N-Substituted 2-(2,6-dinitrophenylamino)propanamides: novel prodrugs that release a primary amine via nitroreduction and intramolecular cyclization.
A series of N-dinitrophenylamino acid amides [(4-CONHZ-2, 6-diNO2Ph)N(R)C(X,Y)CONHPhOMe] were prepared as potential bioreductive prodrugs and reduced radiolytically to study their rates of subsequent intramolecular cyclization. Compounds bearing a free NH group (R = H) underwent rapid cyclization in neutral aqueous buffers (t1/2 < 1 min) following 4-electron reduction, with the generation of a N-hydroxydihydroquinoxalinone and concomitant release of 4-methoxyaniline. Amine release from analogous N-methyl analogues (R = Me) was relatively slow. These results are consistent with intramolecular cyclization of a monohydroxylamine intermediate. The high rates of cyclization/extrusion by these very electron-deficient hydroxylamines suggest that the process is greatly accelerated by the presence of an H-bonding "conformational lock" between the anilino NH group and the adjacent o-nitro group (Kirk and Cohen, 1972). Changes in the phenylcarboxamide side chain or in C-methylation in the linking chain had little effect on the rate of cyclization. The model compounds had 1-electron reduction potentials in the range appropriate for cellular reduction (-373 mV for a measured example) and appeared suitable for development as prodrugs that release amine-based effectors following enzymic or radiolytic reduction. Prodrug examples containing 4-aminoaniline mustard and 5-amino-1-(chloromethyl)benz[e]indoline alkylating units were evaluated but were not activated efficiently by cellular nitroreductases. However, cell killing by the radiation-induced reduction of the latter prodrug was demonstrated.
Sykes
B M
BM
Auckland Cancer Society Research Centre, Department of Pathology, and Department of Chemistry, The University of Auckland, Private Bag 92019, Auckland, New Zealand.
Atwell
G J
GJ
Hogg
A
A
Wilson
W R
WR
O'Connor
C J
CJ
Denny
W A
WA
D000577:Amides / Q000737:chemistry* / Q000494:pharmacology; D000588:Amines / Q000737:chemistry*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008809:Mice, Inbred C3H; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000473:pathology; D010084:Oxidation-Reduction; D011355:Prodrugs / Q000737:chemistry* / Q000494:pharmacology