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The factors that influence the formation of a tetrahedral alkoxide complex related to a critical intermediate of the catalytic cycle of liver alcohol dehydrogenase have been probed by a combined experimental and computational investigation of the reactions of the tris(pyrazolyl)hydroborato zinc hydroxide complexes [Tp RR′ ]ZnOH with alcohols. The study demonstrates that zinc alkoxide formation is electronically favored by incorporation of electron-withdrawing substituents in the alcohol but is sterically disfavored for bulky alkoxides. A computational analysis indicates that these trends are a result of homolytic Zn-OR and Zn-OAr BDEs being more sensitive to the nature of R and Ar than are the corresponding H-OR and H-OAr BDEs. Thus, electron-withdrawing substituents increase Zn-OAr bond energies to a greater extent than H-OAr bond energies, while bulky substituents decrease Zn-OR bond energies to a greater extent than H-OR bond energies. With the exception of derivatives of acidic alcohols (e.g., nitrophenol), the zinc alkoxide complexes [Tp RR′ ]-ZnOR are very unstable toward hydrolysis. This hydrolytic instability of simple zinc alkoxide complexes suggests that the active site environment of LADH plays an important role in stabilizing the alkoxide intermediate, possibly via hydrogen-bonding interactions.

Objectives We previously reported inferior outcomes for locally advanced head and neck cancer treated with cetuximab (C225) versus cisplatin (CDDP). We now examine if this difference persists when accounting for HPV status and update outcomes on the entire cohort. Materials and Methods From 3/106 to 4/1/08, 174 locally advanced head and neck cancer patients received definitive treatment with RT and CDDP (n = 125) or RT and C225 (n = 49). Of these, 62 patients had tissue available for HPV analysis. Results The median follow-up was 47 months. The 3-year loco-regional failure, disease-free survival, and overall survival for CDDP versus C225 were 5.7% versus 40.2% (P < 0.0001), 85.1% versus 35.4% (P < 0.0001), and 90.0% versus 56.6% (P < 0.0001), respectively. In the subset with tissue, there was no difference in rates of HPV or p16 positivity between the 2 groups. In this subset, the 3-year loco-regional failure, disease-free survival, and overall survival for CDDP versus C225 were 5.3% versus 32.0% (P = 0.01), 86.8% versus 43.2% (P = 0.002), and 86.7% versus 76.9% (P = 0.09), respectively. Multivariate analysis continued to show a benefit for CDDP. Conclusions With longer follow-up and the inclusion of HPV and p16 status for about one third of patients where tissue was available, we continued to find superior outcomes with concurrent CDDP versus C225.

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