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Design and Synthesis of Small Molecules as Potential Therapeutic Agents for the Treatment of Cancer and Cystic Fibrosis

Chettiar, Somsundaram Natrajan
http://rave.ohiolink.edu/etdc/view?acc_num=osu1385559040

Abstract Details

2013, Doctor of Philosophy, Ohio State University, Pharmacy.
Cancer is a complex group of distinct genetic disease having common hallmarks. Cancer is characterized by abnormal and uncontrolled cell growth, and may acquire the ability to migrate and invade other parts of the body. The common hallmarks of cancer include limitless replication potential, insensitivity to anti-growth signals, self-sufficiency in growth signals, evading apoptosis, tissue invasion and metastasis, and sustained angiogenesis. Mono polar spindle 1 kinase (Mps1 kinase) is an essential mitotic kinase with multiple functions in cell division. Mps1 kinase plays an important role in spindle assembly checkpoint. It is also involved in centrosome duplication, SMAD signaling, post-mitotic checkpoints, DNA damage response and cytokinesis. The mRNA levels of Mps1 kinase are upregulated in several human cancers including bladder, anaplastic thyroid, breast, lung, esophagus, and prostate. Recently, it has been reported that high levels of Mps1 kinase are correlated with high histologic grade breast cancer. Mps1-Comp1, one of the designed Mps1 kinase inhibitors, demonstrated potent antiproliferative activity with moderate selectivity to PTEN deficient breast cancer cells. Other designed Mps1 kinase inhibitors, such as Mps1-Comp10 and Mps1-Comp13, also showed potent antiproliferative activities across different breast cancer cell lines. Survivin, a member of the inhibitor of apoptosis protein (IAP) family proteins, has important roles in cell division and inhibition of apoptosis. Several clinical studies have shown that elevated levels of survivin correlates with aggressiveness of the disease and resistance to radiation and chemotherapeutic treatments. The disruption of functional survivin along its dimer interface with a small molecule is hypothesized to inhibit the proliferation of cancer cells and sensitize them to therapeutic agents and radiation. Survivin dimerization modulators were designed by computational modeling using Abbott8 as the lead molecule. Two of the most potent survivin modulators, LLP3 and LLP9 at concentrations between 50 and 100 nM, caused delay in mitotic progression and major mitotic defects in proliferating human umbilical vein endothelial cells and prostate cancer cells. Jumonji C containing demethylases (JMJD2) are a group of enzymes that demethylate all three states of lysine methylation in histone. JMJD2 family of proteins, especially JMJD2A, JMJD2B and JMJD2C, has been found to be overexpressed in many cancers. Virtual high throughput screening was employed to identify inhibitors of JMJD2 enzymes. Among the tested compounds, LLJI3 and 28-34 exhibit inhibitory activity against JMJD2 family of enzymes. Cystic fibrosis (CF) is one of the most common lethal genetic disorders in Caucasians. Cystic fibrosis is caused due to mutation to the Cystic Fibrosis Transmembrane Regulator (CFTR) gene. The most common mutation is the deletion of amino acid 508 (phenylalanine) which accounts for 70% of the mutations worldwide. Respiratory insufficiency is the leading cause of morbidity and mortality among CF patients which is caused due to improper functioning of CFTR ion channel. Numerous small molecules were designed that can potentially bind to the druggable binding pocket near V510 of F508 NBD1, using a fragment-based virtual screen approach. Over half of the tested LLCF compounds effectively rescued the misprocessing of delta F508 CFTR in HEK293 cells.
Chenglong Li, PhD (Advisor)
Karl Werbovetz, PhD (Committee Member)
James Fuchs, PhD (Committee Member)
351 p.
Pharmaceuticals; Pharmacy Sciences
Survivin, Mps1 kinase, JMJD2 enzyme, CFTR

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Citations

  • Chettiar, S. N. (2013). Design and Synthesis of Small Molecules as Potential Therapeutic Agents for the Treatment of Cancer and Cystic Fibrosis [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1385559040

    APA Style (7th edition)

  • Chettiar, Somsundaram. Design and Synthesis of Small Molecules as Potential Therapeutic Agents for the Treatment of Cancer and Cystic Fibrosis. 2013. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1385559040.

    MLA Style (8th edition)

  • Chettiar, Somsundaram. "Design and Synthesis of Small Molecules as Potential Therapeutic Agents for the Treatment of Cancer and Cystic Fibrosis." Doctoral dissertation, Ohio State University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=osu1385559040

    Chicago Manual of Style (17th edition)

osu1385559040
90
© 2013, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.