Analogues of the potent nonpolyglutamatable antifolate N(alpha)-(4-amino-4-deoxypteroyl)-N(delta)-hemiphthaloyl-L-ornithine (PT523) with modifications in the side chain, p-aminobenzoyl moiety, or 9,10-bridge: synthesis and in vitro antitumor activity.

Analogues of the potent nonpolyglutamatable antifolate N(alpha)-(4-amino-4-deoxypteroyl)-N(delta)-hemiphthaloyl-L-ornithine (PT523) with modifications in the side chain, p-aminobenzoyl moiety, or 9,10-bridge: synthesis and in vitro antitumor activity.

MedLine Citation:	PMID: 10780919 Owner: NLM Status: MEDLINE
Abstract/OtherAbstract:	Seven N(alpha)-(4-amino-4-deoxypteroyl)-N(delta)-hemiphthaloyl-L-o rnithine (2, PT523) analogues were synthesized by modifications of the literature synthesis of the corresponding AMT (1) analogues and were tested as inhibitors of tumor cell growth. In growth assays against cultured CCRF-CEM human leukemic cells exposed to drug for 72 h, the IC(50) values of analogues in which N(10) was replaced by CH(2) and CHMe were found to be 0.55 +/- 0.07 and 0.63 +/- 0.08 nM, and thus these analogues are more potent than 1 (IC(50) = 4.4 +/- 1.0 nM) or 2 (IC(50) = 1.5 +/- 0.39 nM). The 10-ethyl-10-deaza analogue of 2 (IC(50) = 1.2 +/- 0.25 nM) was not statistically different from 2 but was more potent than edatrexate, the 10-ethyl-10-deaza analogue of 1, which had an IC(50) of 3.3 +/- 0.36 nM. In contrast, the analogue of 2 with both an ethyl and a CO(2)Me group at the 10-position had an IC(50) of 54 +/- 4.9 nM, showing this modification to be unfavorable. The 4-amino-1-naphthoic acid analogue of 2 had an IC(50) of 1.2 +/- 0.22 nM, indicating that replacement of the p-aminobenzoic acid (pABA) moiety does not diminish cytotoxicity. The analogues in which the (CH(2))(3) side chain was replaced by slightly longer CH(2)SCH(2) and (CH(2))(2)SCH(2) groups gave IC(50) values of 4.4 +/- 1.1 and 5.0 +/- 0.56 nM and thus were somewhat less potent than the parent molecule. However the analogues in which the aromatic COOH group was at the meta and para positions of the phthaloyl ring had IC(50) values of 7.5 +/- 0.47 and 55 +/- 0.07 nM, confirming the low potency we had previously observed with these compounds against other cell lines. Overall, the results in this study support the conclusion that, while the position of the phthaloyl COOH group and the length of the amino acid side chain in 2 are important determinants of cytotoxic potency, changes in the pABA region and 9, 10-bridge are well-tolerated and can even increase potency.

Authors:	A Rosowsky; J E Wright; C M Vaidya; R A Forsch; H Bader
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Publication Detail:	Type: Journal Article; Research Support, U.S. Gov't, P.H.S.
Journal Detail:	Title: Journal of medicinal chemistry Volume: 43 ISSN: 0022-2623 ISO Abbreviation: J. Med. Chem. Publication Date: 2000 Apr
Date Detail:	Created Date: 2000-05-11 Completed Date: 2000-05-11 Revised Date: 2007-11-14
Medline Journal Info:	Nlm Unique ID: 9716531 Medline TA: J Med Chem Country: UNITED STATES
Other Details:	Languages: eng Pagination: 1620-34 Citation Subset: IM
Affiliation:	Dana-Farber Cancer Institute and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA. andre_rosowsky@dfci.harvard.edu
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MeSH Terms
Descriptor/Qualifier:	Antineoplastic Agents / chemical synthesis, chemistry, pharmacology Drug Screening Assays, Antitumor Folic Acid Antagonists / chemical synthesis, chemistry, pharmacology Humans Inhibitory Concentration 50 Ornithine / analogs & derivatives, chemical synthesis, chemistry, pharmacology Pterins / chemical synthesis, chemistry, pharmacology Structure-Activity Relationship Tumor Cells, Cultured
Grant Support
ID/Acronym/Agency:	CA25394/CA/NCI NIH HHS; CA70349/CA/NCI NIH HHS
Chemical
Reg. No./Substance:	0/Antineoplastic Agents; 0/Folic Acid Antagonists; 0/Pterins; 113857-87-7/N(alpha)-(4-amino-4-deoxypteroyl)-N(delta)-hemiphthaloyl-L-ornithine; 7006-33-9/Ornithine

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