Hypoxia-selective agents derived from 2-quinoxalinecarbonitrile 1,4-di-N-oxides. 2.
Hypoxic cells are an important target for antitumor therapy because tumors are typically characterized by such cells. Virtually all tumors which are present as solid masses contain hypoxic cells, while normal cells generally have an adequate supply of oxygen. Accordingly, antitumor agents can be made selective for tumors by virtue of high activity under hypoxic conditions. The initial purpose of this work was to determine the influence of different groups in position 3. Thus, the synthesis of some 3-NH-substituted derivatives (2a, 3a, 4a) starting from 3-amino-2-quinoxalinecarbonitrile 1,4-di-N-oxide (1a) is described. Reductive deamination of compounds 1a-k provides the 2-quinoxalinecarbonitriles 5a-k, which are more potent, while selectivity is maintained or increased in some derivatives. The compound 7-(4-nitrophenyl)-2-quinoxalinecarbonitrile 1,4-di-N-oxide (5k) is 150-fold more potent than tirapazamine (3-amino-1,2,4- benzotriazine 1,4-di-N-oxide), which has been used as a standard. Three derivatives (5g,i,k) show a hypoxic cytotoxicity ratio (HCR) > or = 200, better than that of tirapazamine (HCR = 75) in V79 cells. Replacement of the 3-amino group by chlorine affords the potent but nonselective 3-chloro derivatives 6a-k showing similar toxicities under both aerobic and hypoxic conditions. These compounds were used as intermediates for the synthesis of a new series of water-soluble compounds derived from 3-[[(N,N- dialkylamino)alkyl[amino]-2-quinoxalinecarbonitrile 1,4-di-N-oxides 10a-i and 11a-i. The 7-chloro and the 7-trifluoromethyl derivatives 10b,f have demonstrated high potency (0.4 and 0.3 microM) and excellent selectivity (HCR = 250 and 340). Several 7-chloro analogues, 12b, 13b.1,b.2, and 14b, and the dimer 16b have been prepared and evaluated in order to determine the optimum lateral chain in position 3, which appears to be the [(N,N-dimethylamino)propyl]amino moiety.