title: Synthesis and antitumor activity of 10-propargyl-10-deazaaminopterin.
abstract: Successive alkylation of dimethyl homoterephthalate with propargyl bromide and 2,4-diamino-6-(bromomethyl)pteridine followed by ester saponification at room temperature afforded 2,4-diamino-4-deoxy-10-carboxy-10-propargyl-10-deazapteroic acid. The 10-COOH was readily decarboxylated by heating in DMSO at a temperature of only 120 degrees C to yield the diamino-10-propargyl-10-deazapteroic acid intermediate. Coupling with diethyl L-glutamate and ester hydrolysis gave the title compound. The 10-propargyl analogue was about 5 times more potent than MTX as an inhibitor of growth in L1210 cells, but was only one-third as potent as an inhibitor of DHFR from L1210. The analogue was transported inward very effectively in L1210 cells showing a 10-fold advantage over MTX. At a dose of 36 mg/kg the 10-propargyl compound caused shrinkage of the E0771 solid murine mammary tumor to only 1% of untreated controls.
authors.affiliation: Bio-Organic Chemistry Laboratory, SRI International, Menlo Park, California 94025.
authors.forename: J I
authors.initials: JI
authors.lastname: DeGraw
authors.forename: W T
authors.initials: WT
authors.lastname: Colwell
authors.forename: J R
authors.initials: JR
authors.lastname: Piper
authors.forename: F M
authors.initials: FM
authors.lastname: Sirotnak
mesh_terms: D000630:Aminopterin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D005260:Female; D007939:Leukemia L1210 / Q000188:drug therapy; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy; D051379:Mice; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D000630:Aminopterin