Thymic stromal lymphopoietin (TSLP) and IL-7 are cytokines that signal via the IL-7 receptor alpha (IL-7Rα) to exert both overlapping and unique functions during early stages of mouse B cell development. In human B lymphopoiesis the requirement for IL-7Rα signaling is controversial and the roles of IL-7 and TSLP are less clear. Here we evaluated human B cell production using novel in vitro and xenograft models of human B cell development that provide selective IL-7 and human TSLP (hTSLP) stimulation. We show that in vitro human B cell production is almost completely blocked in the absence of IL-7Rα stimulation and that either TSLP or IL-7 can provide a signal critical for the production and proliferation of human CD19+ PAX5+ pro-B cells. Analysis of primary human bone marrow (BM) stromal cells show that they express both IL-7 and TSLP providing an in vivo source of these cytokines. Using novel xenograft models we show that the in vivo production of human pro-B cells under the influence of mouse IL-7 is reduced by anti-IL-7 neutralizing antibodies, and this loss can be restored by hTSLP at physiological levels. These data establish the importance of IL-7Rα-mediated signals for normal human B cell production.
[reaction: see text] The efficient entry to the C(1)-C(12), C(13)-C(19), and C(21)-C(25) fragments of azaspiracid is outlined. The C(1)-C(12) portion is constructed using a key asymmetric allenyl borane addition to the corresponding alpha,beta-unsaturated aldehyde. The synthesis of the C(13)-C(19) portion utilizes an Evans asymmetric alkylation followed by Sharpless asymmetric dihydroxylation. In addition, a novel solution to the mismatched effects of a neighboring chiral oxazolidinone during a Sharpless dihydroxylation is detailed.
A series of cinnamylideneacetophenones were synthesized via a modified Claisen-Schmidt condensation reaction and evaluated for cytotoxicity against breast cancer cells using the Alamar Blue™assay. Derivatives 17 and 18 bearing a 2-nitro group on the B ring, exhibited sub-micromolar cytotoxicity in MCF-7 cells (IC50 = 71 and 1.9 nM) respectively. Derivative 17 also displayed sub-micromolar (IC50 = 780 nM) cytotoxicity in MDA-MB-468 cells. Additionally, 17 and 18 displayed significantly less cytotoxicity than the chemotherapeutic doxorubicin in non-tumorigenic MCF-10A cells. This study provides evidence supporting the continued development of nitro-substituted cinnamylideneacetophenones as small molecules to treat breast cancer.
Studies Directed Toward the Total Synthesis of Azaspiracid: Stereoselective Construction of C 1 -C 12 , C 13 -C 19 , and C 21 -C 25 Fragments.-The synthesis of title fragment (I) utilizes the Cory allenyl borane methodology. Fragment (II) is prepared by using Evans alkylation and subsequent Sharpless asymmetric dihydroxylation. Fragment (III) is obtained in analogy to a literature method. -(CARTER, RICH G.; WELDON, DAVID J.; Org.
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