Potential antitumor agents. 32. Role of agent base strength in the quantitative structure-antitumor relationships for 4'-(9-acridinylamino)methanesulfonanilide analogs

Abstract

Several homologous series of 9-anilinoacridines, each bearing a different pKa modulating acridine substituent, have been synthesized and screened in the L1210 leukemia system, to examine if measures of agent lipophilic-hydrophilic balance utilized in regression analysis should be corrected for the effects of changing base strength. The measure of tumor selectivity modeled was the maximum increase in life span in L1210 tests (ILSmu), and dose potency was gauged as D40, the molar drug dose necessary to provide 40% extension in life span. Agent lipophilic-hydrophilic balance was measured as chromatographic Rm values, and the pK" modulating factors examined were log (1 -a) and log a, where a is the fraction of drug ionized at physiological pH. Regression analyses of data from 78 L1210-active compounds show that the measured Rm values, unmodified by pKa correction factors, furnish superior correlation equations. An equation in Rm2, with indicator variables denoting the presence of acridine 3-N02 or 4-CONRR' substituents, successfully models ILSmal. To develop successful regression equations for D40 it was necessary to restrict attention to close structural congeners which are likely to be metabolized by similar routes. Results for a series of 3-nitroacridine derivatives which may be reduced in vivo to more dose-potent and/or more hydrophilic compounds could not be incorporated. Acceptable equations developed for Z)40 contain terms in Rm, Rm2, and pKe or t1/2. The latter provides a measure of the rate of agent thiolytic cleavage, a prominent contributor to drug decay in vivo.

Potential antitumor agents. 39. Anilino ring geometry of amsacrine and derivatives: relationship to DNA binding and antitumor activity

“…The high degree of transmission of electronic effects from the anilino to the acridine rings is shown12 by eq 1, pKa = -2.03 (±0.08) + 7. 27 (1) = 17, r = 0.984, s = 0.172 (11) Hall, D.; Swann, D. A.; Waters, T. N. J. Chem. Soc., Perkin…”

Structure–activity relationship studies of acridones as potential antipsoriatic agents. 1. Synthesis and antiproliferative activity of simple N-unsubstituted 10H-acridin-9-ones against human keratinocyte growth

“…Substitution pattern AA a IC 50 (mM) Acridones 5b [20], 5c [44], 5d [45], 5l [46], 5q [47], 5s [48], and 5v [49] were prepared from the corresponding methyl ethers (5f, 5g, 5h, 5m, 5r, 5t, and 5w, respectively) by method A. 1,8-dihydroxy-4-methoxy-10H-acridin-9-one (5y).…”

Design and Synthesis of Some Substituted Acridine Derivatives of Anticipated Antitumor Activity

“…Chlorination of 10a using thionyl chloride and few drops of DMF (as catalyst) [22][23][24][25][26] gave phenylhydrazinocarbonylmethyl 9-chloroacridine-4carboxylate 11 which was added to an equimolar amount of aromatic amines or sulfonamides dissolved in DMF acidified with hydrochloric acid and stirred to give compound 12a-k. IR spectra showed stretching of aliphatic CH 2 and carbonyl function group at about 2917, 2860 and 1692, 1668 cm -1 respectively. 1 H NMR exhibited the appearance of a singlet at δ = 5.14 ppm corresponding to CH 2 protons for compounds 12a and 12k.…”