Document Report Card

ID: ALA1127804

Journal: J Med Chem

Title: Synthesis and biological activity of N omega-hemiphthaloyl-alpha,omega- diaminoalkanoic acid analogues of aminopterin and 3',5-dichloroaminopterin.

Authors: Rosowsky A, Bader H, Wright JE, Keyomarsi K, Matherly LH.

Abstract: Analogues of N alpha-(4-amino-4-deoxypteroyl)-N delta-(hemiphthaloyl)-L-ornithine (PT523) with 3',5'-dichloro substitution in the p-aminobenzoyl moiety or with one less or one more CH2 group in the amino acid moiety were synthesized and tested as inhibitors of dihydrofolate reductase (DHFR) activity and cell growth. Replacement of L-ornithine in PT523 by L-2,4-diaminobutanoic acid or L-lysine did not decrease binding to human recombinant DHFR but resulted in some loss of activity against SCC25 human and SCC VII murine squamous cell carcinoma and against MCF-7 human breast carcinoma in culture. PT523 was several times more potent than methotrexate (MTX), aminopterin (AMT), or trimetrexate (TMQ). 3',5'-Dichloro substitution did not decrease either DHFR binding or cytotoxicity. A new synthetic route to PT523 from 2,4-diamino-6-(hydroxymethyl)pteridine and methyl N alpha-(4-aminobenzoyl)-N delta-phthaloyl-L-ornithinate was investigated but was not found superior to previously described methods. In comparative experiments on the ability of PT523 and MTX to competitively inhibit the influx of (6R)-5,10-dideazatetra-hydrofolate (DDATHF, lometrexol), used here as a surrogate for MTX and reduced folates, the Ki of PT523 was lower than that of MTX in both wild-type CCRF-CEM human leukemic lymphoblasts and the transport- and polyglutamylation-defective subline CEM/MTX. The CCRF-CEM cells were 10-fold more sensitive to PT523 than to MTX, whereas the CEM/MTX cells were 240-fold more sensitive. However, in contrast to other MTX-resistant cells where collateral sensitivity to PT523 has been seen. CEM/MTX cells still showed substantial cross resistance to PT523 which may reflect an unusual heightened ability to utilize exogenous folic acid. The good correlation observed with both cell lines between the cytotoxicity of PT523 and MTX and the ability to inhibit DDATHF influx supported the view that PT523 and MTX share, at least in part, a common protein carrier for membrane transport.

CiteXplore: 8035423

DOI: 10.1021/jm00040a008