{"id":{"repo_id":"bradford","oai_identifier":"oai:bradscholars.brad.ac.uk:10454/6311.2"},"canonical_url":"https://search.dev.ndltd.org/etd/bradford/oai:bradscholars.brad.ac.uk:10454/6311.2","repository":{"repo_id":"bradford","name":"University of Bradford","base_url":"https://bradscholars.brad.ac.uk/oai/request"},"display":{"title":"Exploration of [2+2+2] cyclotrimerisation reactions of alkynes. A new methodology for the synthesis of small molecules to probe biological systems","abstract":"The generation of new chemical entities (NCEs) for use in chemical biology and drug discovery is of wide interest to both academia and the pharmaceutical industry. In order to generate NCEs, this project focused on development of new synthetic methodologies using transition-metal mediated [2+2+2] cyclotrimerisation of alkynes and unsaturated molecules to form bi- and tricyclic heterocyclic derivatives, some with structural resemblance to the quinocarcin family of natural products. Three different dialkynes (1,5-di(prop-2-yn-1-yl)pyrrolidin-2-one 2.117a, 1,6-di(prop-2-yn-1-yl)piperidin-2-one 2.118a and 4-benzyl-1,6-di(prop-2-yn-1-yl)piperazin-2-one 2.120a) were successfully synthesised. Several cyclotrimerisations were attempted, with the best yields being obtained when diethylacetylene dicarboxylate 2.113a was used as the monoalkyne and Cp*Ru(cod)Cl as the catalyst in refluxing toluene. New heterocyclic compounds with potential for diversification were synthesised using a diversity-oriented synthesis approach; specifically the build/couple/pair strategy for the synthesis of small molecules. Racemic nitrogen and oxygen building blocks were coupled with acrylonitrile, bromoacetonitrile and acyl chlorides. The pair step involved the intramolecular ring closure using transition-metal catalysed [2+2+2] cyclotrimerisations using microwave assisted radiation. The best catalyst for this approach was found to be CpCo(CO)2 at 150 ºC (300 W) in chlorobenzene. This provided a new methodology with potential for synthesising a diverse set of small molecules for biological testing. 20 compounds were subjected to chemosensitivity testing using the MTT assay. Several compounds were shown to possess activity in bladder (RT112) and breast (MCF-7) cancer cell lines. As these two cell lines are known to express extra-hepatic cytochromes P450 enzymes, it is possible that these are involved in generating cytotoxic metabolites that may damage DNA.","abstract_html":"The generation of new chemical entities (NCEs) for use in chemical biology and drug discovery is of wide interest to both academia and the pharmaceutical industry. In order to generate NCEs, this project focused on development of new synthetic methodologies using transition-metal mediated [2+2+2] cyclotrimerisation of alkynes and unsaturated molecules to form bi- and tricyclic heterocyclic derivatives, some with structural resemblance to the quinocarcin family of natural products. Three different dialkynes (1,5-di(prop-2-yn-1-yl)pyrrolidin-2-one 2.117a, 1,6-di(prop-2-yn-1-yl)piperidin-2-one 2.118a and 4-benzyl-1,6-di(prop-2-yn-1-yl)piperazin-2-one 2.120a) were successfully synthesised. Several cyclotrimerisations were attempted, with the best yields being obtained when diethylacetylene dicarboxylate 2.113a was used as the monoalkyne and Cp*Ru(cod)Cl as the catalyst in refluxing toluene. New heterocyclic compounds with potential for diversification were synthesised using a diversity-oriented synthesis approach; specifically the build/couple/pair strategy for the synthesis of small molecules. Racemic nitrogen and oxygen building blocks were coupled with acrylonitrile, bromoacetonitrile and acyl chlorides. The pair step involved the intramolecular ring closure using transition-metal catalysed [2+2+2] cyclotrimerisations using microwave assisted radiation. The best catalyst for this approach was found to be CpCo(CO)2 at 150 ºC (300 W) in chlorobenzene. This provided a new methodology with potential for synthesising a diverse set of small molecules for biological testing. 20 compounds were subjected to chemosensitivity testing using the MTT assay. Several compounds were shown to possess activity in bladder (RT112) and breast (MCF-7) cancer cell lines. As these two cell lines are known to express extra-hepatic cytochromes P450 enzymes, it is possible that these are involved in generating cytotoxic metabolites that may damage DNA.","abstract_has_math":false,"creators":["Neves dos Santos, Ana Rita"],"institution":"University of Bradford","degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Pors, Klaus","Patterson, Laurence H.","Sheldrake, Helen M."],"committee_chairs":[],"committee_members":[],"year":2014,"date_issued":"2014-05-06","date_published":"2014-05-06","updated_at":"2026-07-24T01:12:58Z","subjects":["[2+2+2] cyclotrimerisation","Alkynes","Biological probe","Diversity-oriented synthesis; DOS","Tetrahydroisoquinoline","Transition-metal chemistry","Organometallic chemistry","Microwave chemistry","Tetrahydronaphthyridine","Dihydropyrrolopyridine"],"languages":["en"],"rights":["\"Creative
The University of Bradford theses are licenced under a Creative Commons Licence."],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://bradscholars.brad.ac.uk/handle/10454/6311.2","outbound_label":"Repository record","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Pors, Klaus","Patterson, Laurence H.","Sheldrake, Helen M."]},{"key":"dc:creator","label":"Author","values":["Neves dos Santos, Ana Rita"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2025-04-30T11:49:45Z"]},{"key":"dc:date.available","label":"Dc Date Available","values":["2014-05-06T12:31:25Z","2025-04-30T11:49:45Z"]},{"key":"dc:date.issued","label":"Date","values":["2014-05-06"]},{"key":"dc:publisher.department","label":"Dc Publisher Department","values":["Institute of Cancer Therapeutics"]},{"key":"dc:publisher.institution","label":"Dc Publisher Institution","values":["University of Bradford"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]},{"key":"dc:type.qualificationlevel","label":"Dc Type Qualificationlevel","values":["doctoral"]},{"key":"dc:type.qualificationname","label":"Dc Type Qualificationname","values":["PhD"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["[2+2+2] cyclotrimerisation","Alkynes","Biological probe","Diversity-oriented synthesis; DOS","Tetrahydroisoquinoline","Transition-metal chemistry","Organometallic chemistry","Microwave chemistry","Tetrahydronaphthyridine","Dihydropyrrolopyridine"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language.iso","label":"Language (ISO)","values":["en"]},{"key":"dc:rights","label":"Dc Rights","values":["\"Creative
The University of Bradford theses are licenced under a Creative Commons Licence."]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://bradscholars.brad.ac.uk/handle/10454/6311.2"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["The generation of new chemical entities (NCEs) for use in chemical biology and drug discovery is of wide interest to both academia and the pharmaceutical industry. In order to generate NCEs, this project focused on development of new synthetic methodologies using transition-metal mediated [2+2+2] cyclotrimerisation of alkynes and unsaturated molecules to form bi- and tricyclic heterocyclic derivatives, some with structural resemblance to the quinocarcin family of natural products. Three different dialkynes (1,5-di(prop-2-yn-1-yl)pyrrolidin-2-one 2.117a, 1,6-di(prop-2-yn-1-yl)piperidin-2-one 2.118a and 4-benzyl-1,6-di(prop-2-yn-1-yl)piperazin-2-one 2.120a) were successfully synthesised. Several cyclotrimerisations were attempted, with the best yields being obtained when diethylacetylene dicarboxylate 2.113a was used as the monoalkyne and Cp*Ru(cod)Cl as the catalyst in refluxing toluene. New heterocyclic compounds with potential for diversification were synthesised using a diversity-oriented synthesis approach; specifically the build/couple/pair strategy for the synthesis of small molecules. Racemic nitrogen and oxygen building blocks were coupled with acrylonitrile, bromoacetonitrile and acyl chlorides. The pair step involved the intramolecular ring closure using transition-metal catalysed [2+2+2] cyclotrimerisations using microwave assisted radiation. The best catalyst for this approach was found to be CpCo(CO)2 at 150 ºC (300 W) in chlorobenzene. This provided a new methodology with potential for synthesising a diverse set of small molecules for biological testing. 20 compounds were subjected to chemosensitivity testing using the MTT assay. Several compounds were shown to possess activity in bladder (RT112) and breast (MCF-7) cancer cell lines. As these two cell lines are known to express extra-hepatic cytochromes P450 enzymes, it is possible that these are involved in generating cytotoxic metabolites that may damage DNA."]},{"key":"dc:title","label":"Title","values":["Exploration of [2+2+2] cyclotrimerisation reactions of alkynes. A new methodology for the synthesis of small molecules to probe biological systems"]}]}],"canonical_facts":{"dc:contributor.advisor":["Pors, Klaus","Patterson, Laurence H.","Sheldrake, Helen M."],"dc:creator":["Neves dos Santos, Ana Rita"],"dc:date.accessioned":["2025-04-30T11:49:45Z"],"dc:date.available":["2014-05-06T12:31:25Z","2025-04-30T11:49:45Z"],"dc:date.issued":["2014-05-06"],"dc:description.abstract":["The generation of new chemical entities (NCEs) for use in chemical biology and drug discovery is of wide interest to both academia and the pharmaceutical industry. In order to generate NCEs, this project focused on development of new synthetic methodologies using transition-metal mediated [2+2+2] cyclotrimerisation of alkynes and unsaturated molecules to form bi- and tricyclic heterocyclic derivatives, some with structural resemblance to the quinocarcin family of natural products. Three different dialkynes (1,5-di(prop-2-yn-1-yl)pyrrolidin-2-one 2.117a, 1,6-di(prop-2-yn-1-yl)piperidin-2-one 2.118a and 4-benzyl-1,6-di(prop-2-yn-1-yl)piperazin-2-one 2.120a) were successfully synthesised. Several cyclotrimerisations were attempted, with the best yields being obtained when diethylacetylene dicarboxylate 2.113a was used as the monoalkyne and Cp*Ru(cod)Cl as the catalyst in refluxing toluene. New heterocyclic compounds with potential for diversification were synthesised using a diversity-oriented synthesis approach; specifically the build/couple/pair strategy for the synthesis of small molecules. Racemic nitrogen and oxygen building blocks were coupled with acrylonitrile, bromoacetonitrile and acyl chlorides. The pair step involved the intramolecular ring closure using transition-metal catalysed [2+2+2] cyclotrimerisations using microwave assisted radiation. The best catalyst for this approach was found to be CpCo(CO)2 at 150 ºC (300 W) in chlorobenzene. This provided a new methodology with potential for synthesising a diverse set of small molecules for biological testing. 20 compounds were subjected to chemosensitivity testing using the MTT assay. Several compounds were shown to possess activity in bladder (RT112) and breast (MCF-7) cancer cell lines. As these two cell lines are known to express extra-hepatic cytochromes P450 enzymes, it is possible that these are involved in generating cytotoxic metabolites that may damage DNA."],"dc:identifier.uri":["https://bradscholars.brad.ac.uk/handle/10454/6311.2"],"dc:language.iso":["en"],"dc:publisher.department":["Institute of Cancer Therapeutics"],"dc:publisher.institution":["University of Bradford"],"dc:rights":["\"Creative
The University of Bradford theses are licenced under a Creative Commons Licence."],"dc:subject":["[2+2+2] cyclotrimerisation","Alkynes","Biological probe","Diversity-oriented synthesis; DOS","Tetrahydroisoquinoline","Transition-metal chemistry","Organometallic chemistry","Microwave chemistry","Tetrahydronaphthyridine","Dihydropyrrolopyridine"],"dc:title":["Exploration of [2+2+2] cyclotrimerisation reactions of alkynes. A new methodology for the synthesis of small molecules to probe biological systems"],"dc:type":["Thesis"],"dc:type.qualificationlevel":["doctoral"],"dc:type.qualificationname":["PhD"]},"updated_at":"2026-07-24T01:12:58Z"}