Synthesis of 5-methyl-5-deaza nonclassical antifolates as inhibitors of dihydrofolate reductases and as potential antipneumocystis, antitoxoplasma, and antitumor agents

Aleem Gangjee, Jufang Shi, Sherry Queener, Louis R. Barrows, Roy L. Kisliuk

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

A series of 2,4-diammo-5-methyl-6-(anilmomethyl)pyrido[2,3-d]pyrimidines 4-9 were synthesized as 5-deaza nonclassical antifolates containing trimethoxy, dichloro-, or trichlorophenyl substitutions and a N-H, N-CH3, or N-CHO at the 10-position. The compounds were evaluated as inhibitors of dihydrofolate reductases (DHFR) from Pneumocystis carinii (P. carinii), Toxoplasma gondii (T. gondii), rat liver (RL), and Lactobacillus casei (L. casei); as inhibitors of T. gondii and P. carinii cell growth in culture; and as antitumor agents. The compounds were prepared by modifications of procedures for classical 5-deaza folates. 2,4-Diamino-5-methyl-6-[(3′,4′,5′-trimethoxy-N-methylanilino) methyl]pyrido[2,3-d]pyrimidine (5a) exhibited high potency as well as selectivity (compared to RL DHFR) for P. carinii and T. gondii DHFR. Compound 5a is one of the most potent and selective nonclassical folate inhibitors of T. gondii DHFR known. The N-10 formyl analogue 2,4-diammo-5-methyl-6-[(N-forrnyl-3′,4′,5′-trimethoxyanilino) methyl]pyrido-[2,3-d]pyrimidine (6a) had decreased potency, but it maintained high selectivity for T. gondii DHFR. The corresponding chloro-substituted analogues maintained potency or had decreased potency; N-10 substitution did not increase potency or selectivity to the extent observed in the 3′,4′,5′-trimethoxy series. Partial reduction of the B ring to afford the dihydro analogue 2,4-diamino-5-methyl-6-[(N-formyl-3′,4′,5′-trimethoxyanilino) methyl]-5,8-dihydropyrido[2,3-d]pyrimidine (7), its 5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine analogue 8, and 2,4-diamino-5-methyl-6-[(3′,4′,5′-trimethoxyanilino)methyl]-5, 6,7,8-tetrahydropyrido[2,3-d]pyrimidine (9) resulted in a significant decrease in potency. In T. gondii cell culture inhibitory studies, 2,4-diamino-5-methyl-6-[(3′,4′,5′-trimethoxyanilino)methyl] pyrido[2,3-d]pyrimidine (4a), 5a, and 6a were less potent compared to their DHFR inhibitory potencies. Against P. carinii cells in culture, 4a and 5a at 10 μg/mL were as effective as the clinically used combination of trimethoprim/sulfamethoxazole (50/250 μg/mL). With the exception of the B ring reduced analogues 7-9, all of the compounds were significantly cytotoxic to leukemia CCRF-CEM cells in culture. The chloro-substituted analogues, in general, were more potent against a variety of other tumor cells in culture than the trimethoxy analogues. These results were corroborated by the preclinical tumor screening program at the National Cancer Institute where the most potent compound 2,4-diamino-5-methyl-6- [(3′,4′-dichloroanilino)methyl]pyrido[2,3-d]pyrimidine (4b) was found to inhibit the growth of 26 tumor cell lines at an IG50 <1.00 × 10-8 M.

Original languageEnglish
Pages (from-to)3437-3443
Number of pages7
JournalJournal of Medicinal Chemistry
Volume36
Issue number22
StatePublished - 1993

Fingerprint

Folic Acid Antagonists
Tetrahydrofolate Dehydrogenase
Toxoplasma
Antineoplastic Agents
Pneumocystis carinii
Cell culture
Tumors
Cell Culture Techniques
Folic Acid
Liver
Rats
Substitution reactions
Cells
Sulfamethoxazole Drug Combination Trimethoprim
Lactobacillus casei
Cell growth
National Cancer Institute (U.S.)
Growth
Tumor Cell Line
Screening

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Synthesis of 5-methyl-5-deaza nonclassical antifolates as inhibitors of dihydrofolate reductases and as potential antipneumocystis, antitoxoplasma, and antitumor agents. / Gangjee, Aleem; Shi, Jufang; Queener, Sherry; Barrows, Louis R.; Kisliuk, Roy L.

In: Journal of Medicinal Chemistry, Vol. 36, No. 22, 1993, p. 3437-3443.

Research output: Contribution to journalArticle

@article{5158a757f22d4a3db140d256a43c62d5,
title = "Synthesis of 5-methyl-5-deaza nonclassical antifolates as inhibitors of dihydrofolate reductases and as potential antipneumocystis, antitoxoplasma, and antitumor agents",
abstract = "A series of 2,4-diammo-5-methyl-6-(anilmomethyl)pyrido[2,3-d]pyrimidines 4-9 were synthesized as 5-deaza nonclassical antifolates containing trimethoxy, dichloro-, or trichlorophenyl substitutions and a N-H, N-CH3, or N-CHO at the 10-position. The compounds were evaluated as inhibitors of dihydrofolate reductases (DHFR) from Pneumocystis carinii (P. carinii), Toxoplasma gondii (T. gondii), rat liver (RL), and Lactobacillus casei (L. casei); as inhibitors of T. gondii and P. carinii cell growth in culture; and as antitumor agents. The compounds were prepared by modifications of procedures for classical 5-deaza folates. 2,4-Diamino-5-methyl-6-[(3′,4′,5′-trimethoxy-N-methylanilino) methyl]pyrido[2,3-d]pyrimidine (5a) exhibited high potency as well as selectivity (compared to RL DHFR) for P. carinii and T. gondii DHFR. Compound 5a is one of the most potent and selective nonclassical folate inhibitors of T. gondii DHFR known. The N-10 formyl analogue 2,4-diammo-5-methyl-6-[(N-forrnyl-3′,4′,5′-trimethoxyanilino) methyl]pyrido-[2,3-d]pyrimidine (6a) had decreased potency, but it maintained high selectivity for T. gondii DHFR. The corresponding chloro-substituted analogues maintained potency or had decreased potency; N-10 substitution did not increase potency or selectivity to the extent observed in the 3′,4′,5′-trimethoxy series. Partial reduction of the B ring to afford the dihydro analogue 2,4-diamino-5-methyl-6-[(N-formyl-3′,4′,5′-trimethoxyanilino) methyl]-5,8-dihydropyrido[2,3-d]pyrimidine (7), its 5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine analogue 8, and 2,4-diamino-5-methyl-6-[(3′,4′,5′-trimethoxyanilino)methyl]-5, 6,7,8-tetrahydropyrido[2,3-d]pyrimidine (9) resulted in a significant decrease in potency. In T. gondii cell culture inhibitory studies, 2,4-diamino-5-methyl-6-[(3′,4′,5′-trimethoxyanilino)methyl] pyrido[2,3-d]pyrimidine (4a), 5a, and 6a were less potent compared to their DHFR inhibitory potencies. Against P. carinii cells in culture, 4a and 5a at 10 μg/mL were as effective as the clinically used combination of trimethoprim/sulfamethoxazole (50/250 μg/mL). With the exception of the B ring reduced analogues 7-9, all of the compounds were significantly cytotoxic to leukemia CCRF-CEM cells in culture. The chloro-substituted analogues, in general, were more potent against a variety of other tumor cells in culture than the trimethoxy analogues. These results were corroborated by the preclinical tumor screening program at the National Cancer Institute where the most potent compound 2,4-diamino-5-methyl-6- [(3′,4′-dichloroanilino)methyl]pyrido[2,3-d]pyrimidine (4b) was found to inhibit the growth of 26 tumor cell lines at an IG50 <1.00 × 10-8 M.",
author = "Aleem Gangjee and Jufang Shi and Sherry Queener and Barrows, {Louis R.} and Kisliuk, {Roy L.}",
year = "1993",
language = "English",
volume = "36",
pages = "3437--3443",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "22",

}

TY - JOUR

T1 - Synthesis of 5-methyl-5-deaza nonclassical antifolates as inhibitors of dihydrofolate reductases and as potential antipneumocystis, antitoxoplasma, and antitumor agents

AU - Gangjee, Aleem

AU - Shi, Jufang

AU - Queener, Sherry

AU - Barrows, Louis R.

AU - Kisliuk, Roy L.

PY - 1993

Y1 - 1993

N2 - A series of 2,4-diammo-5-methyl-6-(anilmomethyl)pyrido[2,3-d]pyrimidines 4-9 were synthesized as 5-deaza nonclassical antifolates containing trimethoxy, dichloro-, or trichlorophenyl substitutions and a N-H, N-CH3, or N-CHO at the 10-position. The compounds were evaluated as inhibitors of dihydrofolate reductases (DHFR) from Pneumocystis carinii (P. carinii), Toxoplasma gondii (T. gondii), rat liver (RL), and Lactobacillus casei (L. casei); as inhibitors of T. gondii and P. carinii cell growth in culture; and as antitumor agents. The compounds were prepared by modifications of procedures for classical 5-deaza folates. 2,4-Diamino-5-methyl-6-[(3′,4′,5′-trimethoxy-N-methylanilino) methyl]pyrido[2,3-d]pyrimidine (5a) exhibited high potency as well as selectivity (compared to RL DHFR) for P. carinii and T. gondii DHFR. Compound 5a is one of the most potent and selective nonclassical folate inhibitors of T. gondii DHFR known. The N-10 formyl analogue 2,4-diammo-5-methyl-6-[(N-forrnyl-3′,4′,5′-trimethoxyanilino) methyl]pyrido-[2,3-d]pyrimidine (6a) had decreased potency, but it maintained high selectivity for T. gondii DHFR. The corresponding chloro-substituted analogues maintained potency or had decreased potency; N-10 substitution did not increase potency or selectivity to the extent observed in the 3′,4′,5′-trimethoxy series. Partial reduction of the B ring to afford the dihydro analogue 2,4-diamino-5-methyl-6-[(N-formyl-3′,4′,5′-trimethoxyanilino) methyl]-5,8-dihydropyrido[2,3-d]pyrimidine (7), its 5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine analogue 8, and 2,4-diamino-5-methyl-6-[(3′,4′,5′-trimethoxyanilino)methyl]-5, 6,7,8-tetrahydropyrido[2,3-d]pyrimidine (9) resulted in a significant decrease in potency. In T. gondii cell culture inhibitory studies, 2,4-diamino-5-methyl-6-[(3′,4′,5′-trimethoxyanilino)methyl] pyrido[2,3-d]pyrimidine (4a), 5a, and 6a were less potent compared to their DHFR inhibitory potencies. Against P. carinii cells in culture, 4a and 5a at 10 μg/mL were as effective as the clinically used combination of trimethoprim/sulfamethoxazole (50/250 μg/mL). With the exception of the B ring reduced analogues 7-9, all of the compounds were significantly cytotoxic to leukemia CCRF-CEM cells in culture. The chloro-substituted analogues, in general, were more potent against a variety of other tumor cells in culture than the trimethoxy analogues. These results were corroborated by the preclinical tumor screening program at the National Cancer Institute where the most potent compound 2,4-diamino-5-methyl-6- [(3′,4′-dichloroanilino)methyl]pyrido[2,3-d]pyrimidine (4b) was found to inhibit the growth of 26 tumor cell lines at an IG50 <1.00 × 10-8 M.

AB - A series of 2,4-diammo-5-methyl-6-(anilmomethyl)pyrido[2,3-d]pyrimidines 4-9 were synthesized as 5-deaza nonclassical antifolates containing trimethoxy, dichloro-, or trichlorophenyl substitutions and a N-H, N-CH3, or N-CHO at the 10-position. The compounds were evaluated as inhibitors of dihydrofolate reductases (DHFR) from Pneumocystis carinii (P. carinii), Toxoplasma gondii (T. gondii), rat liver (RL), and Lactobacillus casei (L. casei); as inhibitors of T. gondii and P. carinii cell growth in culture; and as antitumor agents. The compounds were prepared by modifications of procedures for classical 5-deaza folates. 2,4-Diamino-5-methyl-6-[(3′,4′,5′-trimethoxy-N-methylanilino) methyl]pyrido[2,3-d]pyrimidine (5a) exhibited high potency as well as selectivity (compared to RL DHFR) for P. carinii and T. gondii DHFR. Compound 5a is one of the most potent and selective nonclassical folate inhibitors of T. gondii DHFR known. The N-10 formyl analogue 2,4-diammo-5-methyl-6-[(N-forrnyl-3′,4′,5′-trimethoxyanilino) methyl]pyrido-[2,3-d]pyrimidine (6a) had decreased potency, but it maintained high selectivity for T. gondii DHFR. The corresponding chloro-substituted analogues maintained potency or had decreased potency; N-10 substitution did not increase potency or selectivity to the extent observed in the 3′,4′,5′-trimethoxy series. Partial reduction of the B ring to afford the dihydro analogue 2,4-diamino-5-methyl-6-[(N-formyl-3′,4′,5′-trimethoxyanilino) methyl]-5,8-dihydropyrido[2,3-d]pyrimidine (7), its 5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine analogue 8, and 2,4-diamino-5-methyl-6-[(3′,4′,5′-trimethoxyanilino)methyl]-5, 6,7,8-tetrahydropyrido[2,3-d]pyrimidine (9) resulted in a significant decrease in potency. In T. gondii cell culture inhibitory studies, 2,4-diamino-5-methyl-6-[(3′,4′,5′-trimethoxyanilino)methyl] pyrido[2,3-d]pyrimidine (4a), 5a, and 6a were less potent compared to their DHFR inhibitory potencies. Against P. carinii cells in culture, 4a and 5a at 10 μg/mL were as effective as the clinically used combination of trimethoprim/sulfamethoxazole (50/250 μg/mL). With the exception of the B ring reduced analogues 7-9, all of the compounds were significantly cytotoxic to leukemia CCRF-CEM cells in culture. The chloro-substituted analogues, in general, were more potent against a variety of other tumor cells in culture than the trimethoxy analogues. These results were corroborated by the preclinical tumor screening program at the National Cancer Institute where the most potent compound 2,4-diamino-5-methyl-6- [(3′,4′-dichloroanilino)methyl]pyrido[2,3-d]pyrimidine (4b) was found to inhibit the growth of 26 tumor cell lines at an IG50 <1.00 × 10-8 M.

UR - http://www.scopus.com/inward/record.url?scp=0027484260&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0027484260&partnerID=8YFLogxK

M3 - Article

VL - 36

SP - 3437

EP - 3443

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 22

ER -