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The synthesis and biological activities of representatives of a new class of antitumor agent, the N-[2-(dialkylamino)ethyl ]-9-aminoacridine-4-carboxamides, are reported. Members of this class are stable and very water soluble with high levels of in vitro and in vivo antitumor activity. The compounds bind tightly to double-stranded DNA by intercalation, but the requirements for antitumor activity are more restrictive. They depend critically on the separation distance, positioning, and pKa values of the two cationic centers. For in vivo activity, significant bulk tolerance exists for lipophilic but not hydrophilic groups about the C-9 acridine position and for both lipophilic and hydrophilic groups on the side-chain cationic moiety. Significant attenuation of the pKa of the side-chain cationic center abolishes activity, as does alteration of either the disposition or separation distance of the side-chain charge with respect to the chromophore.

In an investigation of the structure-activity relationships in the 4'-(9-acridinylamino)methanesulfonanilide (AMSA) tumor inhibitory analogues, the DNA-binding properties of a series of simple 9-anilinoacridines were examined. Positional numbering as in the AMSA series has been employed. DNA binding was determined by drug competition with the fluorochrome ethidium for available sites. The decrease in fluorescence of a DNA-ethidium complex by the addition of drug is due to both drug displacement of bound ethidium and quenching of the fluorescence of bound ethidium by bound drug; measurement of both factors allows drug-DNA association constants (K) to be determined. DNA binding is augmented by 1' or 2' electron donor substituents, and significant correlation equations have been derived with Hammett's sigma p or sigma m constants. Group molar refractivity (MR) for 1'-substituents is an additional significant regression equation term for binding, while the values for 2' and 3' groups play no significant role. Most 3'-substituents decrease binding, presumably as a result of steric inhibition of entry of the acridine nucleus into intercalation sites. A 3'-NHSO2CH3 and 3'-NHCOCH3 substituent confer selectivity of binding to poly[d(G-C)] and poly[d(A-T)], respectively. It is suggested that a combination of H-bond formation and stereochemical features, coupled with steric hindrance, provides the selectivity observed. Binding data are consistent with a model in which the acridine nucleus occupies an intercalation site and the noncoplanar 9-anilino ring resides in the DNA minor groove.

Quantitative relationships (QSAR) have been derived between antileukemic (L1210) activity and agent physicochemical properties for 509 tumor-active members of the general class of 9-anilinoacridines. One member of this class is the clinical agent m-AMSA (NSC 249992). Agent hydrophobicity proved a significant but not a dominant influence on in vivo potency. The electronic properties of substituent groups proved important, but the most significant effects on drug potency were shown by the steric influence of groups placed at various positions on the 9-anilinoacridine skeleton. The results are entirely consistent with the physiologically important step in the action of these compounds being their binding to double-stranded DNA by intercalation of the acridine chromophore between the base pairs and positioning of the anilino group in the minor groove, as previously suggested. An equation was also derived for the acute toxicities of 643 derivatives of 9-anilinoacridine. This equation took a somewhat similar form to the one modeling antileukemia potency, emphasizing the usual fairly close relationship between potency and acute toxicity for antitumor agents in general. This study demonstrated the power of QSAR techniques to structure very large amounts of biological data and to allow the extraction of useful information from them bearing on the possible site of action of the compounds concerned.

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The structure-antileukemic activity (L1210) relationships for sulfonanilide ring-substituted variants of 4'-(acridin-9-ylamino)methanesulfonanilides have been investigated. Electron-donor substituents are necessary for antileukemic activity and it is suggested that high electron density at the 6' position is associated with high activity. A 3'-OCH3 function markedly increases (2-8-fold) potency with a variety of acceptable acridine ring substituents. Further variants with hydrophobic acridine 3-substituents have been shown to be more active than expected on the basis of overall molecular hydrophilic-lipophilic balance. There is a size limit to 3-substituents which may acceptably be as large as an iodine atom but should be smaller than an isoporpyl function.

with excess Mel at 5°o vernight. The reaction mixt was evapd to dryness and the residue was crystd from Me,C0-Et,0 to furnish colorless needles of VIb in almost quantitative yield: mp 195°; the quaternary 7V-Me group signaled at 3.30 (9 H, s) in the nmr (D,0) spectrum.2,3-Dihydrohelenalin (II). 2,3-Dihydrohelenalin could be readily synthesized in quantitative yield from any one of the following 3 methods.(a) A soln of VIb (30 mg) in , (1 ml) was heated on a steam bath for 30 min. The reaction mixt was acidified with 5% HC1 and extd with CHCl,, washed with , , dried (NajSOJ, and evapd. The residue was purified in CHCl, by passing through a column of silica gel (0.6 X 3.5 cm) to provide II as fine colorless silky needles after one recrystn from CH,Cl,-hexane: mp 154-155°; nmr 4.88 (1 H, t, /= 7.5 cps, H-8), 4.30 (1 H, d,/= 3 cps, H-6), 1.08 (3 H, d,/ = 6 cps, C10-CH,) and 0.78 (3 H, s, C,-CH,).(b) A soln of VIb (67 mg) in MeOH (20 ml) was treated with excess of freshly prepared Ag,0 and stirred for 30 min at room temp. The reaction mixt was filtered and evapd in vacuo to yield II as an oil. This was chromatogd in CHCl, on silica gel (0.3 X 3 cm) to give colorless needles (35 mg) after one recrystn from PhH-EtOH: mp 154-155°.(c) A soln of VIb (18 mg) in 5% aq NaHCO, soln (5 ml) was stirred at room temp for 1 hr. The reaction mixt was acidified with dil HC1 and extd with CHCl,. The CHCl, ext was washed with , , dried (NajSO,), and evapd to yield 10 mg of II as colorless needles after 1 recrystn from benzene-EtOH: mp 154-155°.Helenalin from Method b. Treatment of Vb (20 mg) in a similar manner as described for II (method b) afforded I as colorless needles. The identity of this compd with helenalin was established by tic, ir comparison, and mmp determination.11.13-DihydrohelenaUn (III) was prepd according to the method of Adams and Herz.4 2.3.11.13-Tetrahydrohelenalin (IV) was prepd by the method of Clark5 and melted at 171-173°.Helenalin Piperidine Adduct (Vg). A soln of helenalin (I) (100 mg) in freshly distd piperidine (1 ml) was allowed to stand at room temp overnight. The reaction mixt was dild with H,0 and extd with CHCl,. The CHCl, layer was washed with , , dried (Na^OJ, and evapd under reduced pressure to yield a residue (30 mg) which crystd upon addn of Et,0. Recrystn from CH,C1,-Et,0 gave colorless