Synthesis and biological activities of tricyclic conformationally restricted tetrahydropyrido annulated furo[2,3-d]pyrimidines as inhibitors of dihydrofolate reductases

Aleem Gangjee, Elfatih Elzein, Sherry Queener, John J. McGuire

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

The synthesis of seven 2,4-diamino-5,6,7,8-tetrahydro-7-substituted pyrido[4',3':4,5]furo[2,3-d]pyrimidines 1-6 are reported as nonclassical antifolate inhibitors of dihydrofolate reductase (DHFR) and compound 7 as a classical antifolate inhibitor of tumor cells in culture. The compounds were designed as conformationally restricted analogues of trimetrexate. The synthesis was accomplished from the cyclocondensation of 3-bromo-4-piperidone with 2,4-diamino-6-hydroxypyrimidine to afford regiospecifically 2,4-diamino- 5,6,7,8-tetrahydropyrido-[4',3':4,5]furo[2,3-d]pyrimidine-7-hydrobromide (16). This in turn was alkylated with the appropriate benzyl halide to afford the target compounds 1-6. The classical antifolate 7 utilized 4- (chloromethyl)benzoyl-L-glutamic acid diethyl ester (17) instead of the benzyl halide for alkylation, followed by saponification to afford 7. Compounds 1-6 showed moderate inhibitory potency against DHFR from Pneumocystis carinii, Toxoplasma gondii, Mycobacterium avium, and rat liver. The classical analogue 7 was 88-fold more potent against M. avium DHFR than against rat liver DHFR. The classical analogue was also inhibitory against the growth of tumor cells, CCRF-CEM, and FaDu, in culture.

Original languageEnglish
Pages (from-to)1409-1416
Number of pages8
JournalJournal of Medicinal Chemistry
Volume41
Issue number9
DOIs
StatePublished - Apr 23 1998

Fingerprint

Folic Acid Antagonists
Pyrimidines
Bioactivity
Tetrahydrofolate Dehydrogenase
Mycobacterium avium
Cell culture
Liver
Rats
Tumors
Trimetrexate
Piperidones
Cells
Saponification
Pneumocystis carinii
Toxoplasma
Alkylation
Glutamic Acid
Neoplasms
Cell Culture Techniques
Growth

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Synthesis and biological activities of tricyclic conformationally restricted tetrahydropyrido annulated furo[2,3-d]pyrimidines as inhibitors of dihydrofolate reductases. / Gangjee, Aleem; Elzein, Elfatih; Queener, Sherry; McGuire, John J.

In: Journal of Medicinal Chemistry, Vol. 41, No. 9, 23.04.1998, p. 1409-1416.

Research output: Contribution to journalArticle

@article{be914e61fad242ff9f078d3ca1531ab0,
title = "Synthesis and biological activities of tricyclic conformationally restricted tetrahydropyrido annulated furo[2,3-d]pyrimidines as inhibitors of dihydrofolate reductases",
abstract = "The synthesis of seven 2,4-diamino-5,6,7,8-tetrahydro-7-substituted pyrido[4',3':4,5]furo[2,3-d]pyrimidines 1-6 are reported as nonclassical antifolate inhibitors of dihydrofolate reductase (DHFR) and compound 7 as a classical antifolate inhibitor of tumor cells in culture. The compounds were designed as conformationally restricted analogues of trimetrexate. The synthesis was accomplished from the cyclocondensation of 3-bromo-4-piperidone with 2,4-diamino-6-hydroxypyrimidine to afford regiospecifically 2,4-diamino- 5,6,7,8-tetrahydropyrido-[4',3':4,5]furo[2,3-d]pyrimidine-7-hydrobromide (16). This in turn was alkylated with the appropriate benzyl halide to afford the target compounds 1-6. The classical antifolate 7 utilized 4- (chloromethyl)benzoyl-L-glutamic acid diethyl ester (17) instead of the benzyl halide for alkylation, followed by saponification to afford 7. Compounds 1-6 showed moderate inhibitory potency against DHFR from Pneumocystis carinii, Toxoplasma gondii, Mycobacterium avium, and rat liver. The classical analogue 7 was 88-fold more potent against M. avium DHFR than against rat liver DHFR. The classical analogue was also inhibitory against the growth of tumor cells, CCRF-CEM, and FaDu, in culture.",
author = "Aleem Gangjee and Elfatih Elzein and Sherry Queener and McGuire, {John J.}",
year = "1998",
month = "4",
day = "23",
doi = "10.1021/jm9705420",
language = "English",
volume = "41",
pages = "1409--1416",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "9",

}

TY - JOUR

T1 - Synthesis and biological activities of tricyclic conformationally restricted tetrahydropyrido annulated furo[2,3-d]pyrimidines as inhibitors of dihydrofolate reductases

AU - Gangjee, Aleem

AU - Elzein, Elfatih

AU - Queener, Sherry

AU - McGuire, John J.

PY - 1998/4/23

Y1 - 1998/4/23

N2 - The synthesis of seven 2,4-diamino-5,6,7,8-tetrahydro-7-substituted pyrido[4',3':4,5]furo[2,3-d]pyrimidines 1-6 are reported as nonclassical antifolate inhibitors of dihydrofolate reductase (DHFR) and compound 7 as a classical antifolate inhibitor of tumor cells in culture. The compounds were designed as conformationally restricted analogues of trimetrexate. The synthesis was accomplished from the cyclocondensation of 3-bromo-4-piperidone with 2,4-diamino-6-hydroxypyrimidine to afford regiospecifically 2,4-diamino- 5,6,7,8-tetrahydropyrido-[4',3':4,5]furo[2,3-d]pyrimidine-7-hydrobromide (16). This in turn was alkylated with the appropriate benzyl halide to afford the target compounds 1-6. The classical antifolate 7 utilized 4- (chloromethyl)benzoyl-L-glutamic acid diethyl ester (17) instead of the benzyl halide for alkylation, followed by saponification to afford 7. Compounds 1-6 showed moderate inhibitory potency against DHFR from Pneumocystis carinii, Toxoplasma gondii, Mycobacterium avium, and rat liver. The classical analogue 7 was 88-fold more potent against M. avium DHFR than against rat liver DHFR. The classical analogue was also inhibitory against the growth of tumor cells, CCRF-CEM, and FaDu, in culture.

AB - The synthesis of seven 2,4-diamino-5,6,7,8-tetrahydro-7-substituted pyrido[4',3':4,5]furo[2,3-d]pyrimidines 1-6 are reported as nonclassical antifolate inhibitors of dihydrofolate reductase (DHFR) and compound 7 as a classical antifolate inhibitor of tumor cells in culture. The compounds were designed as conformationally restricted analogues of trimetrexate. The synthesis was accomplished from the cyclocondensation of 3-bromo-4-piperidone with 2,4-diamino-6-hydroxypyrimidine to afford regiospecifically 2,4-diamino- 5,6,7,8-tetrahydropyrido-[4',3':4,5]furo[2,3-d]pyrimidine-7-hydrobromide (16). This in turn was alkylated with the appropriate benzyl halide to afford the target compounds 1-6. The classical antifolate 7 utilized 4- (chloromethyl)benzoyl-L-glutamic acid diethyl ester (17) instead of the benzyl halide for alkylation, followed by saponification to afford 7. Compounds 1-6 showed moderate inhibitory potency against DHFR from Pneumocystis carinii, Toxoplasma gondii, Mycobacterium avium, and rat liver. The classical analogue 7 was 88-fold more potent against M. avium DHFR than against rat liver DHFR. The classical analogue was also inhibitory against the growth of tumor cells, CCRF-CEM, and FaDu, in culture.

UR - http://www.scopus.com/inward/record.url?scp=0032560134&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0032560134&partnerID=8YFLogxK

U2 - 10.1021/jm9705420

DO - 10.1021/jm9705420

M3 - Article

C2 - 9554874

AN - SCOPUS:0032560134

VL - 41

SP - 1409

EP - 1416

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 9

ER -