In this study, twelve series of classical 5-, 6- and 7-substituted pyrrolo[2, 3-d]pyrimidines were designed and synthesized. Extensive structure modifications of the pyrrolo[2, 3-d] pyrimidine scaffold were investigated to determine selective transport via FR or/and PCFT and tumor targeted antifolates with GARFTase or multiple folate metabolizing enzyme inhibition.
The design strategies employed include: variation of the side chain substitution position (5-, 6- and 7-substituted); variation of the side chain length (n=1-6); isosteric replacement of the 1, 4-disubstituted phenyl ring with 1, 2- and 1, 3- disubstituted phenyl ring and 2, 5- disubstituted thiophenyl ring; replacement the L-glutamate with variation at the α and γ carboxylic acids.
As a part of this study, a total of one hundred and fifty six new compounds (including new intermediates) were synthesized and separated. Of these, twelve series consisting of forty two classical antifolate final compounds were submitted for biological evaluation. In addition, bulk synthesis of some potent final compounds (2, 2.0 g; 161, 500 mg; 175, 1.0 g; 166, 500 mg; 194, 500 mg) was carried out to facilitate in vivo evaluation.
More importantly, a new Heck coupling of the thiophene iodide 301 and allyl alcohols to synthesize aldehydes in one step was discovered. Due to its potential use in analog synthesis of clinically used antifolates such as RTX and PMX, this mild conditioned and easy to handle Heck coupling reaction is highly attractive.
During this study, the SAR of folate transporters (RFC, FR and PCFT) and GARFTase inhibitors were extensively explored. The 6-substituted straight chain compound 166 (n=7) was extremely potent against KB tumor cells (IC50=1.3 nM, about 80-fold more potent than clinically used PMX) without any RFC activity. The 5- substituted phenyl compound 175 (n=4) showed AICARFTase as the primary target with potent KB tumor cell inhibition (IC50=7.9 nM, about 8-fold more potent than PMX) and also indirectly inhibited the mTOR pathway leading to tumor cell apoptosis. Due to their potent antitumor activities, these two compounds serve as leads for future structural optimization.","abstract_html":"This dissertation comprises an introduction, background and current research progress in the area of classical antifolates as the targeted anticancer therapies.</p><p> In this study, twelve series of classical 5-, 6- and 7-substituted pyrrolo[2, 3-d]pyrimidines were designed and synthesized. Extensive structure modifications of the pyrrolo[2, 3-d] pyrimidine scaffold were investigated to determine selective transport via FR or/and PCFT and tumor targeted antifolates with GARFTase or multiple folate metabolizing enzyme inhibition.</p><p> The design strategies employed include: variation of the side chain substitution position (5-, 6- and 7-substituted); variation of the side chain length (n=1-6); isosteric replacement of the 1, 4-disubstituted phenyl ring with 1, 2- and 1, 3- disubstituted phenyl ring and 2, 5- disubstituted thiophenyl ring; replacement the L-glutamate with variation at the α and γ carboxylic acids.</p><p> As a part of this study, a total of one hundred and fifty six new compounds (including new intermediates) were synthesized and separated. Of these, twelve series consisting of forty two classical antifolate final compounds were submitted for biological evaluation. In addition, bulk synthesis of some potent final compounds (2, 2.0 g; 161, 500 mg; 175, 1.0 g; 166, 500 mg; 194, 500 mg) was carried out to facilitate in vivo evaluation.</p><p> More importantly, a new Heck coupling of the thiophene iodide 301 and allyl alcohols to synthesize aldehydes in one step was discovered. Due to its potential use in analog synthesis of clinically used antifolates such as RTX and PMX, this mild conditioned and easy to handle Heck coupling reaction is highly attractive.</p><p> During this study, the SAR of folate transporters (RFC, FR and PCFT) and GARFTase inhibitors were extensively explored. The 6-substituted straight chain compound 166 (n=7) was extremely potent against KB tumor cells (IC50=1.3 nM, about 80-fold more potent than clinically used PMX) without any RFC activity. The 5- substituted phenyl compound 175 (n=4) showed AICARFTase as the primary target with potent KB tumor cell inhibition (IC50=7.9 nM, about 8-fold more potent than PMX) and also indirectly inhibited the mTOR pathway leading to tumor cell apoptosis. Due to their potent antitumor activities, these two compounds serve as leads for future structural optimization.","abstract_has_math":false,"creators":["Wang, Yiqiang"],"institution":null,"degree_name":"PhD","degree_level":"Immediate Access","degree_discipline":"Medicinal Chemistry","degree_department":null,"school":null,"contributors":["Aleem Gangjee","Marc Harrold","Patrick Flaherty","David Lapinsky","Lawrence Block","Douglas Bricker"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2013,"date_issued":"2013-01-01T08:00:00Z","date_published":"2013-01-01T08:00:00Z","updated_at":"2026-07-24T02:10:36Z","subjects":["AICARFTase","Folate receptor","GARFTase","mTOR","Multiple targeted inhibitor","Proton coupled folate transporter"],"languages":["English"],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://dsc.duq.edu/etd/1335","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Aleem Gangjee","Marc Harrold","Patrick Flaherty","David Lapinsky","Lawrence Block","Douglas Bricker"]},{"key":"dc:creator","label":"Author","values":["Wang, Yiqiang"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.available","label":"Dc Date Available","values":["2018-03-28T07:00:00Z"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Medicinal Chemistry"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Immediate Access"]},{"key":"thesis:degree_name","label":"Degree Name","values":["PhD"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["AICARFTase","Folate receptor","GARFTase","mTOR","Multiple targeted inhibitor","Proton coupled folate transporter"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["English"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://dsc.duq.edu/etd/1335"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["This dissertation comprises an introduction, background and current research progress in the area of classical antifolates as the targeted anticancer therapies.
In this study, twelve series of classical 5-, 6- and 7-substituted pyrrolo[2, 3-d]pyrimidines were designed and synthesized. Extensive structure modifications of the pyrrolo[2, 3-d] pyrimidine scaffold were investigated to determine selective transport via FR or/and PCFT and tumor targeted antifolates with GARFTase or multiple folate metabolizing enzyme inhibition.
The design strategies employed include: variation of the side chain substitution position (5-, 6- and 7-substituted); variation of the side chain length (n=1-6); isosteric replacement of the 1, 4-disubstituted phenyl ring with 1, 2- and 1, 3- disubstituted phenyl ring and 2, 5- disubstituted thiophenyl ring; replacement the L-glutamate with variation at the α and γ carboxylic acids.
As a part of this study, a total of one hundred and fifty six new compounds (including new intermediates) were synthesized and separated. Of these, twelve series consisting of forty two classical antifolate final compounds were submitted for biological evaluation. In addition, bulk synthesis of some potent final compounds (2, 2.0 g; 161, 500 mg; 175, 1.0 g; 166, 500 mg; 194, 500 mg) was carried out to facilitate in vivo evaluation.
More importantly, a new Heck coupling of the thiophene iodide 301 and allyl alcohols to synthesize aldehydes in one step was discovered. Due to its potential use in analog synthesis of clinically used antifolates such as RTX and PMX, this mild conditioned and easy to handle Heck coupling reaction is highly attractive.
During this study, the SAR of folate transporters (RFC, FR and PCFT) and GARFTase inhibitors were extensively explored. The 6-substituted straight chain compound 166 (n=7) was extremely potent against KB tumor cells (IC50=1.3 nM, about 80-fold more potent than clinically used PMX) without any RFC activity. The 5- substituted phenyl compound 175 (n=4) showed AICARFTase as the primary target with potent KB tumor cell inhibition (IC50=7.9 nM, about 8-fold more potent than PMX) and also indirectly inhibited the mTOR pathway leading to tumor cell apoptosis. Due to their potent antitumor activities, these two compounds serve as leads for future structural optimization."]},{"key":"dc:title","label":"Title","values":["Classical Antifolates: Synthesis of 5-Substituted, 6-Substituted and 7-Substituted Pyrrolo[2,3-d]Pyrimidines as Targeted Anticancer Therapies"]}]}],"canonical_facts":{"dc:contributor":["Aleem Gangjee","Marc Harrold","Patrick Flaherty","David Lapinsky","Lawrence Block","Douglas Bricker"],"dc:creator":["Wang, Yiqiang"],"dc:date.available":["2018-03-28T07:00:00Z"],"dc:description.abstract":["This dissertation comprises an introduction, background and current research progress in the area of classical antifolates as the targeted anticancer therapies.
In this study, twelve series of classical 5-, 6- and 7-substituted pyrrolo[2, 3-d]pyrimidines were designed and synthesized. Extensive structure modifications of the pyrrolo[2, 3-d] pyrimidine scaffold were investigated to determine selective transport via FR or/and PCFT and tumor targeted antifolates with GARFTase or multiple folate metabolizing enzyme inhibition.
The design strategies employed include: variation of the side chain substitution position (5-, 6- and 7-substituted); variation of the side chain length (n=1-6); isosteric replacement of the 1, 4-disubstituted phenyl ring with 1, 2- and 1, 3- disubstituted phenyl ring and 2, 5- disubstituted thiophenyl ring; replacement the L-glutamate with variation at the α and γ carboxylic acids.
As a part of this study, a total of one hundred and fifty six new compounds (including new intermediates) were synthesized and separated. Of these, twelve series consisting of forty two classical antifolate final compounds were submitted for biological evaluation. In addition, bulk synthesis of some potent final compounds (2, 2.0 g; 161, 500 mg; 175, 1.0 g; 166, 500 mg; 194, 500 mg) was carried out to facilitate in vivo evaluation.
More importantly, a new Heck coupling of the thiophene iodide 301 and allyl alcohols to synthesize aldehydes in one step was discovered. Due to its potential use in analog synthesis of clinically used antifolates such as RTX and PMX, this mild conditioned and easy to handle Heck coupling reaction is highly attractive.
During this study, the SAR of folate transporters (RFC, FR and PCFT) and GARFTase inhibitors were extensively explored. The 6-substituted straight chain compound 166 (n=7) was extremely potent against KB tumor cells (IC50=1.3 nM, about 80-fold more potent than clinically used PMX) without any RFC activity. The 5- substituted phenyl compound 175 (n=4) showed AICARFTase as the primary target with potent KB tumor cell inhibition (IC50=7.9 nM, about 8-fold more potent than PMX) and also indirectly inhibited the mTOR pathway leading to tumor cell apoptosis. Due to their potent antitumor activities, these two compounds serve as leads for future structural optimization."],"dc:identifier":["https://dsc.duq.edu/etd/1335"],"dc:language":["English"],"dc:subject":["AICARFTase","Folate receptor","GARFTase","mTOR","Multiple targeted inhibitor","Proton coupled folate transporter"],"dc:title":["Classical Antifolates: Synthesis of 5-Substituted, 6-Substituted and 7-Substituted Pyrrolo[2,3-d]Pyrimidines as Targeted Anticancer Therapies"],"thesis:degree_discipline":["Medicinal Chemistry"],"thesis:degree_level":["Immediate Access"],"thesis:degree_name":["PhD"]},"updated_at":"2026-07-24T02:10:36Z"}