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Anti-cancer Agents in Medicinal... Feb 2008Antifolates that inhibit the key enzymes thymidylate synthase (TS) and dihydrofolate reductase (DHFR) have found clinical utility as antitumor and antiopportunistic... (Review)
Review
Antifolates that inhibit the key enzymes thymidylate synthase (TS) and dihydrofolate reductase (DHFR) have found clinical utility as antitumor and antiopportunistic agents. Methotrexate {MTX, (1)} and 5-fluorouracil (5-FU) were among the first clinically useful DHFR and TS inhibitors, respectively. The development of resistance to 5-FU, its occasional unpredictable activity and toxicity resulted in the search of novel antifolates. Pemetrexed (4) and raltitrexed (5) are newer antifolates that specifically inhibit TS, and are clinically useful as antitumor agents. A major mechanism of tumor resistance to clinically useful antifolates is based on their need for polyglutamylation via the enzyme folylpoly-gamma-glutamate synthetase (FPGS). Recently, classical antifolates that do not need to be polyglutamylated have also been developed and include plevitrexed (6) and GW1843 (7). Nolatrexed (8), trimethoprim {TMP, (11)} and piritrexim {PTX, (12)} are nonclassical antifolates for antitumor and parasitic chemotherapy that passively diffuse into cells and hence do not have to depend on FPGS or the reduced folate carrier (RFC). Structural requirements for inhibition with antifolates have been studied extensively and novel agents that exploit key interactions in the active site of TS, DHFR, FPGS, and RFC have been proposed. This two-part review discusses the design, synthesis and structural requirements for TS and DHFR inhibition and their relevance to antitumor and parasitic chemotherapy, since 1996. Monocyclic and 6-5 fused bicyclic antifolates were discussed in Part I. The 6-6 bicyclic and tricyclic antifolates will be discussed here in Part II.
Topics: Anti-Infective Agents; Antineoplastic Agents; Folic Acid Antagonists; Humans; Molecular Structure; Neoplasms; Opportunistic Infections; Stereoisomerism; Structure-Activity Relationship
PubMed: 18288923
DOI: 10.2174/187152008783497064 -
The Journal of Organic Chemistry Feb 2005[reaction: see text] A regiospecific and convergent route the lipophilic antifolate piritrexim (PTX) is described in which a key step is a Pd(0)-catalyzed cross-coupling...
[reaction: see text] A regiospecific and convergent route the lipophilic antifolate piritrexim (PTX) is described in which a key step is a Pd(0)-catalyzed cross-coupling reaction between 2-amino-3-cyano-4-methyl-5-bromopyridine and 2,5-dimethoxybenzylzinc chloride to form 2-amino-4-methyl-5-(2,5-dimethoxybenzyl)nicotinonitrile. To complete the synthesis, the amino group is replaced by a more reactive bromine atom via nonaqueous diazotization with tert-butyl nitrite, and the resultant bromo nitrile is cyclized with guanidine.
Topics: Catalysis; Folic Acid Antagonists; Molecular Structure; Palladium; Pyrimidines
PubMed: 15704971
DOI: 10.1021/jo040268z -
Anti-cancer Agents in Medicinal... Sep 2007Antifolates that inhibit the key enzymes thymidylate synthase (TS) and dihydrofolate reductase (DHFR) have found clinical utility as antitumor and antiopportunistic... (Review)
Review
Antifolates that inhibit the key enzymes thymidylate synthase (TS) and dihydrofolate reductase (DHFR) have found clinical utility as antitumor and antiopportunistic agents. Methotrexate {MTX, (1)} and 5-fluorouracil (5-FU) were among the first clinically useful DHFR and TS inhibitors, respectively. The development of resistance to 5-FU, its occasional unpredictable activity and toxicity resulted in the search of novel antifolates. Pemetrexed (4) and raltitrexed (5) specifically inhibit TS, and are clinically useful as antitumor agents. A major mechanism of tumor resistance to clinically useful antifolates is based on their need for polyglutamylation via the enzyme folylpoly-gamma-glutamate synthetase (FPGS). Novel antifolates have been developed that do not need to be polyglutamylated and include plevitrexed (6) and GW1843 (7). Nonclassical antifolates for antitumor and parasitic chemotherapy, such as nolatrexed (8), trimethoprim {TMP, (11)} and piritrexim {PTX, (12)}, can passively diffuse into cells and hence do not have to depend on FPGS or the reduced folate carrier (RFC). Variations in the structures of antifolates have helped delineate the structural influence on the interaction with TS, DHFR, FPGS, and RFC utilization. The differences in the active site of human and pathogen DHFR have also been exploited. The literature contains excellent reviews on the design and synthesis of antifolates prior to 1996. This two-part review discusses the design, synthesis and structural requirements for TS and DHFR inhibition and their relevance to antitumor and parasitic chemotherapy, since 1996. Monocyclic and 6-5 fused bicyclic antifolates will be discussed in Part I, while 6-6 bicyclic and tricyclic antifolates will be discussed in Part II.
Topics: Animals; Antineoplastic Agents; Antiparasitic Agents; Drug Design; Folic Acid Antagonists; Humans; Neoplasms; Opportunistic Infections; Peptide Synthases; Tetrahydrofolate Dehydrogenase; Thymidylate Synthase
PubMed: 17896913
DOI: 10.2174/187152007781668724 -
Analytical and Bioanalytical Chemistry Sep 2003Molecularly imprinted microspheres were synthesised using the antitumor drug piritrexim (PTX) as a template molecule by aqueous microsuspension polymerisation and were...
Molecularly imprinted microspheres were synthesised using the antitumor drug piritrexim (PTX) as a template molecule by aqueous microsuspension polymerisation and were used as a high-performance liquid chromatographic stationary phase. The molecularly imprinted column exhibited strong retention behaviour to the template molecule. The influences of pH of the buffer and the ratio of methanol to buffer on the retention behaviour were investigated in detail. Results indicated that the baseline separation of PTX, trimetrexate (TMX), trimethoprim (TMP) and sulfamethazine (SMZ) was achieved when the pH value of the acetate buffer was above pH 3.5 and the ratio of methanol to the buffer was 6:4 (v/v). A gradient elution programme was employed to enhance the separation, which led to an improvement in sensitivity and a reduction in determination errors. The method developed was used to analyse urine samples supplemented with PTX. The recoveries of 5 microg mL(-1) PTX in the urine sample were 99.1+/-3.0% and 93.3+/-2.8% at the beginning and 24 h later, respectively.
Topics: Animals; Antineoplastic Agents; Chromatography, High Pressure Liquid; Hydrogen-Ion Concentration; Microspheres; Polymers; Pyrimidines; Trimetrexate
PubMed: 12845402
DOI: 10.1007/s00216-003-2086-8 -
Annual Review of Medicine 1991Several drugs are now available for the treatment and prevention of Pneumocystis carinii pneumonia. These include trimethoprim-sulfamethoxazole and pentamidine... (Review)
Review
Several drugs are now available for the treatment and prevention of Pneumocystis carinii pneumonia. These include trimethoprim-sulfamethoxazole and pentamidine isethionate as first-line drugs and dapsone-trimethoprim, trimetrexate, piritrexim, fansidar, difluoromethylornithine, and clindamycin plus primaquine as drugs in later stages of clinical development. A hydroxynaphthoquinone, called 566C80, offers promise in preclinical studies. The use of corticosteroids in the supportive management of P. carinii pneumonitis is undergoing clinical study.
Topics: Humans; Pneumonia, Pneumocystis
PubMed: 2035974
DOI: 10.1146/annurev.me.42.020191.001443 -
A phase I clinical and pharmacological study of weekly intravenous infusions of piritrexim (BW301U).European Journal of Cancer & Clinical... Dec 1989Thirty-eight patients with advanced resistant cancers were enrolled on this study of piritrexim (PTX; BW 301U) administered intravenously weekly for 4 weeks. Of 50...
Thirty-eight patients with advanced resistant cancers were enrolled on this study of piritrexim (PTX; BW 301U) administered intravenously weekly for 4 weeks. Of 50 courses of treatment begun, 39 evaluable 4-week courses of the drug were completed by this group of patients. Dosages ranged from 44 to 530 mg/m2/week. One patient at each dosage level received an initial weekly dose of PTX in oral form accompanied by pharmacokinetic blood sampling after the oral dose and also after a subsequent intravenous dose. Toxicities included mild nausea and vomiting, and moderate to severe peripheral vein phlebitis. Anemia and thrombocytopenia were the dominant hematological toxicities. One patient with pulmonary metastases from malignant fibrous histiocytoma experienced a 12-week partial response to PTX treatment at a dosage of 400 mg/m2/week. Pharmacokinetic analysis of plasma for PTX concentrations was accomplished utilizing a competitive protein binding assay. The estimated total body clearance ranged from 136 to 173 ml/min/1.73 m2. Mean terminal half-life after intravenous administration was 5.61 +/- 2.38 h (S.D.), and after oral administration was 5.72 +/- 2.04 h. Mean systemic bioavailability after oral administration was 75 +/- 56%.
Topics: Adult; Aged; Antineoplastic Agents; Drug Administration Schedule; Drug Evaluation; Female; Folic Acid Antagonists; Humans; Infusions, Intravenous; Middle Aged; Neoplasms; Pyrimidines
PubMed: 2632268
DOI: 10.1016/0277-5379(89)90360-x -
Cancer Research Aug 1990Piritrexim, a new nonclassical antifolate, was evaluated in a multiinstitutional phase I trial in children. The starting dose was 290 mg/m2/day, administered p.o. every...
Piritrexim, a new nonclassical antifolate, was evaluated in a multiinstitutional phase I trial in children. The starting dose was 290 mg/m2/day, administered p.o. every 12 h for 5 consecutive days, with courses repeated every 21 days. Dose reduction, initially to 200 mg/m2/day and subsequently to 140 mg/m2/day, was required because dose limiting myelosuppression and mucositis were encountered at the 290- and 200-mg/m2/day dose levels. Non-dose limiting toxicities included transient elevations in liver function tests, mild nausea, and skin rashes. The maximum tolerated dose was 140 mg/m2/day for 5 days. Pharmacokinetic monitoring was performed at steady state during the first course. For the 140-, 200-, and 290-mg/m2/day dose groups, the mean +/- SE peak plasma concentrations were 5.3 +/- 0.84, 9.3 +/- 1.7, and 10.2 +/- 2.3 microM, respectively, and occurred at a median of 1.5 h following the p.o. dose. The mean area under the plasma concentration-time curves were 18.1 +/- 2.3, 45.4 +/- 8.9, and 56.9 +/- 16.3 microM.h, respectively. Absolute bioavailability in two patients who were also monitored following a single i.v. dose of 140 and 200 mg/m2/day of piritrexim was 35 and 93%, respectively. Dose limiting toxicities were observed in 9 of 10 patients with 12-h trough piritrexim concentrations greater than 0.5 microM, whereas only 2 of 7 patients with trough concentrations less than 0.5 microM experienced dose limiting toxicities. A limited pharmacokinetic sampling strategy that allowed the area under the plasma concentration-time curve to be accurately predicted from the 3- and 6-h plasma drug concentration was developed. The recommended dose for future phase II trials is 140 mg/m2/day administered p.o. every 12 h for 5 consecutive days. Pharmacokinetic monitoring at 3, 6, and 12 h postdose may be useful for estimating bioavailability and for predicting which patients are at greatest risk for developing toxicity.
Topics: Adolescent; Adult; Antineoplastic Agents; Child; Drug Evaluation; Half-Life; Humans; Metabolic Clearance Rate; Neoplasms; Pyrimidines
PubMed: 2369724
DOI: No ID Found -
Journal of Medicinal Chemistry Dec 1994Ten heretofore undescribed 2,4-diamino-5-chloroquinazoline analogues of trimetrexate (TMQ) and piritrexim (PTX) were synthesized and tested as inhibitors of...
Ten heretofore undescribed 2,4-diamino-5-chloroquinazoline analogues of trimetrexate (TMQ) and piritrexim (PTX) were synthesized and tested as inhibitors of dihydrofolate reductase (DHFR) from rat liver, Pneumocystis carinii, and Toxoplasma gondii. The most active quinazolines against both the P. carinii and the T. gondii enzyme were those with an ArCH2-NH or ArNHCH2 side chain. Among ArNH(CH2)n compounds with n = 1-3 and either 2',5'-dimethoxyphenyl or 3',4',5'-trimethoxyphenyl as the Ar moiety, activity decreased in the order n = 1 > n = 2 > n = 3. The best inhibitor of P. carinii DHFR, 2,4-diamino-5-chloro-6-[(N-methyl-3',4',5'-trimethoxyanilino)methy l] quinazoline (10) had an IC50 of 0.012 microM and was slightly more potent than TMQ and PTX. Compound 10 was also the best inhibitor of T. gondii DHFR, with an IC50 of 0.0064 microM corresponding again to a minor increase in activity over TMQ and PTX. However, as with these standard agents, 10 showed no appreciable selectivity for either the P. carinii or T. gondii enzyme relative to the rat liver enzyme. The highest selectivity achieved in this limited series was with 2,4-diamino-5-chloro-6-[N-(3',4',5'-trimethoxybenzyl)-N-methylamino] quinazoline (17) against T. gondii DHFR. While 17 (IC50 = 0.016 microM) was somewhat less potent than 10, its selectivity, as defined by the ratio IC50(rat liver)/IC50(T. gondii) was ca. 30-fold higher than that of TMQ or PTX. Two compounds, 2,4-diamino-5-chloro-6-[(3',4',5'-trimethoxyanilino)methyl] quinazoline (9) and 2,4-diamino-5-chloro-6-[N-(3',4',5'-trimethoxybenzyl) amino]quinazoline (15), were also tested against human DHFR and were found to have an IC50/[E] of 0.5, indicating that their binding was near-stoichiometric.
Topics: Animals; Folic Acid Antagonists; Humans; Pyrimidines; Rats; Structure-Activity Relationship; Trimetrexate
PubMed: 7799402
DOI: 10.1021/jm00052a011 -
Journal of the National Cancer Institute Jan 1991A phase I trial of piritrexim was conducted by use of a prolonged, low-dose oral schedule. A number of different regimens were tested, including daily dosing for 21 days... (Clinical Trial)
Clinical Trial
A phase I trial of piritrexim was conducted by use of a prolonged, low-dose oral schedule. A number of different regimens were tested, including daily dosing for 21 days followed by 7 days of no drug therapy; continuous dosing; and daily dosing for 5 of 7 days for 3 consecutive weeks followed by a week of rest. Dose escalation was accomplished by increasing the dosing frequency from once a day to twice a day and then to three times a day and by increasing the number of days of administration. Fifty-one patients with advanced cancer were entered in the study. One hundred twenty-four (96%) of 129 courses were considered assessable. Myelosuppression proved to be the dose-limiting toxic effect. Other toxic effects included stomatitis, nausea and vomiting, anorexia, diarrhea, skin rash, fatigue, and elevation of liver transaminase levels. Antitumor activity was observed in patients with melanoma and bladder cancer, and disease stabilization occurred in those with sarcoma and pheochromocytoma. The recommended dosing schedule for phase II clinical trials is 25 mg three times a day for 5 days for 3 consecutive weeks followed by 1 week of no drug therapy.
Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Dose-Response Relationship, Drug; Drug Evaluation; Female; Humans; Male; Middle Aged; Neoplasms; Pyrimidines
PubMed: 1984518
DOI: 10.1093/jnci/83.1.51 -
Antimicrobial Agents and Chemotherapy Jun 1998
Review
Topics: Anti-Bacterial Agents; Anti-Infective Agents; Atovaquone; Clindamycin; Dapsone; Eflornithine; Humans; Macrolides; Naphthoquinones; Pentamidine; Pneumocystis; Pneumocystis Infections; Pneumonia, Pneumocystis; Pyrimidines; Trimethoprim, Sulfamethoxazole Drug Combination; Trimetrexate
PubMed: 9624465
DOI: 10.1128/AAC.42.6.1309