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

Abstract

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.

Potential antitumor agents. 28. Deoxyribonucleic acid polyintercalating agents

“…There are compounds with relatively high and low values which are tumor active and examples where the reverse holds. Further, within homologous series of agents greatest antitumor activity is not displayed by those compounds with the lowest C50 values (43, 50, 55, 58); higher activity is provided by agents in which the heterocyclic nuclei are separated by somewhat longer alkyl chains (45, 51,56,59). Similarly when the DNA unwinding criterion for bisintercalation is considered, C50 values alone pinpointed a bisintercalator (58), in the homologous series 57-60, but this agent was not the most effective antitumor agent; greater activity was observed at longer chain length (59).…”

“…Further, within homologous series of agents greatest antitumor activity is not displayed by those compounds with the lowest C50 values (43, 50, 55, 58); higher activity is provided by agents in which the heterocyclic nuclei are separated by somewhat longer alkyl chains (45, 51,56,59). Similarly when the DNA unwinding criterion for bisintercalation is considered, C50 values alone pinpointed a bisintercalator (58), in the homologous series 57-60, but this agent was not the most effective antitumor agent; greater activity was observed at longer chain length (59). As the first member (57) of this series is suggested to be supralipophilic, activity would, on this basis, be expected to decrease as lipophilic character was further increased by lengthening the linking alkyl chain.…”

“…The use of a -(CH2)4-linking chain in the preparation of the latter, and also the tumor-inactive bisquinoline 61, was dictated by the early observed nadir in C50 values at this chain length in the bis-AMSA series (55,58). When animal screening data later became available, a -(CH2)5-alkyl chain length appeared optimal for antitumor activity (56,59). Despite this deficiency 58, with a tetramethylene linking chain, is biologically active and the more hydrophilic 62 would then have been expected to be more active.…”

Synthesis of Acridines from o-Aminoaryl Ketones and Arylboronic Acids by Copper Trifluoroacetate-Mediated Relay Reactions

“…As early as 1949, the effects of acridine compounds on respiration of the brain of chick embryos were reported . Because of their ability to intercalate into DNA and disrupt unwanted cellular processes, various acridines have been used in many areas of medicine, and significant biological activities toward cancers, viruses, bacteria, parasites, funguses, and Alzheimer’s disease have been reported. , In addition, the 9-mesityl-10-methylacridinium ion has been used as an effective electron-transfer photocatalyst for oxygenation of anthracenes and olefins and direct catalytic anti-Markovnikov hydroetherification of alkenols . 9-Methylacridines and other acridine-containing analogues have also been used in the construction of new fluorescent probes and as triplet-state, light-emitting materials for organic light-emitting diodes .…”

α,ε-Hybrid Peptide Foldamers: Self-Assembly of Peptide with Trans Carbon–Carbon Double Bonds in the Backbone and Its Saturated Analogue

“…18 Herein, we have synthesized a tetrapeptide containing trans α,β-unsaturated ε-amino acid and α-aminoisobutyric acid. Although the 3-(3-aminophenyl)propionic acid has been extensively investigated in biology and material science, 19,20 very little is known about the conformational properties of the unsaturated analogue 3-aminocinnamic acid. The natural existence and very good bioactivities of unsaturated amino acids motivated us to examine the conformational preferences of these amino acids in hybrid peptides.…”