1. One of the major challenges in the development of pharmaceuticals is their formulation with other materials to give them the desired bioavailability profile when administered into the body. 2. We have developed a flexible platform technology (Tris lipidation) to simply and effectively alter the lipophilicity of drugs. As implied by the name, the technology uses the common buffer Tris as a linker between the drugs of interest and a domain of variable hydrophobicity. 3. We demonstrate, using a mouse melanoma model, that Tris-lipidated conjugates of the widely used cytotoxic and anti-inflammatory drug methotrexate (MTX) display enhanced potency in the local treatment of tumours and reduced systemic toxicity when compared with the unconjugated drug. 4. With genes now being predicted to be the pharmaceuticals of the future, we show that Tris-lipidated cationic peptides can efficiently deliver DNA into (transfect) cells in culture. Furthermore, by comparing the abilities of variants of these Tris-based cationic lipids to transfect cultured cells, we demonstrate that modifications made to variable regions of Tris-lipidated compounds can dramatically alter their delivery profiles.

Three previously reported methanesulfonate insecticides, 6-isobutylthio-2-pyridyl methanesulfonate (I) and its sulfoxide (11) and sulfone (111) analogues were examined in two insect species Lucilia cuprina and Blattella germanica and in tissues from vertebrates. The results of B. germanica tests and cholinesterase assays confirmed the insecticidal activity of the compounds, with cholinesterase inhibition being the most likely mode of insecticidal action. The inactivity of the sulfide I and sulfoxide I1 in vertebrate in-vitro studies may indicate that conversion, in vivo, of the sulfide and sulfoxide methanesulfonates to the sulfone (111) is a requirement for activity. In mouse toxicity tests, matching high toxicity was observed for the alkylthio-, alkylsulfoxy-and alkylsulfone analogues indicating fast metabolic oxidation of the injected alkylthio-and alkylsulfoxy-compounds. However, in in-vitro tissue tests, the sulfone, although active, did not exhibit the characteristic pharmacological profile of the standard acetylcholinesterase inhibitor, physostigmine. The sulfone demonstrated a mixed action, with indications that it acts as an inhibitor of specific cholinesterase isozymes, or that it may modify responses at cholinoceptors.

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