Lu Lin

Defense Date

2-20-2013

Graduation Date

2013

Availability

Immediate Access

Submission Type

dissertation

Degree Name

PhD

Department

Medicinal Chemistry

School

School of Pharmacy

Committee Chair

Aleem Gangjee

Committee Member

Marc Harrold

Committee Member

Patrick Flaherty

Committee Member

David Lapinsky

Committee Member

Block Lawrence

Keywords

Anticancer, HSP90, Microtubule, Pyrrolopyrimidine, Synthesis, Tubulin

Abstract

An introduction, background and recent advances in the areas of microtubule-binding agents and heat shock protein 90 (HSP90) inhibitors as anticancer agents are briefly reviewed. The work in this dissertation is centered on the synthesis of substituted pyrrolo[2, 3-d]pyrimidines as potential anticancer agents that act via microtubule inhibition or HSP90 inhibition..

Microtubule-binding agents are effective against a broad range of tumors and lymphomas and have been common components of combination cancer-chemotherapy in the clinic. Despite the unparalleled success, drawbacks among microtubule-binding agents such as multi-drug resistance, dose-limiting toxicity, poor pharmacokinetic profile and high cost have supported the sustaining momentum in searching for novel agents of this class.

The research on microtubule-binding agents in this dissertation was initiated by an unexpected discovery. The lead compound, a 4-N-methyl-4'-methoxyaniline-substituted pyrrolo[2, 3-d]pyrimidine, was found to inhibit the majority cancer cell lines in the NCI-60 panel at sub-micromolar concentration. The COMPARE analysis based on the activity profile indicated microtubule inhibition as the main mechanism of action of this compound, and was later confirmed through multiple assays. Further, the lead compound displaced 70% of [3H]colchicine from tubulin at a concentration of 5 μM, and was identified as a colchicine-site binder. The compound has also shown unabated or even increased activities against several drug-resistant cancer cell lines, especially the cell lines overexpressing P-glycoprotein or βIII-tubulin. In addition, the compound has favorable physicochemical properties such as high water solubility as its hydrochloride salt.

Based on the preliminary data and molecular modeling, a hypothesis on the relationship between binding affinity and the lowest-energy conformation of pyrrolo[2, 3-d]pyrimidines was proposed. To test the hypothesis and search for compounds with improved potency, 38 pyrrolo[2, 3-d]pyrimidine analogs in six series were designed and synthesized. The biological evaluations of these compounds are currently in progress at the time this dissertation is submitted.

HSP90 is one the molecular chaperones that assist the proper folding of the newly synthesized polypeptides and proteins. The majority of its client proteins are signal transducers with unstable conformations, which play critical roles in growth control, cell survival and development. The expressions of these proteins in normal cells were much less than cancer cell, making HSP90 a viable target for cancer chemotherapy. As of 2012, there are 16 HSP90 inhibitors in clinical trial, among which four are based on the purine-scaffold. All the compounds in clinical trials bind to or overlap with the ATP site on the N-terminal of HSP90.

The pyrrolo[2, 3-d]pyrimidine scaffold is structurally close to purines. In the design of receptor tyrosine kinase (RTK) inhibitors, Gangjee et al. have shown that properly functionalized pyrrolo[2, 3-d]pyrimidines bind to the ATP site and achieve high degrees of selectivity. This was partly attributed to the incorporation of substitution patterns that are impossible on the purine scaffold. Based on these previous findings and the established SAR of the two purine derivatives in clinical trials (PU-H71 and BIIB021), 18 substituted pyrrolo[2, 3-d]pyrimidines in three series (in connection with this dissertation) were designed and synthesized. The biological evaluations of these compounds are currently in progress..

Format

PDF

Language

English

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