Potential antitumor agents. 25. Azalogs of the 4'-(9-acridinylamino)methanesulfonanilides

Denny, William A.; Atwell, Graham J.; Cain, B. F.

doi:10.1021/jm00220a003

Cited by 20 publications

(7 citation statements)

References 6 publications

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“…79, 80), as nonclassical isosteres of the nitro derivatives, have comparable low pKa values and are tumor active eliminates the latter criticism. 21 In this series of agents high acridine pKa (>7) is therefore not a necessary condition for antitumor activity. Of the two parameters pKa and , the latter must then be considered a dominant factor influencing biologic activity.…”

Section: Resultsmentioning

confidence: 99%

Potential antitumor agents. 26. Anionic congeners of the 9-anilinoacridines

Denny¹,

Atwell²,

Cain³

1978

J. Med. Chem.

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To investigate the possible importance of small levels of sulfonamide anion in the antileukemia (L1210) 4'-(9-acridinylamino)methanesulfonanilides, an anionic derivative was prepared, in which -COOH replaced -NHSO2CH3, and shown to have experimental antitumor activity. Analogue synthesis and evaluation show that acceptable placement of the carboxylate function on the 9-anilino ring is restricted to the 1'-position. While the 1'-COOH and 1'-(CH2)2COOH analogues proved active, the intermediate acetate variant (1'-CH2COOH) was inactive. There were marked differences in the effects of added acridine ring substituents, on biologic activity, depending on the function attached to the 9-anilino ring (1'-NHSO2CH3 or 1'-COOH). Consideration of the vector components of possible drug-binding forces, acting on a DNA-intercalated agent, suggests that there may be low-energy barriers to two-dimensional reorientation of a planar, intercalated chromophore in relation to the neighboring purine-pyrimidine base pairs. It is proposed that site forces from an added substituent could lead to modified DNA-binding orientations. Observed acridine-ring substituent effects on biologic activity would then depend on the 9-anilino ring function (1'-NHSO2CH3, 1'-COOH) employed.

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Section: Resultsmentioning

confidence: 99%

Potential antitumor agents. 26. Anionic congeners of the 9-anilinoacridines

Denny¹,

Atwell²,

Cain³

1978

J. Med. Chem.

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“…The title compound, (I), has been employed as a reagent in the synthesis of potential DNA intercalative drugs (Denny, Atwell & Cain, 1977). During the attempted crystallization of one such intercalator, small yellow crystals formed which were subsequently shown by Xray crystallography to be those of the title compound.…”

Section: Commentmentioning

confidence: 99%

4-Aza-9(10H)-acridone

Clark¹,

Squire²

1996

Acta Crystallogr C

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The crystal packing of the title compound, CI2H8N20, is dominated by hydrogen bonding and 7r-Tr-type interactions along the short axial direction. Each molecule is hydrogen bonded to two adjacent molecules which are part of the same stacked column. The N--H...N hydrogen bonds have an N...N distance of 2.95 A,. CommentThe title compound, (I), has been employed as a reagent in the synthesis of potential DNA intercalative drugs (Denny, Atwell & Cain, 1977). During the attempted crystallization of one such intercalator, small yellow crystals formed which were subsequently shown by Xray crystallography to be those of the title compound.2.14,~ between atoms 09 and H3 (-x, ½+y, 3-z), which results in a deviation for H3 of 0.21 (8)1( from the calculated six-membered ring plane.The replacement of atom C4 in the parent acridone (II) with N4 in the present structure provides an extra potential hydrogen bond. The N--H..-O hydrogen bond of compound (II) is replaced with an N--H...N bond involving N4 in (I). The hydrogen-bond pattern of (II) connects adjacent stacks of molecules extending through the crystal in a direction perpendicular to the 7r-Tr stacking direction. In compound (I), the stacking is also in the short axial direction, but the hydrogen bonding only links two stacked piles of molecules. Each molecule is hydrogen bonded to two adjacent molecules taking part in 7r-Tr stacking interactions such that the chain of hydrogen-bonded molecules extends The majority of the bond lengths in compound (I) (between non-H atoms) are within 3cr of those of the parent 9(10H)-acridone compound, (II) (Potts & Jones, c 1995), and most of the bond angles at the C atoms in the title compound fall in the range 118-120 ° . The angles falling outside this range are those involving atoms C9 and N10, and most of the angles that are part of the 4-aza ring. The bonds to atom N4 in (I) are significantly shorter than those to C4 in (II) and the internal ring angle at N4 is significantly smaller than that at C4. The two outer tings of the 4-aza three-ring system are individually planar, with no ring atoms dev!ating from their calculated planes by more than 0.01 A. The central ring adopts a slight boat-type conformation with atoms C9 and N10 each deviating from the calculated ring plane by 0.036 (4)

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“…( 29 34 482 7• 1•0.5 2 ) C, , N. Methods of elaboration of substituted acridones to the desired aroducts have been earlier well described. [1][2][3][4][5][6][7][8] ti/2 Values for Thiolytic Cleavage. Formerly,16 half-lives "or drug decay in the presence of thiol were determined in 50% YleOH-H20 solution.…”

Section: Modeling Dose Potency (D#) As Shown In Tablementioning

confidence: 99%

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

Denny¹,

Atwell²,

Cain³

1979

J. Med. Chem.

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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.

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Potential antitumor agents. 25. Azalogs of the 4'-(9-acridinylamino)methanesulfonanilides

Cited by 20 publications

References 6 publications

Potential antitumor agents. 26. Anionic congeners of the 9-anilinoacridines

Potential antitumor agents. 26. Anionic congeners of the 9-anilinoacridines

4-Aza-9(10H)-acridone

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

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