Further evaluation of 5‐alkyl‐5‐deaza antifolates. 5‐propyl‐ and 5‐butyl‐5‐deaza analogues of aminopterin and methotrexate

Piper, James R.; Ramamurthy, B.; Johnson, Cheryl A.; Maddry, Joseph A.; Otter, Glenys M.; Sirotnak, Francis M.

doi:10.1002/jhet.5570320419

Cited by 4 publications

(6 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…N 10 -Substituted 6-(Aminomethyl)-2,4-diamino-5-methylpyrido[2,3-d]pyrimidines 13a, 13k-u, and 14a-m. All compounds of this group except 13a and 13q were prepared by method A, reaction of bromomethyl compound 2 [25][26][27][28] with the appropriate amine. Method B, reductive amination of nitrile 4 25,29 with the appropriate amine, was used to prepare 13a and 13q. N-Methylaniline precursors used in method A to prepare N 10 -methyl target compounds 13o and 14e,f,h,j,k,m were derived from the corresponding anilines by the general N-monomethylation procedure of Krishnamurthy.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Lipophilic Antifolates as Agents against Opportunistic Infections. 1. Agents Superior to Trimetrexate and Piritrexim against Toxoplasma gondii and Pneumocystis carinii in in Vitro Evaluations

et al. 1996

Self Cite

View full text Add to dashboard Cite

2,4-Diaminopteridines (21 compounds) and 2,4-diamino-5-methyl-5-deazapteridines (34 compounds) along with three 2,4-diamino-5-unsubstituted-5-deazapteridines and four 2,4-diaminoquinazolines, each with an aryl groups attached to the 6-position of the heterocyclic moiety through a two-atom bridge (either CH2NH, CH2N(CH3),CH2S, or CH2CH2), were synthesized and evaluated as inhibitors of the growth of Toxoplasma gondii in culture and as inhibitors of dihydrofolate reductase enzymes from T. gondii, Pneumocystis carinii, and rat liver. Exceptionally high levels of combined potency and selectivity as growth inhibitors of T. gondii and as inhibitors of the microbial enzymes relative to the mammalian enzyme were found among the 5-methyl-5-deazapteridines but not for the other heterocyclic types. Thirty of the 34 5-methyl-5-deaza compounds gave growth inhibition IC50 values lower than that of pyrimethamine (0.4 microM) with 14 compounds below 0.1 microM, values that compare favorably with those for piritrexim and trimetrexate (both near 0.02 microM). As inhibitors of T gondii DHFR, all but three of the 34 5-methyl-5-deaza compounds gave IC50 values in the order of magnitude with those of piritrexim (0.017 microM) and trimetrexate (0.010 microM), and 17 compounds of this group gave IC50 values versus P. carinii DHFR similarly comparable with those of piritrexim (0.031 microM) and trimetrexate (0.042 microM). Thirteen of these congeners gave both T. gondii growth inhibition and DHFR inhibition IC50 values of 0.10 microM or less, thus indicating facile penetration of the cell membrane. Eleven of these inhibitors of both T. gondii growth and DHFR have selectivity ratios (IC50 rat liver divided by IC50 T. gondii) of 5 or greater for the parasite DHFR. The highest selectivity ratio of nearly 100 belongs to the 5-methyl-5-deaza compound whose 6-substituent is CH2CH2C6H3(OCH3)2-2,5. This compound is over 10(3)-fold more selective for T. gondii DHFR than bridge homologue piritrexim (selectivity ratio 0.088), a compound now in clinical trials. The candidate with CH2NHC6H3(CH3)2-2,5 in the 6-position gave the highest P. carinii DHFR selectivity ratio of 4.0, which is about 60-fold more selective than trimetrexate (0.071) and 80-fold more selective than piritrexim (0.048) toward this enzyme. The 10 best compounds with respect to potency and selectivity includes six compounds bearing 2,5-disubstituted phenyl groups in the side chain (with little, if any, difference in effects of methyl, methoxy, or ethoxy), two side chains bearing 1-naphthyl groups, and two with 5,6,7,8-tetrahydro-1-naphthyl groups. Bridge groups represented in the 10 choice compounds are CH2NH, CH2N(CH3), CH2CH2, and CH2S. The high levels of both potency and selectivity among these agents suggest that in vivo studies now underway may lead to agents that could replace trimetrexate and piritrexim in treatment of toxoplasmosis and P. carinii pneumonia.

show abstract

Section: Methodsmentioning

confidence: 99%

“…The method used for each candidate is given in the Experimental Section. The reported methodology − was also applied by Gangjee et al in syntheses of analogues along with some of the compounds included in this study.…”

mentioning

confidence: 99%

Lipophilic Antifolates as Agents against Opportunistic Infections. 1. Agents Superior to Trimetrexate and Piritrexim against Toxoplasma gondii and Pneumocystis carinii in in Vitro Evaluations

et al. 1996

Self Cite

View full text Add to dashboard Cite

show abstract

“…In the current work, bromomethyl compounds were 6-(bromomethyl)-2,4-diaminopteridine ( 1a ) 20 and 6-(bromomethyl)-2,4-diamino-5-alkylpyrido[2,3- d ] pyrimidines 1b 12 and 1c ; the malonate vinylogue was 4-carboxy-1-naphthaleneacetic acid dimethyl ester ( 2 ). The dicarboxylic acid precursor of 2 was prepared in three steps from commercial 1-naphthaleneacetic acid (bromination, displacement of Br by CN, hydrolysis of CN to CO 2 H) according to reported procedures. , The Scheme sequence afforded ready access to target compounds 9a − c , naphthalene analogues of 10-DAM, 5-methyl-5,10-dideazaaminopterin, and 5-ethyl-5,10-dideazaaminopterin, respectively.…”

Section: Chemistrymentioning

confidence: 83%

Analogues of 10-Deazaaminopterin and 5-Alkyl-5,10-dideazaaminopterin with the 4-Substituted 1-Naphthoyl Group in the Place of 4-Substituted Benzoyl

et al. 1996

Self Cite

View full text Add to dashboard Cite

10-Deaza modifications of classical antifolate analogues bearing the 1,4-disubstituted naphthalene ring in place of the 1,4-disubstituted benzene ring were prepared and tested for antitumor activity. Naphthalene analogues (9a-c, respectively) of 10-deazaaminopterin, 5-methyl-5, 10-dideazaaminopterin, and 5-ethyl-5,10-dideazaaminopterin were prepared by a route consisting of C-alkylations of the anion derived from 4-carboxyl-1-naphthaleneacetic acid dimethyl ester (2) by 6-(bromomethyl)-2,4-diaminopteridine (1a) and 6-(bromomethyl)-2,4-diamino-5-methyl- and -5-deazapteridines (1b and 1c, respectively) followed by ester hydrolysis and subsequent decarboxylation to give naphthalene analogues (7a-c, respectively) of 4-amino-4-deoxy-10-deazapteroic acid and 4-amino-4-deoxy-5- methyl- and -5-ethyl-5,10-dideazapteroic acids. Peptide coupling of 7a-c with L-glutamic acid dialkyl ester followed by mild ester hydrolysis gave target compounds 9a-c. The key advantage of this route is circumvention of a hydrogenation step requiring selectivity as in earlier approaches involving 9,10-olefinic precursors. Steric limitations thwarted plans to prepare the naphthalene analogue of 10-ethyl-10-deazaaminopterin; attempted alkylations of 2-(4-carboxy-1-naphthyl)butyric acid dimethyl ester with 1a failed as did attempted further alkylation (by EtBr) of the product derived from 1a and 2. Growth inhibition tests against three tumor cell lines (L1210, S180, and HL60) showed 9a to be 4-6-fold more inhibitory than methotrexate but not as inhibitory as 10-ethyl-10-deazaaminopterin; 9b and 9c were no more inhibitory than MTX. In tests against the EO771 mammary adenocarcinoma in mice, 9a was less active than MTX.

show abstract

“…Synthetic procedures for 5-deazaaminopterin and its N 10 -alkyl and 5-alkyl analogues have been previously reported. − The most convenient processes featured reductive alkylation of diethyl N -(4-aminobenzoyl)- l -glutamate with an appropriate 2,4-diamino-5-deazapteridine-6-carbonitrile or direct alkylation with 2,4-diamino-6-(bromomethyl)-5-deazapteridine or a 5-alkyl derivative. − Following purification by column chromatography, the glutamate esters were saponified by dilute alkali at room temperature to provide the target 5-deazaaminopterins.…”

Section: Chemistrymentioning

confidence: 99%

“…The corresponding propyl compound 4a was available from previous work in these laboratories. 7 Subsequent alkylation of 4a-c with the (bromomethyl)-5-deazapteridines 3b,c 8,9 yielded the N 10 -substituted 5-alkyl-5-deazaaminopterin esters 5a-d which were then hydrolyzed to the targets 1i,j,l,m.…”

Section: Chemistrymentioning

confidence: 99%

Analogues of Methotrexate in Rheumatoid Arthritis. 2. Effects of 5-Deazaaminopterin, 5,10-Dideazaaminopterin, and Analogues on Type II Collagen-Induced Arthritis in Mice

et al. 1997

Self Cite

View full text Add to dashboard Cite

Twenty-six compounds derived from the 5-deaza- and 5,10-dideazaaminopterin series of aminopterin analogues were evaluated for antiarthritic activity in the mouse type II collagen model. New compounds in the 5-deaza series were prepared by alkylation of an appropriate N-substituted (4-aminobenzoyl)-L-glutamic acid dialkyl ester or N-(5-amino-2-thenoyl)-L-glutamate diester with a 2,4-diamino-5-alkyl-6-(bromomethyl)-5-deazapteridine. The resultant 5-deazaaminopterin diesters were saponified to provide the target 5-deaza analogues. 5,10-Dideazaaminopterins were synthesized by similar alkylation of the carbanions of appropriate 4-carboxyphenylacetic, (5-carboxy-2-thienyl)acetic, or (5-carboxy-2-pyridyl)acetic acid dimethyl esters. The diesters of the 2,4-diamino-4-deoxy-10-carboxy-5,10-dideazapteroic acid types so obtained were saponified and then readily decarboxylated by heating in Me2SO solution to provide the 2,4-diamino-5,10-dideazapteroic acid-type intermediates. Peptide coupling with diethyl L-glutamate followed by ester hydrolysis at room temperature afforded the new 5,10-dideazaaminopterin analogues. 5-Deazaaminopterins bearing an alkyl substituent at the 5-position were generally quite effective as antiinflammatory agents. Thus 5-propyl-5-deazaaminopterin, 5-methyl-10-propargyl-5-deazaaminopterin, 5-methyl-10-allyl-5-deazaaminopterin, 5-ethyl-5-deazamethotrexate, and 2,5-disubstituted thiophene analogue of 5-methyl-5-deazaaminopterin showed potencies greater than methotrexate by intraperitoneal or oral administration and were active over a considerably broader dose range. Useful activity in the 5,10-dideaza series was only observed for 5,10-dideazaaminopterin and its 10-methyl analogue. Alkyl substitution at C-5 or C-10 was generally detrimental to antiinflammatory activity in this series.

show abstract

Further evaluation of 5‐alkyl‐5‐deaza antifolates. 5‐propyl‐ and 5‐butyl‐5‐deaza analogues of aminopterin and methotrexate

Cited by 4 publications

References 17 publications

Lipophilic Antifolates as Agents against Opportunistic Infections. 1. Agents Superior to Trimetrexate and Piritrexim against Toxoplasma gondii and Pneumocystis carinii in in Vitro Evaluations

Lipophilic Antifolates as Agents against Opportunistic Infections. 1. Agents Superior to Trimetrexate and Piritrexim against Toxoplasma gondii and Pneumocystis carinii in in Vitro Evaluations

Analogues of 10-Deazaaminopterin and 5-Alkyl-5,10-dideazaaminopterin with the 4-Substituted 1-Naphthoyl Group in the Place of 4-Substituted Benzoyl

Analogues of Methotrexate in Rheumatoid Arthritis. 2. Effects of 5-Deazaaminopterin, 5,10-Dideazaaminopterin, and Analogues on Type II Collagen-Induced Arthritis in Mice

Contact Info

Product

Resources

About