Design, synthesis and applications of chiral cyclobutanes

Cyclobutanes are 4-carbon cyclic molecules that are found in many naturally occurring compounds with biological activities including antibiotics, antivirals and cytotoxics, and in insect pheromones, which can be used in agriculture to control pests. As a result, methods of preparing cyclobutanes are of great interest to chemists. Many syntheses have been developed but a large number involve the use of specialist equipment and hazardous reagents. This difficulty of synthesis means cyclobutane-containing molecules are rarely used in industry.This proposal aims to take a simple, but limited, method of forming the cyclobutane ring and extend it into a general route to prepare and attach a wide range of sidechains to the cyclobutane ring. These methods will find many applications in total synthesis of natural products, and the synthesis of molecules of interest to the agrochemical and pharmaceutical industries. As illustrations of these potential applications, we will be applying the new methods to, amongst other applications, the synthesis of a group of molecules with potential in the therapy of cancer.Each year, more than a quarter of a million people in the UK will be diagnosed with cancer. Most commonly used cancer treatments cause serious side-effects which reduce the patients' quality of life. There is an urgent need to develop new medicines which do not cause these side-effects in the body. One way of doing this is to create drugs to act on receptors which are found at different levels on tumour cells compared to normal cells. One such class of receptor is the integrins; receptors which allow a cell to interact with its surroundings. Beta3 integrins are highly expressed in prostate, colon, cervical and breast cancers and malignant melanoma, among others, where they encourage growth and distribution of the tumour to new areas of the body. We have designed a library of cyclobutane-containing compounds that are expected to block the interaction between a beta3-expressing cancer cell and its surroundings. This compound library will be synthesised employing the methods developed in this proposal and used in other investigations to improve our knowledge of the role of beta3 integrins in cancer and the structural features required for integrin-targeted drugs to be safe and effective; information which could ultimately lead to new medicines for the treatment of cancer.