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B F Cain

Publications and source records attributed to B F Cain.

At least 37 records · Page 2Linked to original sources
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

Cancer chemotherapy: drug combination and multiple modality treatment.

Research has provided many antitumour agents which show varying degrees of effectness against both experimental animal and human cancers. Successful selection of drugs for use in combination can increase antitumour effectiveness. Combination toxicity indices can assist in selecting potentially useful drug combinations. As a result of the first-order kinetics of drug induced tumour cell kill, ability to cure by chemotherapy is inversely related to the size of the tumour population. For chemotherapeutic cure of advanced relatively drug-resistant cancers (animal or human) with existing drugs, there must be prior reduction of tumour burden by alternative treatment methods. In such cases the correct target for present agents is the metastases remaining after noncurative surgery and/or radiotherapy.

Animals↗
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. 19. Multiply substituted 4'-(9-acridinylamino)methanesulfonanilides.

A series of 42 multiply substituted 4'-(9-acridinylamino)methanesulfonanilides has been prepared and evaluated in the L1210 system. In addition to biologic activity changes resulting from altered agent lipophilic-hydrophilic balance variants containing both acridine 4-CH3 and 3-NH2, NHCOCH3 or NO2 substituents have reduced activity. Variants 3,6-disubstituted, using functions of differing electronic character, have depressed activity, suggesting that there is limited site bulk tolerance. Asymmetric 3,5-disubstitution should then be the preferred pattern; the 3-ND-5CH-3'-OCH variant is the most dose potent (optimum dose qd 1-5, 1.25 mg/kg/day) of the high activity agents of this series so far prepared.

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↗