Triple-negative breast cancer (TNBC) has limited treatment options and the worst prognosis among all types of breast cancer. We describe two prodrugs, namely, CWB-20145 (1) and its methyl analogue FAN-NM-CH 3 (2) that reduced the size of TNBC-derived tumors. The DNA cross-linking of nitrogen mustard prodrugs 1 and 2 was superior to that of chlorambucil and melphalan once activated in the presence of H 2 O 2 . The cellular toxicity of 1 and 2 was demonstrated in seven human cancer cell lines. The TNBC cell line MDA-MB-468 was particularly sensitive toward 1 and 2. Compound 2 was 10 times more cytotoxic than chlorambucil and 16 times more active than melphalan. An evaluation of the gene expression demonstrated an upregulation of the tumor suppressor genes p53 and p21 supporting a transcriptional mechanism of a reduced tumor growth. Pharmacokinetic studies with 1 showed a rapid conversion of the prodrug. The introduction of a methyl group generated 2 with an increased half-life. An in vivo toxicity study in mice demonstrated that both prodrugs were less toxic than chlorambucil. Compounds 1 and 2 reduced tumor growth with an inhibition rate of more than 90% in athymic nude mice xenografted with MDA-MB-468 cells. Together, the in vivo investigations demonstrated that treatment with 1 and 2 suppressed tumor growth without affecting normal tissues in mice. These phenylboronic acid nitrogen mustard prodrugs represent promising drug candidates for the treatment of TNBC. However, the mechanisms underlying their superior in vivo activity and selectivity as well as the correlation between H 2 O 2 level and in vivo efficacy are not yet fully understood.
Our recently developed method for combinatorial synthesis leads efficiently to linear arrays, where the location of a compound in the array encodes its complete synthetic history. Such arrays prepared using an optical fiber as a linear support can be probed with a fiber-guided pulse, allowing evanescent interaction with fluorescent probe molecules at the core-cladding interface. Optical time-of-flight distinction among output signals of fluorescent regions distributed along the fiber is carried out, allowing for the measurement of the location of the emitting fluorescent probes. A unique two-fiber, double-evanescent process overcomes limitations in spatial discrimination, due to fluorescence decay times in comparison to the speed of light. Investigation of an array of 102 fluorescent regions is described, with discussion of its features and limitations.
Sensor arrays are useful for many purposes. Our interests include quasi-distributed intrinsic fiber optic arrays, those distributed along the length of an optical fiber. We have demonstrated an optical time-of-flight approach to distinguishing the fluorescence output of such arrays, as well as a synthesis of combinatorial libraries that takes advantage of a support of linear morphology to make numerous compounds in a simple manner without information loss in the synthesis. To unite these research areas, we needed an optical fiber cladding material that meets demanding synthetic and optical requirements. We have chosen the Meldal SPOCC polymer support as the best candidate for such a material and report here our initial results with this material.
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