Synthesis and Structure−Activity Relationships of Potential Anticancer Agents:  Alkylcarbamates of 3-(9-Acridinylamino)-5-hydroxymethylaniline

Abstract

A series of potential 9-anilinoacridine antitumor agents, 3-(9-acridinylamino)-5-hydroxymethylaniline (AHMA) derivatives with monosubstituent at C4' and disubstituents at C4' and C5' of the acridine ring and their alkylcarbamates, were synthesized for evaluation of their antitumor activity. A structure-activity relationship (SAR) study showed that the AHMA-alkylcarbamates were more potent than their corresponding parent AHMA compounds. In addition, the cytotoxicity of the AHMA-alkylcarbamate decreased with increasing length and size of the alkyl function. Among these compounds, AHMA-ethylcarbamate (18) and 4'-methyl-5'-dimethylaminoethylcarboxamido-AHMA-ethylcarb amate (34) possess potent cytotoxicity on the inhibition of human leukemic HL-60 cell growth in culture. Further in vivo studies of these compounds displayed significant anticancer therapeutic effects in mice bearing sarcoma 180, Lewis lung carcinoma, and P388 leukemia.

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.…”

DFT‐based QSAR study and molecular design of AHMA derivatives as potent anticancer agents

“…Anticancer activity data of these compounds from the literature are listed in Table I 10, 12. IC 50 refers to the millimolar concentration of the compound required for 50% inhibition of human leukemic HL‐60 cell line.…”

“…A series of AHMA derivatives with mono‐ or disubstituents on the acridine ring, as well as their alkylcarbamates, have been synthesized. Most of them, especially AHMA‐alkylcarbamates possess a significant cytotoxicity against human leukemic HL‐60 cell growth 12.…”

“…DNA–Topo II is considered a chemotherapeutic target for a diverse group of antitumor agents. It was suggested that the interaction of drug with DNA and the procedure producing a ternary complex with DNA–Topo II are essential for the antitumor activity of drug 1, 12, 17, 18. However, the nature of drug–DNA–Topo II ternary complex is not fully clear, the anti‐cancer mechanism of this series of 9‐anilinoacridines has not been properly clarified yet.…”

“…Among different descriptors for describing electronic characteristics of the molecules, the quantum chemical descriptors based on the density functional theory (DFT) and semi‐empirical methods have been found to be useful in several QSAR studies 20–23. In the present study, a series of 9‐anilinoacridine derivatives (AHMA derivatives and AHMA‐alkylcarbamates) reported in the literatures 10, 12 were selected to perform the QSAR study. Thirty‐four compounds were calculated using the DFT method 24–26 to obtain the quantum‐chemical descriptors.…”