Solid-phase synthesis of duocarmycin analogues and the effect of C-terminal substitution on biological activity

YesThe duocarmycins are potent antitumour agents with potential in the development of antibody drug conjugates (ADCs) as well as being clinical candidates in their own right. In this paper, we describe the synthesis of a duocarmycin monomer (DSA) that is suitably protected for utilisation in solid phase synthesis. The synthesis was performed on a large scale and the resulting racemic protected Fmoc-DSA subunit was separated by supercritical fluid chromatography (SFC) into the single enantiomers. Application to solid phase synthesis methodology gave a series of monomeric and extended duocarmycin analogues with amino acid substituents. The DNA sequence selectivity was similar to previous reports for both the monomeric and extended compounds. The substitution at the C-terminus of the duocarmycin caused a decrease in antiproliferative activity for all of the compounds studied. An extended compound containing an alanine at the C-terminus was converted to the primary amide or to an extended structure containing a terminal tertiary amine but this had no beneficial effects on biological activity.MJS was funded by Novartis and UEA. We thank the EPSRC Mass Spectrometry Service, Swansea. We thank Richard Robinson and Julia Hatto at Novartis for help in the large scale synthesis

TMEM16A Potentiation: A Novel Therapeutic Approach for the Treatment of Cystic Fibrosis

Rationale: Enhancing non–CFTR (cystic fibrosis transmembrane conductance regulator)-mediated anion secretion is an attractive therapeutic approach for the treatment of cystic fibrosis (CF) and other mucoobstructive diseases. Objectives: To determine the effects of TMEM16A potentiation on epithelial fluid secretion and mucociliary clearance. Methods: The effects of a novel low-molecular-weight TMEM16A potentiator (ETX001) were evaluated in human cell and animal models of airway epithelial function and mucus transport. Measurements and Main Results: Potentiating the activity of TMEM16A with ETX001 increased the Ca21-activated Cl2 channel activity and anion secretion in human bronchial epithelial (HBE) cells from patients with CF without impacting calcium signaling. ETX001 rapidly increased fluid secretion and airway surface liquid height in CF-HBE cells under both static conditions and conditions designed to mimic the shear stress associated with tidal breathing. In ovine models of mucus clearance (tracheal mucus velocity and mucociliary clearance), inhaled ETX001 was able to accelerate clearance both when CFTR function was reduced by administration of a pharmacological blocker and when CFTR was fully functional. Conclusions: Enhancing the activity of TMEM16A increases epithelial fluid secretion and enhances mucus clearance independent of CFTR function. TMEM16A potentiation is a novel approach for the treatment of patients with CF and non-CF mucoobstructive diseases

What is (accounting) history?

I am grateful for the invitation to present this paper to you today. I have had a long association with Victoria University and as an undergraduate here I was introduced to the fathers of history - Herodotus and Thucydides. Unfortunately, although I had to read their main works, at the time I remained oblivious to their full significance, namely, that they represent two extremes of historiography that have remained throughout the history of history - two approaches to how history is created and written. These themes are the background for this paper. However, before I go any further I want to make a clarification - Philip was keen that my presentation remain consistent with the theme of the conference - history and the state. This is not difficult as the great majority of written history has been about the state . Both Herodotus and Thucydides were, of course, writing histories of the state , namely Athens. And, of course, if we are considering theories of history we can recall that Plato pointed out, any theory of man (sic), implicit or explicit, will be reflected in a theory of the state (cf Rist, 2002, pp 228 - 229)