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Biomedical subjects

G J Atwell

Publications and source records attributed to G J Atwell.

At least 73 records · Page 4Linked to original sources
PubMed1978

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

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.

Acridines↗
PubMed1977

Potential antitumor agents. 22. Latentiated congeners of the 4'-(9-acridinylamino)methanesulfonanilides.

N1-Acyl derivatives of the tumor inhibitory 4'-(9-acridinylamino)methanesulfonanilide agents act as prodrugs undergoing deacylation to liberate the core agents on incubation with pH 7.5 buffer or mouse blood. Against L1210 tumor implanted remotely from the drug administration site, lower acyl derivatives often provide enhanced effects over that obtained with nonacylated precursor alone. In certain homologous series of acyl derivatives, toxicity first increased with increasing lipophilic character, until greater than that of the core agent alone, and then at higher lipophilic levels decreased. Tumor inhibitory properties of the acyl derivatives in such series appeared inversely related to their toxicity. Several 3-(3,3-dialkyl-1-triazeno)acridine-substituted congeners provided excellent L1210 activity. Contrasting with most other tumor-active triazenes, one alkyl group need not be a methyl group of antileukemic activity to be observed. 3-Methyl-3-propyl-1-triazene and 3,3-diethyl-1-trazene analogues had comparable lipophilic-hydrophilic balance, toxicity, and antileukemic effectiveness; usual metabolic activation of the triazene N-methyl group may make little contribution to antitumor properties in the examples presented. Prepared as a nonalkylated triazene analogue, a 3-azidoacridine congener had high L1210 activity.

Anilides↗
PubMed1977

Potential antitumor agents. 23. 4'-(9-Acridinylamino)alkanesulfonanilide congeners bearing hydrophilic functionality.

From structure--anti-L1210 relationships developed earlier for the 4'-(9-acridinylamino)alkanesulfonanilides it was predicted that congeners bearing both lipophilic 3-acridine substituents and compensatory hydrophilic function(s), together providing an overall molecular lipophilic--hydrophilic balance close to optimum, should have augmented antitumor properties. The acceptability of a variety of hydrophilic functions, and optimum positioning of these, has now been investigated. A variety of sterically demanding, hydrophilic functions may be acceptably appended to the acridine 4(5) position suggesting considerable site bulk tolerance. A variant with both a lipophilic 3-acridine substituent (3-iodo) and a hydrophilic 5-(2,3-dihydroxypropoxy) function is markedly more active than previous examples in the early treated, intraperitoneally (ip) dosed, ip implanted L1210 system, the assay system employed in the structure--activity analyses. However, this latter compound, on ip administration, failed to significantly inhibit subcutaneously implanted L1210 whereas earlier variants, under the same conditions, provided significant tumor inhibition. In this drug series the observed order of relative drug effectiveness alters with changing site of tumor implantation.

Animals↗
PubMed1977

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

Tumor inhibition inhibition produced by isomeric, nitro-substituted 4'-(9-acridinylamino)methanesulfonanilide analogues of low base strength (pKa=4.79-5.72) might result from in vivo reduction to the corresponding, higher pKa (7.15-9.80), tumor active amines. The aza analogues,-N=in place of -C(NO2)=, have been prepared as nonclassical bioisosteres and screened in the L1210 system. Significant L1210 inhibition produced by isomeric 3- and 4-azalogues, of similar base strength to the corresponding nitro-substituted derivatives, demonstrates that weakly basic analogues can provide biologic activity when there is no prospect of in vivo reduction to more strongly basic products. Obligatory reduction of nitro function, for biologic activity, need not be postulated in this drug series.

Acridines↗
PubMed1976

Potential antitumor agents. 17. 9-Anilino-10-methylacridinium salts.

9-Anilino-10-methylacridinium salts result from reaction of substituted anilines and 9-chloro-10-methylacridinium salts in turn prepared from the 10-methyl-9(10H)-acridones and SOCl2 or POCl3. Antileukemic (L1210) activities of the quaternary salts were uniformly depressed compared to their unquaternized counterparts. If drug-solvent partition properties (log P) of the cations were considered, log P-activity relationships were similar for both base and quaternary salt series. Substituent effects on antitumor activity were similar in both series.

Acridines↗
PubMed1976

Potential antitumor agents. 20. Structure-activity-site relationships for the 4'(9-acridinylamino)alkanesulfonanilides.

A series of 87 L1210 active 4'-(9-acridinylamino)alkanesulfonanilides has been screened against L1210 cells (10(5)) implanted at various sites (ip, sc, ic) employing early ip drug administration for a limited time. With each implantation site a different most active congener was selected. For good activity against tumor implanted remotely from the ip drug administration site, an agent should be more lipophilic than that found optimal for ip implanted tumor. An acridine 4-CH3 group appears to assist drug translocation, possibly by sterically hindering binding to nonproductive sites. An unprotected NH2 group on the acridine ring system is incompatible with activity against sc implanted tumor. Agents in which NH2 is shielded by N-acetylation, N-monomethylation, or ortho substitution with a bulky group can inhibit sc implanted tumor.

Abdominal Neoplasms↗
PubMed1976

Potential antitumor agents. 18. Bisquaternary ammonium heterocycles.

It was earlier proposed that a close approach to overall planarity was a structural prerequisite for antileukemic activity (L1210) in bisquaternary ammonium heterocycles. The preparation of L1210 active 3,3'-[bicyclo[2.2.2]octane-1,4-dicarbonylbis(mino-p-phenylenecarbonylimino)bis(1-alkylpyridinium) salts, containing a nonplanar bridged ring system, negates this view. A replacement proposal is that a relatively rigid molecular framework in necessary to maintain the spacing and positioning of the quaternary functions, thereby ensuring correct site selection. Replacement of a terephthaloyl drug component by a bicyclo[2.2.2]octane-1,4-dicarbonyl residue lowers DNA binding. A terephthaloyl unit confers necessary molecular rigidity, greater DNA binding, and higher L1210 activity.

Animals↗
PubMed1975

Potential antitumor agents. 16.4'-(Acridin-9-ylamino)methanesulfonanilides.

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.

Acridines↗