An efficient method for the α-methylenation of carbonyl groups is reported, and this transformation is accomplished by a facile elimination of trifluoroacetate during the formation of the olefin. This method represents an improvement beyond existing protocol in cases of steric hindrance, and we have demonstrated the utility of the process across a series of ketones, lactams, and lactones. Additionally, we have applied this method to produce semisynthetic derivatives of the natural products (+)-sclareolide and (-)-eburnamonine, in which the carbonyl group is proximal to bulky functional groups. Mechanistic insight is also provided from a time course of (19)F NMR. Biological evaluation of the natural-product-derived enones led to the identification of a derivative of (-)-eburnamonine with significant cytotoxicity (LC(50) = 14.12 μM) in drug-resistant MDA-MB-231 breast cancer cells.

Multiple myeloma (MM) is an incurable bone marrow malignancy of the B cell lineage. Utilizing multiplex Luminex technology we measured levels of 25 cytokines in the plasma of normal donors (n = 177), those with monoclonal gammopathy of undetermined significance (n = 8), and MM patients (n = 55) with either active disease, on treatment, or in remission. The cytokine levels were compared between normal donors and MM patients as well as between various phases of MM, and discriminant analysis was used to create a predictive classification model based on the differentially expressed cytokines. Evaluating age- and gender-dependence of cytokine expression, we determined that with age there is a shift toward a pro-inflammatory environment. Moreover, we observed a strong gender bias in cytokine expression. However, the profile of differentially expressed cytokines was heavily skewed toward an anti-inflammatory, pro-tumorigenic response in patients with MM. Significantly, our predictive model placed all patients in remission in the same category as those with active disease. Thus, our study demonstrates that the homeostasis of systemic cytokines is not restored when MM patients enter remission, suggesting that once an individual has cancer, the microenvironment is permanently altered and the system is primed for a relapse.

The biological role of installing a critical exocyclic enone into the structure of the alkaloid, (−)-eburnamonine, and characterization of the new chemical reactivity by quantitative NMR without using deuterated solvents are described. This selective modification to a natural product imparts potent anticancer activity as well as bestows chemical reactivity toward nucleophilic thiols, which was measured by quantitative NMR. The synthetic strategy provides an overall conversion of 40%. In the key synthetic step, a modified Peterson olefination was accomplished through the facile release of trifluoroacetate to create the requisite enone in the presence of substantial steric hindrance.

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BACKGROUND: While most studies investigate the biology of the active disease, the focus of our study was on the state of clinical remission, during which patients are considered healthy and tumor free. We demonstrate that the ‘disease-promoting latency’ factor(s) are sustained post therapy and likely contribute to tumor re-growth and drug-resistance that accompanies the relapse. We propose that therapies aimed at shrinking the tumor do not restore the homeostasis within the tissue; thus, tumor-associated stroma remains post therapy sustaining the production of pro-tumorigenic factors that ultimately induce a relapse. Multiple myeloma (MM) is an incurable bone marrow malignancy of B cell lineage that accounts for 20% of deaths from hematologic malignancies. Despite the development of potent new regimens, nearly all MM patients relapse and become refractory to treatment; thus the median survival rate remains 3-5 years. The goal of this study was to determine whether the balance of the systemic cytokines returns to normal during complete remission and whether we can identify a cytokine signature specific for various phases of the disease. METHODS: Utilizing multiplex technology of Luminex we measured the plasma levels of 25 cytokines in normal donors (n=177) and MM patients (n=54) either at diagnosis/relapse, treatment, or remission phases of MM. The cytokine levels were compared between normal donors and MM patients as well as between various phases of the MM, and discriminant analysis was used to create predictive classification of disease phase based on the levels of differentially expressed cytokines. RESULTS: Based on fold-change analysis, we identified 15 cytokines that were differentially expressed between normal donors and MM patients, whose profile was heavily skewed toward a pro-tumorigenic Th2 response. Moreover, chemokines (IL-8, eotaxin, MCP1) were also upregulated in plasma of patients. Significantly, the expression of cytokines in patients in clinical remission was maintained at the same levels as in patients with active disease and our predictive model placed all patients in remission in the same category as those at diagnosis/relapse. CONCLUSIONS: Our study demonstrates that remission is not a state of health, but tumor latency, and that once an organism has cancer, the system is primed for relapse and emergence of secondary neoplasms. Thus, the cytokines maintained in circulation will induce proliferation and confer drug resistance of the minimal residual disease, and chemokines will stimulate systemic dissemination of tumor cells leading to the colonization of secondary sites. We believe that such systemic alteration of tissue homeostasis is consistent for all cancers; thus our findings suggest the need to shift the paradigm of clinical intervention to include homeostasis-stabilizing interventions. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-499. doi:1538-7445.AM2012-LB-499