Synthesis and antifolate properties of 5,10-ethano-5,10-dideazaaminopterin

DeGraw, Joseph I.; Christie, P. H.; Colwell, W. T.; Sirotnak, Francis M.

doi:10.1021/jm00080a017

Cited by 73 publications

(21 citation statements)

References 5 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Syntheses of the target compounds 4-7 were accomplished via the regiospecific cyclocondensation of the β-keto ester 18 (as the biselectrophile) with 2,4,6-triaminopyrimidine (Scheme 2). Hurlbert et al [29] as well as reports from Gangjee et al [30,31] and DeGraw et al [32] have confirmed that β-keto esters condense with appropriate 6-aminopyrimidines to afford regiospecifically angular, 5,6-disubstituted pyrido [2,3-d]pyrimidines rather than the linear, 6,7-disubstituted isomers. Compound 16 was synthesized by the reaction of 3,4,5-trimethoxybenzylamine 9 with ethyl acrylate (15) followed by alkylation with ethylbromoacetate to afford 17 which on Dieckmann cyclization gave the desired β-ketoester 18.…”

Section: Jan-feb 2001 213mentioning

confidence: 86%

Conformationally restricted tricyclic analogues of lipophilic pyrido[2,3‐d]pyrimidine antifolates

Gangjee

Mavandadi

Queener

2001

Journal of Heterocyclic Chem

View full text Add to dashboard Cite

The effect of conformational restriction of the C9-N10 bridge on inhibitory potency and selectivity of trimetrexate against dihydrofolate reductase, was studied. Specifically three nonclassical tricyclic 1, 3-diamino-8-(3',4',5'-trimethoxybenzyl)-7,9-dihydro-pyrrolo[3,4-c]pyrido [2,3-d]pyrimidin-6(5H,8H)-one (4), 1,3-diamino-8-(3',4',5'-trimethoxybenzyl)-9-hydro-pyrrolo [3,4-c]pyrido [2,3-d]pyrimidin-6-(8H)-one (5) and 1,3-diamino-(8H)-(3',4',5'-trimethoxybenzyl)-7,9-dihydro-pyrrolo [3,4-c]pyrido [2,3-d]pyrimidine (7) antifolates were synthesized. The tricyclic analogues 4 and 5 were obtained via the regiospecific cyclocondensation of the β-keto ester 17 with 2,4,6-triaminopyrimidine. The analogue 7 was obtained via reduction of the lactam 4 with borane in tetrahydrofuran. Compounds 4, 5 and 7 were evaluated as inhibitors of dihydrofolate reductase from Pneumocystis carinii, Toxoplasma gondii and rat liver. All three compounds were more selective than trimetrexate against Pneumocystis carinii dihydrofolate reductase and significantly more selective than trimetrexate against Toxoplasma gondii dihydrofolate reductase compared with rat liver dihydrofolate reductase. Currently available treatments for Pneumocystis carinii (P. carinii) and Toxoplasma gondii (T. gondii), which are often fatal opportunistic infections in AIDS patients, are usually a combination of agents [2][3][4]. The use of trimethoprim and sulfamethoxazole is considered to be the most effective combination for the treatment and prophylaxis of P. carnii infections [5]. T. gondii infections are treated by the first line combination of pyrimethamine and sulfadiazine [6]. Both these combinations utilize a selective dihydrofolate reductase inhibitor trimethoprim or pyrimethamine along with a dihydropteroate synthase inhibitor that is the sulfa drug. Though these combinations are effective, a significant number of patients suffer side effects primarily attributed to the sulfonamide drug which limits the dose and in many cases forces a discontinuation of therapy [7,8]. The dihydrofolate reductase inhibitors in these combinations are weak ineffective agents when used as monotherapy and require the sulfonamide to afford a synergistic, clinically effective combination [9,10]. In an attempt to circumvent the use of the sulfonamide in these combinations, due to its toxicity which necessitates discontinuation of treatment, considerable effort has been expended to design and synthesize pathogen selective dihydrofolate reductase inhibitors that also possess increased potencies against P. carinii dihydrofolate reductase and T. gondii dihydrofolate reductase. Such a potent and selective dihydrofolate reductase inhibitor would preclude the necessity of the sulfonamide and hence the toxicity associated with the combination and could be clinically viable monotherapy for P. carinii and T. gondii infections.The 3,000 to 10,000 fold selectivity of trimethoprim (TMP) for bacterial dihydrofolate reductase over the mammalian enzyme has been attributed, in part, to the adoptio...

show abstract

Section: Jan-feb 2001 213mentioning

confidence: 86%

Conformationally restricted tricyclic analogues of lipophilic pyrido[2,3‐d]pyrimidine antifolates

Gangjee

Mavandadi

Queener

2001

Journal of Heterocyclic Chem

View full text Add to dashboard Cite

show abstract

“…In particular, the synthesis of pyridopyrimidine and their derivatives remains of great interest in organic chemistry, because some of them exhibit significant biological and pharmacological activities, such as antifolate activity [16], antibacterial activity [17], tyrosine kinase activity [18], antimicrobial activity [19], calcium channel antagonists activity [20], anti-inflammatory and analgesic activity [21], antileishmanial activity [22], tuber-culostatic activity [23], anticonvulsants activity [24], diuretic and potassium-sparing activity [25], antiaggressive activity [26], and antitumor activity [27].…”

Section: Introductionmentioning

confidence: 99%

One-Pot Synthesis of Novel Derivatives of Dithioxopyrido[2,3-d:6,5-d’]dipyrimidine-4,6-diones Using Hap-Encapsulated γ-Fe2O3 Supported Sulfonic Acid Nanocatalyst

Mamaghani¹,

Moslemi²,

Badrian³

2018

MOCR

View full text Add to dashboard Cite

Abstract.A series of novel dithioxopyrido [2,3-d:6,5-d ' ]dipyrimidine-4,6-dione derivatives were synthesized through a one-pot three-component approach using ] catalyzed condensation of 6-amino-2,3-dihydro-2-thioxopyrimidin-4(1H)-one and various substituted aryl aldehydes at 110 o C in DMF. In this protocol the use of nanocatalyst provided a green, useful and rapid method to generate the products in short reaction times and good to excellent yields (70-95%) and the catalyst is easily separated by applying an external magnetic field.

show abstract

“…[8][9][10] However, none of these modified analogues showed better DHFR inhibitory or antitumor activity than MTX. Linear, conformationally restricted, tricyclic analogues of MTX or its pyrido [2,3-d]pyrimidine analogues have not been explored to any significant extent in the literature as potential antifolate or antitumor agents.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Classical and Nonclassical, Partially Restricted, Linear, Tricyclic 5-Deaza Antifolates

et al. 2002

View full text Add to dashboard Cite

Seven novel 2,4-diamino-5-deaza-6,7,8,9-tetrahydropyrido[3,4-g]pteridine derivatives 3-9 with different benzyl and a benzoyl substitution at the N7 position were designed and synthesized, as classical and nonclassical, partially restricted, linear tricyclic 5-deaza antifolates. The purpose was to investigate the effect of conformational restriction of the C6-C9 (tau(1)) and C9-N10 (tau(2)) bonds via an ethyl bridge from the N10 to the C7 position of 5-deaza methotrexate (MTX) on the inhibitory potency against dihydrofolate reductase (DHFR) from different sources and on antitumor activity. The synthetic methodology for most of the target compounds was a concise five-step total synthesis to construct the tricyclic nucleus, 2,4-diamino-5-deaza-7H-6,7,8,9-tetrahydropyrido[3,4-g]pteridine (23), followed by regioselective alkylation of the N7 nitrogen. Biological results indicated that this partial conformational modification for the classical analogue N-[4-[(2,4-diamino-5-deaza-6,7,8,9-tetrahydropyrido[3,4-g]pteridin-7-yl)methyl]benzoyl]-L-glutamic acid 3 was detrimental to DHFR inhibitory activity as well as to antitumor activity compared to MTX or 5-deaza MTX. However, the classical analogue 3 was a better substrate for folypolyglutamate synthetase (FPGS) than MTX. These results show that a classical 5-deaza folate partially restricted via a bridge between the N10 and C7 positions retains FPGS substrate activity and that the antitumor activity of classical tricyclic analogues such as 3 would be influenced by FPGS levels in tumor systems. Interestingly, the nonclassical analogues 4-9 showed moderate to good selectivity against DHFR from pathogenic microbes compared to recombinant human DHFR. These results support the idea that removal of the 5-methyl group of piritrexim along with restriction of tau(1) and tau(2) can translate into selectivity for DHFR from pathogens.

show abstract

Synthesis and antifolate properties of 5,10-ethano-5,10-dideazaaminopterin

Cited by 73 publications

References 5 publications

Conformationally restricted tricyclic analogues of lipophilic pyrido[2,3‐d]pyrimidine antifolates

Conformationally restricted tricyclic analogues of lipophilic pyrido[2,3‐d]pyrimidine antifolates

One-Pot Synthesis of Novel Derivatives of Dithioxopyrido[2,3-d:6,5-d’]dipyrimidine-4,6-diones Using Hap-Encapsulated γ-Fe2O3 Supported Sulfonic Acid Nanocatalyst

Synthesis of Classical and Nonclassical, Partially Restricted, Linear, Tricyclic 5-Deaza Antifolates

Contact Info

Product

Resources

About