissertation, Cleveland State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=csu1421084668

    APA Style (7th edition)

  • Chennamaneni, Snigdha. FROM NON-STEROIDAL ANTI-INFLAMMATORY DRUG (NSIAD) INDOMETHACIN TO ANTI-CANCER AGENTS: DESIGN, SYNTHESIS, BIOLOGICAL EVALUATION AND MECHANISM INVESTIGATION. 2014. Cleveland State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=csu1421084668.

    MLA Style (8th edition)

  • Chennamaneni, Snigdha. "FROM NON-STEROIDAL ANTI-INFLAMMATORY DRUG (NSIAD) INDOMETHACIN TO ANTI-CANCER AGENTS: DESIGN, SYNTHESIS, BIOLOGICAL EVALUATION AND MECHANISM INVESTIGATION." Doctoral dissertation, Cleveland State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=csu1421084668

    Chicago Manual of Style (17th edition)