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Quinazoline antifolate thymidylate synthase inhibitors: difluoro-substituted benzene ring analogs

The synthesis of a series of new C2-methyl-N10-alkylquinazoline-based thymidylate synthase (TS) inhibitors containing difluroinated p-aminobenzoate rings is described. Derivatives of the N10-propargyl and N10-methylquinazoline antifolates were prepared with 2',3'-, 2',5'-, and 2&...

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Published in:Journal of medicinal chemistry 1992-06, Vol.35 (12), p.2321-2327
Main Authors: Thornton, Timothy J, Jackman, Ann L, Marsham, Peter R, O'Connor, Brigid M, Bishop, Joel A. M, Calvert, A. Hilary
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container_issue 12
container_start_page 2321
container_title Journal of medicinal chemistry
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creator Thornton, Timothy J
Jackman, Ann L
Marsham, Peter R
O'Connor, Brigid M
Bishop, Joel A. M
Calvert, A. Hilary
description The synthesis of a series of new C2-methyl-N10-alkylquinazoline-based thymidylate synthase (TS) inhibitors containing difluroinated p-aminobenzoate rings is described. Derivatives of the N10-propargyl and N10-methylquinazoline antifolates were prepared with 2',3'-, 2',5'-, and 2',6'-difluoro substitution. The synthesis of the 2',5'-difluoro analogues involved oxidation of the difluoronitrotoluene to 2,5-difluoro-4-nitrobenzoic acid followed by glutamation, reduction, and alkylation (propargyl bromide or MeI) to the diethyl N-(4-(alkylamino)-2,5-difluorobenzoyl)-L-glutamates. For the synthesis of the 2',3'- and 2',6'-difluoro compounds a new route was devised starting from methyl 4-((tert-butoxycarbonyl)amino)-2,6-difluorobenzoate and its 2,3-substituted counterpart. Treatment with NaH and then an alkyl halide introduced the N10-substituent. The methyl ester was hydrolyzed and the resulting acid was condensed with diethyl L-glutamate. The secondary amine was liberated using CF3CO2H and coupled with 6-(bromo-methyl)-3,4-dihydro-2-methyl-4-oxoquinazoline to yield the antifolate diesters. Final deprotection with mild alkali completed the synthesis in each case. The target compounds were tested as inhibitors of partially purified L1210 TS and also examined for their inhibition of the growth of L1210 cells in culture. Compared to their nonfluorinated parent compounds all the difluoro analogues were poorer inhibitors of TS. The greatest loss of enzyme activity was seen in the N10-propargyl analogues which contained one of the fluorine atoms ortho to the amine substituent. This loss was less apparent in the N10-methyl derivatives. Despite this lower inhibition of TS the majority of new compounds have equivalent cytotoxicity to their nonfluorinated predecessors.
doi_str_mv 10.1021/jm00090a024
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M ; Calvert, A. Hilary</creator><creatorcontrib>Thornton, Timothy J ; Jackman, Ann L ; Marsham, Peter R ; O'Connor, Brigid M ; Bishop, Joel A. M ; Calvert, A. Hilary</creatorcontrib><description>The synthesis of a series of new C2-methyl-N10-alkylquinazoline-based thymidylate synthase (TS) inhibitors containing difluroinated p-aminobenzoate rings is described. Derivatives of the N10-propargyl and N10-methylquinazoline antifolates were prepared with 2',3'-, 2',5'-, and 2',6'-difluoro substitution. The synthesis of the 2',5'-difluoro analogues involved oxidation of the difluoronitrotoluene to 2,5-difluoro-4-nitrobenzoic acid followed by glutamation, reduction, and alkylation (propargyl bromide or MeI) to the diethyl N-(4-(alkylamino)-2,5-difluorobenzoyl)-L-glutamates. For the synthesis of the 2',3'- and 2',6'-difluoro compounds a new route was devised starting from methyl 4-((tert-butoxycarbonyl)amino)-2,6-difluorobenzoate and its 2,3-substituted counterpart. 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M</creatorcontrib><creatorcontrib>Calvert, A. Hilary</creatorcontrib><title>Quinazoline antifolate thymidylate synthase inhibitors: difluoro-substituted benzene ring analogs</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>The synthesis of a series of new C2-methyl-N10-alkylquinazoline-based thymidylate synthase (TS) inhibitors containing difluroinated p-aminobenzoate rings is described. Derivatives of the N10-propargyl and N10-methylquinazoline antifolates were prepared with 2',3'-, 2',5'-, and 2',6'-difluoro substitution. The synthesis of the 2',5'-difluoro analogues involved oxidation of the difluoronitrotoluene to 2,5-difluoro-4-nitrobenzoic acid followed by glutamation, reduction, and alkylation (propargyl bromide or MeI) to the diethyl N-(4-(alkylamino)-2,5-difluorobenzoyl)-L-glutamates. 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Chem</addtitle><date>1992-06-01</date><risdate>1992</risdate><volume>35</volume><issue>12</issue><spage>2321</spage><epage>2327</epage><pages>2321-2327</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>The synthesis of a series of new C2-methyl-N10-alkylquinazoline-based thymidylate synthase (TS) inhibitors containing difluroinated p-aminobenzoate rings is described. Derivatives of the N10-propargyl and N10-methylquinazoline antifolates were prepared with 2',3'-, 2',5'-, and 2',6'-difluoro substitution. The synthesis of the 2',5'-difluoro analogues involved oxidation of the difluoronitrotoluene to 2,5-difluoro-4-nitrobenzoic acid followed by glutamation, reduction, and alkylation (propargyl bromide or MeI) to the diethyl N-(4-(alkylamino)-2,5-difluorobenzoyl)-L-glutamates. For the synthesis of the 2',3'- and 2',6'-difluoro compounds a new route was devised starting from methyl 4-((tert-butoxycarbonyl)amino)-2,6-difluorobenzoate and its 2,3-substituted counterpart. Treatment with NaH and then an alkyl halide introduced the N10-substituent. The methyl ester was hydrolyzed and the resulting acid was condensed with diethyl L-glutamate. The secondary amine was liberated using CF3CO2H and coupled with 6-(bromo-methyl)-3,4-dihydro-2-methyl-4-oxoquinazoline to yield the antifolate diesters. Final deprotection with mild alkali completed the synthesis in each case. The target compounds were tested as inhibitors of partially purified L1210 TS and also examined for their inhibition of the growth of L1210 cells in culture. Compared to their nonfluorinated parent compounds all the difluoro analogues were poorer inhibitors of TS. The greatest loss of enzyme activity was seen in the N10-propargyl analogues which contained one of the fluorine atoms ortho to the amine substituent. This loss was less apparent in the N10-methyl derivatives. Despite this lower inhibition of TS the majority of new compounds have equivalent cytotoxicity to their nonfluorinated predecessors.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>1613755</pmid><doi>10.1021/jm00090a024</doi><tpages>7</tpages></addata></record>
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ispartof Journal of medicinal chemistry, 1992-06, Vol.35 (12), p.2321-2327
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source ACS CRKN Legacy Archives
subjects Animals
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - pharmacology
Benzene - chemistry
Cell Division - drug effects
Chemistry
Exact sciences and technology
Fluorine - chemistry
Folic Acid Antagonists - chemical synthesis
Folic Acid Antagonists - pharmacology
Heterocyclic compounds
Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings
Leukemia L1210 - pathology
Molecular Structure
Organic chemistry
Preparations and properties
Quinazolines - chemical synthesis
Quinazolines - pharmacology
Structure-Activity Relationship
Thymidylate Synthase - antagonists & inhibitors
title Quinazoline antifolate thymidylate synthase inhibitors: difluoro-substituted benzene ring analogs
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