9-Substituted acridine derivatives with long half-life and potent antitumor activity: synthesis and structure-activity relationships

Abstract

A series of DNA-intercalating 9-anilinoacridines, namely 9-phenoxyacridines, 9-(phenylthio)acridines, and 9-(3',5'-disubstituted anilino)acridines, were synthesized as potential antitumor agents with inhibitory effects on DNA topoisomerase II. Unlike amsacrine (m-AMSA), these agents were designed to avoid the oxidative metabolic pathway. These acridine derivatives were, therefore, expected to have long half-life in plasma. Both 9-phenoxyacridines and 9-(phenylthio)acridines were found to have moderate cytotoxicity against mouse leukemia L1210 and human leukemic HL-60 cell growth in culture. Among 9-(3',5'-disubstituted anilino)acridines, 3-(9-acridinylamino)-5-(hydroxymethyl)aniline (AHMA) was found to be a potent topoisomerase II inhibitor and exhibited significant antitumor efficacy both in vitro and in vivo. Chemotherapy of solid-tumor-bearing mice with 10, 10, and 5 mg/kg (QD x 4, ip) AHMA, VP-16, and m-AMSA, respectively, resulted in more tumor volume reduction by AHMA than by VP-16 or m-AMSA for E0771 mammary adenocarcinoma and B-16 melanoma. For Lewis lung carcinoma, AHMA was as potent as VP-16 but more active than m-AMSA. Structure-activity relationships of AHMA derivatives are discussed.

Theoretical Basis, Experimental Design, and Computerized Simulation of Synergism and Antagonism in Drug Combination Studies

“…iii. DNA intercalculating agents: Koyama et al (1989), Su et al (1995Su et al ( , 1999, Rastogi et al, (2002), Chang et al (2003). iv.…”

Modification of polyethylene glycol onto solid lipid nanoparticles encapsulating a novel chemotherapeutic agent (PK-L4) to enhance solubility for injection delivery

“…Previous research has focused on synthesizing a series of structureactivity relationships (SARs) for amsacrine analogs, such as DNA-intercalated 9-anilinoacridine derivatives, to increase the potential antitumor activity, decrease side effects, and prolong the half-life. 4,5 In a past study, Chen et al successfully synthesized a series of amsacrine analogs, among which 3-chloro-4-[(4-methoxyphenyl)amono]furo [2,3-b]-quinoline (PK-L4) exhibited potential antitumor activity and also overcame certain disadvantages of amsacrine. 6 In terms of the SARs, acridine is the backbone of amsacrine's structure and is related to its antitumor activity.…”

DNA Interaction and Topoisomerase II Inhibition by the Antitumor Agent 3′-(9-Acridinylamino)-5′-hydroxymethylaniline and Derivatives

“…More than 50% of the dose was excreted as the glutathione conjugate in the bile when mice were treated with m-AMSA. The half-life of m-AMSA in the presence of fresh mouse blood at 37ЊC is approximately 30 min (12). Recently, we have synthesized and evaluated the cytotoxicity of a series of 3-(9-acridinylamino)-5-hydroxymethyl aniline (AHMA) derivatives (12) (Fig.…”

“…Unlike m-AMSA, the substituents on the anilino ring of AHMA are in the meta position to each other, and therefore cannot form an iminoquinone intermediate via biooxidation, thus AHMA possesses a longer plasma half-life (1.5 h) than m-AMSA (12). We also found that AHMA has greater efficacy against murine leukemia and solid tumors (Lewis lung carcinoma, E0771 mammary adenocarcinoma and B-16 melanoma) than m-AMSA (12). In our preliminary report, we showed that AHMA inhibited Topo II-mediated DNA decatenation and relaxation (13).…”

“…We have synthesized a series of AHMA derivatives by introducing various substituents at the NH 2 and/or CH 2 OH functions (12) and found that these substituents, with only a few exceptions, do not greatly affect the cytotoxicity of the parent compound. Therefore, formation of a stable ternary structure between the drug (AHMA derivatives), DNA, and the degree of cleavage of DNA by Topo II was not adversely affected; this indicates that the position of the substituent is more important than the kind.…”