Structure−Activity Relationships for Substituted Bis(acridine-4-carboxamides):  A New Class of Anticancer Agents

Abstract

A series of acridine-substituted bis(acridine-4-carboxamides) linked by a (CH2)3N(Me)(CH2)3 chain have been prepared by reaction of the isolated imidazolides of the substituted acridine-4-carboxylic acids with N,N-bis(3-aminopropyl)methylamine. These dimeric analogues of the mixed topoisomerase I/II inhibitor N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA), currently in clinical trial, show superior potencies to the corresponding monomeric DACA analogues in a panel of cell lines, including wild-type (JLC) and mutant (JLA and JLD) forms of human Jurkat leukemia. The latter mutant lines are resistant to topoisomerase II targeted agents because of lower levels of the enzyme. Analogues with small substituents (e.g., Me, Cl) at the acridine 5-position were clearly superior, with IC50's as low as 2 nM against the Lewis lung carcinoma and 11 nM against JLC. Larger substituents at any position caused a steady decrease in potency, likely due to lowering of DNA binding affinity. A small series of analogues of the most potent bis(5-methylDACA) compound, with second substituents (Me and Cl) in the 1- or 8- position had broadly similar potencies to the 5-Me compound, indicating that, while the 1- and 8-substituents are acceptable, they add little to the enhancing effect of the 5-methyl group. All of the compounds were at least equitoxic (some up to 4-fold more cytotoxic) against the mutant Jurkat lines than in the wild-type, consistent with a relatively greater effect on topoisomerase I compared with topoisomerase II. The bis(5-methylDACA) compound was found to inhibit the action of purified topoisomerase I in a cell-free assay. Compounds were on average 10-fold less cytotoxic in an MCF7 breast cancer line overexpressing P-glycoprotein than in the wild-type line and showed some selectivity for colon tumor lines in the NCI human tumor cell line panel. Several analogues produced significant growth delays in the relatively refractory subcutaneous colon 38 tumor model in vivo at substantially lower doses than DACA. The bis(acridine-4-carboxamides) represent a new and interesting class of potent topoisomerase inhibitors.

Synthesis and Antispasmodic Activity Evaluation of Bis-(Papaverine) Analogues

“…Table 1 summarizes the concentration of papaverine and test compounds producing 50% relaxation (IC 50 ) of acetylcholine induced contraction for compounds 6-13 and (6)(7)(8)(9)(10)(11)(12)(13). Second category has piperazinyl, substituted piperazinyl ring placed between two acetyl groups, as linkers (15)(16)(17)(18). Third category consists of piperazinyl, substituted piperazinyl ring placed between two carbamoyl groups, as linkers (21)(22)(23)(24).…”

“…bis-(triazoloacridinones), 11) bis-(anthracyclines), 12,13) bis-(acridine-4-carboxamides), 14) bis-(phenazine-1-carboxamides) 15,16) and bis-(indeno [1,2-b]quinoline-6-carboxamides). 17) A comparative study of a variety of bis analogues with their monomeric counterparts has revealed that there are variable but significant gains in potency for the dimeric species.…”

A simple one-pot synthesis of new 9-aroyl-3,4,6,7,9,10-hexahydro-1,8(2H,5H)-acridinediones

“…The 1,8-acridinediones and their derivatives are known to exhibit a wide range of biological and pharmaceutical properties such as antibacterial, 1 antimicrobial, 2 anticancer, [3][4][5] antitumor, [6][7] antifungal, 8 antimalarial, 9 antiviral, 10 larvicidal 11 and hypertensive 12 activities. Electroluminescent devices based on decahydroacridinedione (DAD) derivatives exhibit good efficiencies and excellent color purity.…”

Synthesis of novel acridine bis-sulfonamides with effective inhibitory activity against the carbonic anhydrase isoforms I, II, IX and XII

“…Acridine shows a similarity in its structure to nicotinamide adenine dinucleotide (NADH), 1 a molecule possessing important biological functions as a coenzyme/cofactor. 2 Thus there are many acridine-like compounds showing anticancer, 3,4 or antimicrobial activity, 5 whereas other such derivatives were reported to act as effective b-channel opener in cardiovascular disease, 6 in the photodynamic therapy, 7 or as anti-Alzheimer's agents. 8 Well-known drugs containing the acridine moiety include Amsacrine, Asulacrine, Acronycine, Acridine carboxamide (DACA), Proflavine and Ascididemin (Chart 1), and they have been used as anti-cancer or anti-bacterial agents.…”