Synthesis and biological activities of conformationally restricted, tricyclic nonclassical antifolates as inhibitors of dihydrofolate reductases

A. Gangjee, J. Shi, Sherry Queener

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21 Citations (Scopus)

Abstract

Seven novel tricyclic pyrimido[4,5-c][2,7]naphthyridones 5-8 and the corresponding naphthyridines 9-11 were synthesized as conformationally restricted inhibitors of dihydrofolate reductase (DHFR) and as antitumor and/or antiinfectious agents. The analogues were designed to orient the side chain trimethoxyphenyl group in different conformationally defined positions in order to explore the effect of the side chain orientation on binding affinity and selectivity for DHFR from various species. The semirigid orientations were achieved by bridging the C5 and N10 of compound 12 with a N-ethyl bridge and by variation of the position of double bonds in rings B and C as well as substitution at the 2',6'- positions of the phenyl ring. The synthesis of compounds 5-11 were accomplished by cyclocondensation of the appropriate keto ester (as the biselectrophile) with 2,4,6-triaminopyrimidine to afford the lactam 5. The dehydrolactams 6 and 7 were prepared by air oxidation and PtO2-catalyzed dehydrogenation of 7, respectively. The dichloro dehydro lactam 8 was obtained by refluxing lactam 5 and/or 6 in POCl3 or a mixture of POCl3/PCI5. Compounds 9-11 were obtained by two methods, direct borane reduction of lactam 5 or 6 or thiation of the dipivoylated lactam 15 followed by reductive dethiation. Compounds 9-11 were interconverted by air oxidation or PtO2-catalyzed reduction/oxidation, respectively. The compounds were evaluated as inhibitors of DHFR from Pneumocystis carinii (pc) and Toxoplasma gondii (tg) with rat liver (rl) serving as the reference mammalian enzyme. In the lactam series 5-8, the most unsaturated analogue 7 showed an IC50 of 86 nM against rlDHFR, almost 100- fold more active than 5 and 3-fold more active than 6. The 2',6'-dichloro dehydro lactam 8 was less active than the corresponding dehydro lactam 6 against rlDHFR. In the naphthyridine series 9-11, the dehydro analogue 10 was more active than 9 against rlDHFR. The fully reduced analogue 11 (as a mixture of cis and trans isomers) was the most active in the naphthyridine series. The analogues were, in general, more inhibitory against rlDHFR than against pcDHFR, or tgDHFR, and thus lacked selectivity. In addition, they were less potent than the bicyclic compounds trimetrexate 3 (TMQ) and piritrixim 4 (PTX).

Original languageEnglish (US)
Pages (from-to)1930-1936
Number of pages7
JournalJournal of Medicinal Chemistry
Volume40
Issue number12
DOIs
StatePublished - 1997
Externally publishedYes

Fingerprint

Folic Acid Antagonists
Lactams
Bioactivity
Naphthyridines
Oxidation
Trimetrexate
Air
Boranes
Pneumocystis carinii
Tetrahydrofolate Dehydrogenase
Toxoplasma
Dehydrogenation
Isomers
Liver
Inhibitory Concentration 50
Rats
Esters
Substitution reactions

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

@article{1b9aa54009ed4cb8bedcfd6c6a48222c,
title = "Synthesis and biological activities of conformationally restricted, tricyclic nonclassical antifolates as inhibitors of dihydrofolate reductases",
abstract = "Seven novel tricyclic pyrimido[4,5-c][2,7]naphthyridones 5-8 and the corresponding naphthyridines 9-11 were synthesized as conformationally restricted inhibitors of dihydrofolate reductase (DHFR) and as antitumor and/or antiinfectious agents. The analogues were designed to orient the side chain trimethoxyphenyl group in different conformationally defined positions in order to explore the effect of the side chain orientation on binding affinity and selectivity for DHFR from various species. The semirigid orientations were achieved by bridging the C5 and N10 of compound 12 with a N-ethyl bridge and by variation of the position of double bonds in rings B and C as well as substitution at the 2',6'- positions of the phenyl ring. The synthesis of compounds 5-11 were accomplished by cyclocondensation of the appropriate keto ester (as the biselectrophile) with 2,4,6-triaminopyrimidine to afford the lactam 5. The dehydrolactams 6 and 7 were prepared by air oxidation and PtO2-catalyzed dehydrogenation of 7, respectively. The dichloro dehydro lactam 8 was obtained by refluxing lactam 5 and/or 6 in POCl3 or a mixture of POCl3/PCI5. Compounds 9-11 were obtained by two methods, direct borane reduction of lactam 5 or 6 or thiation of the dipivoylated lactam 15 followed by reductive dethiation. Compounds 9-11 were interconverted by air oxidation or PtO2-catalyzed reduction/oxidation, respectively. The compounds were evaluated as inhibitors of DHFR from Pneumocystis carinii (pc) and Toxoplasma gondii (tg) with rat liver (rl) serving as the reference mammalian enzyme. In the lactam series 5-8, the most unsaturated analogue 7 showed an IC50 of 86 nM against rlDHFR, almost 100- fold more active than 5 and 3-fold more active than 6. The 2',6'-dichloro dehydro lactam 8 was less active than the corresponding dehydro lactam 6 against rlDHFR. In the naphthyridine series 9-11, the dehydro analogue 10 was more active than 9 against rlDHFR. The fully reduced analogue 11 (as a mixture of cis and trans isomers) was the most active in the naphthyridine series. The analogues were, in general, more inhibitory against rlDHFR than against pcDHFR, or tgDHFR, and thus lacked selectivity. In addition, they were less potent than the bicyclic compounds trimetrexate 3 (TMQ) and piritrixim 4 (PTX).",
author = "A. Gangjee and J. Shi and Sherry Queener",
year = "1997",
doi = "10.1021/jm960693n",
language = "English (US)",
volume = "40",
pages = "1930--1936",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "12",

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TY - JOUR

T1 - Synthesis and biological activities of conformationally restricted, tricyclic nonclassical antifolates as inhibitors of dihydrofolate reductases

AU - Gangjee, A.

AU - Shi, J.

AU - Queener, Sherry

PY - 1997

Y1 - 1997

N2 - Seven novel tricyclic pyrimido[4,5-c][2,7]naphthyridones 5-8 and the corresponding naphthyridines 9-11 were synthesized as conformationally restricted inhibitors of dihydrofolate reductase (DHFR) and as antitumor and/or antiinfectious agents. The analogues were designed to orient the side chain trimethoxyphenyl group in different conformationally defined positions in order to explore the effect of the side chain orientation on binding affinity and selectivity for DHFR from various species. The semirigid orientations were achieved by bridging the C5 and N10 of compound 12 with a N-ethyl bridge and by variation of the position of double bonds in rings B and C as well as substitution at the 2',6'- positions of the phenyl ring. The synthesis of compounds 5-11 were accomplished by cyclocondensation of the appropriate keto ester (as the biselectrophile) with 2,4,6-triaminopyrimidine to afford the lactam 5. The dehydrolactams 6 and 7 were prepared by air oxidation and PtO2-catalyzed dehydrogenation of 7, respectively. The dichloro dehydro lactam 8 was obtained by refluxing lactam 5 and/or 6 in POCl3 or a mixture of POCl3/PCI5. Compounds 9-11 were obtained by two methods, direct borane reduction of lactam 5 or 6 or thiation of the dipivoylated lactam 15 followed by reductive dethiation. Compounds 9-11 were interconverted by air oxidation or PtO2-catalyzed reduction/oxidation, respectively. The compounds were evaluated as inhibitors of DHFR from Pneumocystis carinii (pc) and Toxoplasma gondii (tg) with rat liver (rl) serving as the reference mammalian enzyme. In the lactam series 5-8, the most unsaturated analogue 7 showed an IC50 of 86 nM against rlDHFR, almost 100- fold more active than 5 and 3-fold more active than 6. The 2',6'-dichloro dehydro lactam 8 was less active than the corresponding dehydro lactam 6 against rlDHFR. In the naphthyridine series 9-11, the dehydro analogue 10 was more active than 9 against rlDHFR. The fully reduced analogue 11 (as a mixture of cis and trans isomers) was the most active in the naphthyridine series. The analogues were, in general, more inhibitory against rlDHFR than against pcDHFR, or tgDHFR, and thus lacked selectivity. In addition, they were less potent than the bicyclic compounds trimetrexate 3 (TMQ) and piritrixim 4 (PTX).

AB - Seven novel tricyclic pyrimido[4,5-c][2,7]naphthyridones 5-8 and the corresponding naphthyridines 9-11 were synthesized as conformationally restricted inhibitors of dihydrofolate reductase (DHFR) and as antitumor and/or antiinfectious agents. The analogues were designed to orient the side chain trimethoxyphenyl group in different conformationally defined positions in order to explore the effect of the side chain orientation on binding affinity and selectivity for DHFR from various species. The semirigid orientations were achieved by bridging the C5 and N10 of compound 12 with a N-ethyl bridge and by variation of the position of double bonds in rings B and C as well as substitution at the 2',6'- positions of the phenyl ring. The synthesis of compounds 5-11 were accomplished by cyclocondensation of the appropriate keto ester (as the biselectrophile) with 2,4,6-triaminopyrimidine to afford the lactam 5. The dehydrolactams 6 and 7 were prepared by air oxidation and PtO2-catalyzed dehydrogenation of 7, respectively. The dichloro dehydro lactam 8 was obtained by refluxing lactam 5 and/or 6 in POCl3 or a mixture of POCl3/PCI5. Compounds 9-11 were obtained by two methods, direct borane reduction of lactam 5 or 6 or thiation of the dipivoylated lactam 15 followed by reductive dethiation. Compounds 9-11 were interconverted by air oxidation or PtO2-catalyzed reduction/oxidation, respectively. The compounds were evaluated as inhibitors of DHFR from Pneumocystis carinii (pc) and Toxoplasma gondii (tg) with rat liver (rl) serving as the reference mammalian enzyme. In the lactam series 5-8, the most unsaturated analogue 7 showed an IC50 of 86 nM against rlDHFR, almost 100- fold more active than 5 and 3-fold more active than 6. The 2',6'-dichloro dehydro lactam 8 was less active than the corresponding dehydro lactam 6 against rlDHFR. In the naphthyridine series 9-11, the dehydro analogue 10 was more active than 9 against rlDHFR. The fully reduced analogue 11 (as a mixture of cis and trans isomers) was the most active in the naphthyridine series. The analogues were, in general, more inhibitory against rlDHFR than against pcDHFR, or tgDHFR, and thus lacked selectivity. In addition, they were less potent than the bicyclic compounds trimetrexate 3 (TMQ) and piritrixim 4 (PTX).

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