10-Propargyl-10-deazaaminopterin

Bezeichnung:10-Propargyl-10-deazaaminopterin

CAS-Nr146464-95-1

Englisch Name:10-Propargyl-10-deazaaminopterin

CBNumberCB31856065

SummenformelC23H23N7O5

Molgewicht477.47

MOL-Datei146464-95-1.mol

10-Propargyl-10-deazaaminopterin physikalisch-chemischer Eigenschaften

Schmelzpunkt	215 °C(dec.)
Dichte	1.471±0.06 g/cm3(Predicted)
storage temp.	2-8°C
Wasserlöslichkeit	Insoluble in water
Löslichkeit	≥23.85 mg/mL in DMSO; insoluble in H2O; insoluble in EtOH
pka	3.53±0.10(Predicted)
Aggregatzustand	powder to crystal
Farbe	White to Light yellow

Sicherheit

HS Code	2933.59.5300
Giftige Stoffe Daten	146464-95-1(Hazardous Substances Data)

Gefahreninformationscode (GHS)

10-Propargyl-10-deazaaminopterin Chemische Eigenschaften,Einsatz,Produktion Methoden

Beschreibung
Pralatrexate, an injectable DHFR inhibitor, was launched for the treatment of patients with relapsed or refractory PTCL. PTCL is an aggressive form of non-Hodgkin’s lymphoma (NHL) characterized by the proliferation of abnormal T-lymphocytes that circulate in the peripheral bloodstream. The inhibition of the folate enzymes DHFR and thymidylate synthase is a well-validated method of cancer treatment. In vitro, pralatrexate is slightly less potent than MTX in inhibiting DHFR derived from murine leukemia L1210 cells (K_i = 18.2 pM vs. 5.75 pM) and human leukemia CCRF-CEM cells (K_i = 13.4 pM vs. 5.4 pM). However, it is transported into both types of cells with 10-fold higher efficiency than MTX, thereby providing a more potent inhibition of cell growth as compared with MTX. In vivo, intraperitonally administered pralatrexate at 60 mg/ kg twice weekly for three or four doses caused complete lymphoma regressions in 89, 56, and 30% of HT, RL, and SKI-DLBCL-1 xenografted mice, respectively, whereas a similar dosing of MTX at 40 mg/kg twice weekly did not produce complete regression. The posttreatment tumor diameter was also smaller in pralatrexate-treated animals.
Beschreibung
Pralatrexate is a dihydrofolate reductase (DHFR) inhibitor (K_i = 13.4 pM) and antifolate. It inhibits growth of CCRF-CEM acute lymphocytic leukemia cells (IC₅₀ = 0.04 μM), MDA-468, SK-BR-3, and ZR-75-1 breast cancer cells (IC₅₀s = 0.11, 0.28, and 0.26 μM, respectively), and SK-LC8 and SK-LC16 non-small cell lung cancer cells (NSCLC; IC₅₀s = 0.42 and 0.11 μM, respectively). In vivo, pralatrexate increases median survival from 21 to 40 days when administered in 4 doses of 15 mg/kg over 11 days in an H9 T cell lymphoma mouse xenograft model. Pralatrexate is transported into cells via the reduced folate carrier (RFC) and undergoes polyglutamation by folylpolyglutamate synthetase (FPGS) to a greater extent than methotrexate or pemetrexed . Formulations containing pralatrexate have been used in the treatment of relapsed or refractory peripheral T cell lymphoma.
Originator
SRI International/ Southern Research Institute/Sloan-Kettering (US)
Verwenden
An antifolate with high affinity for the reduced folate carrier-type 1, produces marked complete and durable remissions in a diversity of chemotherapy refractory cases of T-cell lymphoma.
Definition
ChEBI: A pteridine that is the N-4-[1-(2,4-diaminopteridin-6-yl)pent-4-yn-2-yl]benzoyl derivative of L-glutamic acid. Used for treatment of Peripheral T-Cell Lymphoma, an aggressive form of non-Hodgkins lymphoma.
Trademarks
Folotyn
Clinical Use
Pralatrexate, an injectable dihydrofolate reductase (DHFR) inhibitor, has a superior potency and toxicity profile compared to other DHFR inhibitors. In 2009, the compound was launched by Allos and approved in the U.S. for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL) as a single agent. It is the first drug approved for this indication.70 In 2010, orphan drug designation was received in the E.U. for the treatment of cutaneous T-cell lymphoma (CTCL).
Nebenwirkungen
The most common adverse reactions associated with pralatrexate are mucositis, thrombocytopenia, nausea, and fatigue. Folic acid and vitamin B12 supplements are administered as adjunct therapies to potentially reduce pralatrexate-related hematological toxicity and mucositis.
Synthese
The chemical synthesis of pralatrexate starts with the alkylation of the anion of dimethyl homoterephthalate with propargyl bromide, promoted by potassium hydride in dimethylformamide, to afford the corresponding a-propargyl diester. Further alkylation of the potassium salt of a-propargyl diester with 2,4-diamino-6-(bromomethyl)pteridine followed by saponification with sodium hydroxide yields a diacid intermediate (2,4diamino- 4-deoxy-10-propargyl-10-deazapteroic acid). Mono-decarboxylation of the diacid intermediate by heating in dimethylsulfoxide at 120 C, followed by coupling with diethyl L-glutamate, and subsequent ester hydrolysis with sodium hydroxide yields pralatrexate.
Einzelnachweise
[1]. izbicka e, diaz a, streeper r, et al. distinct mechanistic activity profile of pralatrexate in comparison to other antifolates in in vitro and in vivo models of human cancers. cancer chemother pharmacol, 2009, 64(5): 993-999.
[2]. serova m, bieche i, sablin mp, et al. single agent and combination studies of pralatrexate and molecular correlates of sensitivity. br j cancer, 2011, 104(2): 272-280.

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