Analogues of N alpha-(4-amino-4-deoxypteroyl)-N delta-hemiphthaloyl-L-ornithine (PT523) modified in the side chain: synthesis and biological evaluation.

Abstract

Four heretofore undescribed side chain analogues of N alpha-(4-amino-4-deoxypteroyl)-N delta-hemiphthaloyl-L-ornithine (PT523, 4) were synthesized via straightforward methods of antifolate chemistry, and their properties were compared with those of PT523 and two related compounds with the aim of defining the contribution of the hemiphthaloyl-L-ornithine moiety to the exceptional in vitro antitumor activity of this novel non-polyglutamatable aminopterin analogue. The IC50 values of N alpha-(4-amino-4-deoxypteroyl)-N beta-hemiphthaloyl-L-2,3-diaminopropanoic acid (10) and N alpha-(4-amino-4-deoxypteroyl)-N gamma-hemiphthaloyl-L-2,4- diaminobutanoic acid (9) against A549 human non-small-cell lung carcinoma cells in culture were 23 and 22 nM, whereas those of PT523 and N alpha-(4-amino-4-deoxypteroyl)-N epsilon-hemiphthaloyl-L-lysine (8) were 1.3 and 5.2 nM. A decrease in the in vitro activities of 8 and 9 relative to PT523 was also observed against the panel of cell lines used by the National Cancer Institute to screen new drugs. However the potency of 8 and 9 remained several times greater than that of the historical control methotrexate against many of the cell lines in the screening panel. In an in vivo tumor model, SCC-VII murine squamous cell carcinoma, 9 and methotrexate were well tolerated as 5-day continuous infusions at doses of 0.52 and 0.75 mg/kg/day, whereas the highest tolerated dose of PT523 on this schedule was 0.19 mg/kg/day, in agreement with its lower IC50 in culture. To assess the importance of the hemiphthaloyl group in PT523, N alpha-(4-amino-4-deoxypteroyl)-N delta-isophthaloyl-L-ornithine (11), N alpha-(4-amino-4-deoxypteroyl)-N delta-terephthaloyl-L-ornithine (12), and N alpha-(4-amino-4-deoxypteroyl)-N delta-(4,5-dichlorohemiphthaloyl)-L-ornithine (13) were also synthesized. The IC50 values of 11 and 12 against A549 cells were 45 and 3300 nM, as compared with 1.3 nM for PT523 and 23 nM for methotrexate. In a clonogenic assay against SCC25 human squamous cell carcinoma cells, the IC50 values of 11 and 12 were 2.9 and 72 nM, as compared with 0.3 nM for PT523 and 27 nM for methotrexate. Thus, activity was decreased by moving the aromatic carboxyl group in PT523 to the meta position and was further diminished by moving it to the para position. The IC50 of the halogenated analogue 13 against SCC25 human head and neck squamous carcinoma cells was 18 nM, suggesting lack of tolerance for this 4,5-disubstitution in the phthaloyl moiety. Our results suggest that the combination of a hemiphthaloyl group and three CH2 groups in the side chain are critical determinants of the potent in vitro activity of PT523.

• Authors: A Rosowsky, C M Vaidya, H Bader, J E Wright, B A Teicher
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 40 Issue 3 Pg. 286-99 (Jan 31 1997) ISSN: 0022-2623 [Print] United States
• PMID: 9022795 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• Folic Acid Antagonists
• Glutamates
• Pterins
• N(alpha)-(4-amino-4-deoxypteroyl)-N(delta)-hemiphthaloyl-L-ornithine
• Ornithine
• Tetrahydrofolate Dehydrogenase
• Methotrexate

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, metabolism, pharmacology)
• Carcinoma, Squamous Cell (drug therapy)
• Cell Division (drug effects)
• Drug Screening Assays, Antitumor
• Folic Acid Antagonists (chemical synthesis, chemistry, metabolism, pharmacology)
• Glutamates (chemical synthesis, pharmacology)
• Humans
• Magnetic Resonance Spectroscopy
• Methotrexate (pharmacology)
• Mice
• Molecular Structure
• Ornithine (analogs & derivatives, chemical synthesis, chemistry, metabolism, pharmacology)
• Pterins (chemical synthesis, chemistry, metabolism, pharmacology)
• Structure-Activity Relationship
• Tetrahydrofolate Dehydrogenase (metabolism)
• Tumor Cells, Cultured