Design, synthesis and applications of chiral cyclobutanes

Lead Research Organisation: University of Bradford
Department Name: Sch of Life Sciences

Abstract

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.
 
Description We have developed new chemical methods for the synthesis of small ring molecules with a diverse range of structures. These methods have been used in work towards total synthesis of the natural products whisky lactones and are now being used towards the total synthesis more complex natural products with anticancer activity. These methods have also been used to prepare a library of 75 compounds designed to target the beta3 integrins. We have shown that members of this library block the interaction between beta3-expressing melanoma cells and their surroundings more effectively than commercial anti-integrin agents. The effect of the compounds on cancer cell growth and survival has been fully characterised, providing a 'structure activity relationship' that will be used to select the most active agents for future work. Further investigations of these agents are underway to fully characterise the effect of the compound library on melanoma and prostate cancer growth and spreading (adhesion and migration), and their effect on the blood vessels that feed tumours, in order to select a lead compound that could ultimately be developed into a new medicine for the treatment of cancer.
Exploitation Route The synthetic methods developed will be of use to the pharmaceutical industry, providing a new and efficient route to highly functionalised structures that are currently under-represented in drug development.

The synthesis of compounds shown to antagonise integrin receptors on cancer cells could have substantial benefit for cancer clinicians/cancer patients. Integrin antagonists could be applicable to treating a wide range of cancers; Of particular inportance are prostate cancer and malignant melanoma, where integrins encourage aggressive growth and spread of the tumour to new areas of the body. These tumours are areas of unmet clinical need; existing drugs are insufficient to treat advanced disease so there is an urgent need to develop more therapies. Development of our compounds should yield an improved treatment, effective against tumour growth and invasion in advanced disease and presents an excellent opportunity to develop a new, molecularly targeted, therapy for these intractable cancers. The research can be used by chemists in academia or the pharmaceutical industry who need to synthesise compounds containing a highly substituted cyclobutane ring.

The compound library contains molecules that will be of use to biological and biomedical researchers in the areas of integrin biology and cell signalling; the compounds can be used as probe molecules to characterise the effects on altering integrin function and signalling in a number of diseases, including cancer. This information on integrin antagonism, combined with analysis of the structure-function relationships within the compounds can be used by researchers in drug discovery and the pharmaceutical industry to assist the development of new integrin antagonists as safe and effective drugs.
Sectors Chemicals,Healthcare,Pharmaceuticals and Medical Biotechnology

URL http://www.bradford.ac.uk/research/our-research/research-in-schools/life-sciences/areas-centres/cancer-therapeutics/staff/academic/dr-helen-sheldrake.php
 
Description In ongoing research towards developing new anticancer therapeutics
First Year Of Impact 2011
Sector Pharmaceuticals and Medical Biotechnology
Impact Types Societal

 
Description The Prostate Cancer Charity
Amount £49,992 (GBP)
Funding ID PA10-01 Sheldrake 
Organisation Prostate Cancer UK 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2011 
End 08/2012
 
Description Yorkshire Cancer Research PhD Studentships
Amount £51,960 (GBP)
Funding ID B002PhD 
Organisation Yorkshire Cancer Research 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2011 
End 09/2014
 
Description Dissemination to academic community 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Poster Presentation
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact Poster presentation at RSC Symposium.

Initial non-confidential research results were presented at the Royal Society of Chemistry Postgraduate Symposium held at the University of Bradford.

Increased awareness of research among undergraduate students, stimulating interest in medicinal chemistry options as degree choices.
Year(s) Of Engagement Activity 2010,2012
 
Description Dissemination to local community 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact University of Bradford Research and Knowledge Transfer Showcase.

The research project was included in the Institute of Cancer Therapeutic's presentation/stall at Bradford's Research and Knowledge Transfer Showcase - a public event which communicates the University's world-class research to visitors from the local community, industrial collaborators, and sponsoring organisations.

Information not currently available
Year(s) Of Engagement Activity 2009
 
Description Dissemination to the public 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Third sector organisations
Results and Impact Attendance at Research in Action event organised by The Prostate Cancer Charity.

As a result of receiving a Pilot grant from the Prostate Cancer Charity to follow up results from the EPSRC award, we attended the Research in Action event to introduce our work to the charity's supporters and cancer patients.

Interactions with fundraisers is mutually inspirational
Year(s) Of Engagement Activity 2011
 
Description Research Open days for student recruitment 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Undergraduate students
Results and Impact Aim to highlight the research done in the faculty, encouraging students to become involved (undergraduate or postgraduate research projects) and cross-disciplinary collaboration.
Year(s) Of Engagement Activity 2010,2011,2012,2013,2014
 
Description YCR Scientific Meeting 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Other audiences
Results and Impact Yorkshire Cancer Research annual meeting to highlight the quality and breadth of research it funds and promote interaction between researchers.
Year(s) Of Engagement Activity 2013,2014
URL http://yorkshirecancerresearch.org.uk/for-researchers/2014-annual-scientific-meeting/