Article: PT523 and other aminopterin analogs with a hemiphthaloyl-L-ornithine side chain: exceptionally tight-binding inhibitors of dihydrofolate reductase which are transported by the reduced folate carrier but cannot form polyglutamates.
1999 Volume 6, Issue 4, Page(s) 329–352
Abstract: Nonpolyglutamatable antifolates are potentially of therapeutic interest for the treatment of tumors that are inherently refractory, or have become resistant, to classical antifolates as a result of decreased expression of the enzyme folylpolyglutamate ... ...
| Abstract | Nonpolyglutamatable antifolates are potentially of therapeutic interest for the treatment of tumors that are inherently refractory, or have become resistant, to classical antifolates as a result of decreased expression of the enzyme folylpolyglutamate synthetase. An interesting class of water-soluble nonpolyglutamatable analogs of aminopterin (AMT) have been developed, which are much more cytotoxic because they bind more tightly to dihydrofolate reductase (DHFR) and also utilize the reduced folate carrier (RFC) pathway more efficiently for influx into the cell. This review summarizes the in vitro and in vivo preclinical data on the initial lead compound, Nalpha-(4-amino-4-deoxypteroyl)-Ndelta- hemiphthaloyl-L-ornithine (PT523). In addition, the synthesis and in vitro biochemical and biological properties of several types of second-generation analogs are discussed. Analogs modified in the B-ring of the pteridine moiety have been found to be of particular interest because their affinity for DHFR and their influx rate into cells via the RFC pathway are even greater than those of PT523. The hemiphthaloylornithine moiety, which is larger and more hydrophobic than the glutamate side chain of classical antifolates, appears to be chiefly responsible for the exceptionally high biological potency of PT523 and its B-ring analogs. |
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| MeSH term(s) | ATP-Binding Cassette, Sub-Family B, Member 1/metabolism ; Aminopterin/analogs & derivatives ; Animals ; Antineoplastic Agents/pharmacology ; DNA Damage/drug effects ; Folic Acid Antagonists/chemistry ; Folic Acid Antagonists/metabolism ; Folic Acid Antagonists/pharmacology ; Humans ; Ornithine/analogs & derivatives ; Ornithine/chemistry ; Ornithine/metabolism ; Ornithine/pharmacology ; Polyglutamic Acid/metabolism ; Pterins/chemistry ; Pterins/metabolism ; Pterins/pharmacology ; Structure-Activity Relationship ; Tetrahydrofolate Dehydrogenase/metabolism ; Tissue Distribution |
| Chemical Substances | ATP-Binding Cassette, Sub-Family B, Member 1 ; Antineoplastic Agents ; Folic Acid Antagonists ; Pterins ; N(alpha)-(4-amino-4-deoxypteroyl)-N(delta)-hemiphthaloyl-L-ornithine (113857-87-7) ; Polyglutamic Acid (25513-46-6) ; Ornithine (E524N2IXA3) ; Tetrahydrofolate Dehydrogenase (EC 1.5.1.3) ; Aminopterin (JYB41CTM2Q) |
| Language | English |
| Publishing date | 1999-04 |
| Publishing country | Netherlands |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S. ; Review |
| ZDB-ID | 1319315-6 |
| ISSN | 1875-533X ; 0929-8673 |
| ISSN (online) | 1875-533X |
| ISSN | 0929-8673 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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