A series of group 10 bis(benzimidazolylidene) complexes featuring chelating N-(o-phenol) moieties were synthesized and characterized. The ligand was prepared in 85% overall yield from 1-fluoro-2-nitrobenzene using a short SNAr/reductive cyclization/alkylation reaction sequence. Direct metalation of the respective benzimidazolium precursor with Ni(II), Pd(II), and Pt(II) salts under ambient atmosphere at 50−80 °C provided the discrete chelating complexes in excellent yields (≥91%). Whereas chelation occurred spontaneously in the case of the Ni complex, an intermediate displaying ligation from the NHCs without chelation from pendent phenol groups was isolated and characterized when Pd was used. This complex was subsequently converted to its chelated form upon treatment with base. The effect of chelation was measured via thermogravimetric analysis and found to enhance the stability of the complex by 24 °C. The chelation also did not significantly effect overall electronic characteristics. A similar reaction sequence was observed when Pt was used, but the respective intermediate could not be isolated. Chelated Ni, Pd, and Pt complexes were characterized by X-ray crystallography and found to exhibit cis configurations about their respective square-planar metal centers. Based on these model systems, a new class of main-chain organometallic polymers comprised of a benzobis(imidazolylidene) ligand with chelating phenolate moieties and group 10 transition metals was synthesized and characterized. The respective bis(bidentate) ligand was prepared from 1,5-dichloro-2,4-dinitrobenzene in three chromatography-free steps in 78% overall yield from commercially-available starting materials and used as monomer. Consistent with the model studies, direct metalation of the monomer was accomplished by addition of a stoichiometric amount of metal(II) salt under basic conditions, which resulted in excellent yields (≥95%) of the respective organometallic polymers with molecular weights up to 363,000 g/moL (relative to polystyrene standards). The polymers were found to be exceptionally air- and moisture-stable and displayed thermal stabilities exceeding 350 °C (under nitrogen), as measured by thermogravimetric analysis. Electronic absorption measurements indicated the λmax values of these polymers ranged between 312 and 322 nm, depending on the incorporated transition metal, and were bathochromically shifted by up to 27 nm relative to their corresponding model complexes.

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OBJECTIVE(S) Develop a plasma-based microRNA (miRNA) diagnostic assay specific for colorectal neoplasms, building upon our prior work. BACKGROUND Colorectal neoplasms (colorectal cancer [CRC] and colorectal advanced adenoma [CAA]) frequently develop in individuals at ages when other common cancers also occur. Current screening methods lack sensitivity, specificity, and have poor patient compliance. METHODS Plasma was screened for 380 miRNAs using microfluidic array technology from a “Training” cohort of 60 patients, (10 each) control, CRC, CAA, breast (BC), pancreatic (PC) and lung (LC) cancer. We identified uniquely dysregulated miRNAs specific for colorectal neoplasia (p<0.05, false discovery rate: 5%, adjusted α=0.0038). These miRNAs were evaluated using single assays in a “Test” cohort of 120 patients. A mathematical model was developed to predict blinded sample identity in a 150 patient “Validation” cohort using repeat-sub-sampling validation of the testing dataset with 1000 iterations each to assess model detection accuracy. RESULTS Seven miRNAs (miR-21, miR-29c, miR-122, miR-192, miR-346, miR-372, miR-374a) were selected based upon p-value, area-under-the-curve (AUC), fold-change, and biological plausibility. AUC (±95% CI) for “Test” cohort comparisons were 0.91 (0.85-0.96), 0.79 (0.70-0.88) and 0.98 (0.96-1.0), respectively. Our mathematical model predicted blinded sample identity with 69-77% accuracy between all neoplasia and controls, 67-76% accuracy between colorectal neoplasia and other cancers, and 86-90% accuracy between colorectal cancer and colorectal adenoma. CONCLUSIONS Our plasma miRNA assay and prediction model differentiates colorectal neoplasia from patients with other neoplasms and from controls with higher sensitivity and specificity compared to current clinical standards.