6H-Pyrazolo[4,5,1-de]acridin-6-ones as a Novel Class of Antitumor Agents.Synthesis and Biological Activity

Abstract

The 7-substituted 6H-pyrazolo[4,5,1-de]acridin-6-ones with (aminoalkyl)amino and/or (hydroxyalkyl)amino groups in the side chains were synthesized by bromination using N-bromosuccinimide and the subsequent reaction with amines from the 7-substituted 5-bromo-2-methyl-6H-pyrazolo-[4,5,1-de]acridin-6-one. The substitution reaction of the amines with alkyl bromide (the C2 position) and aryl bromide (the C5 position) was accomplished by choosing the proper reaction conditions. These compounds show DNA intercalating ability in ethidium fluorescence assay and antiproliferative activity against Hela S3 cells. Impressive antitumor activity in vivo against murine P388 leukemia and murine sarcoma 180 solid tumor in mice was demonstrated for the 7-hydroxy analogs. In addition, some of these showed excellent antitumor activity against adriamycin-resistant murine P388 leukemia (P388/ADM) in mice.

Crystal structure of 9-(3-bromo-5-chloro-2-hydroxyphenyl)-10-(2-hydroxyethyl)-3,3,6,6-tetramethyl-3,4,6,7,9,10-hexahydroacridine-1,8(2H,5H)-dione

“…Acridine derivatives occupy an important position in medicinal chemistry due to their wide range of biological applications. They exhibit fungicidal (Misra & Bahel, 1984;Srivastava et al, 1985), anti-cancer (Sondhi et al, 2004;Sugaya et al, 1994;Kimura et al, 1993), anti-parasitic (Ngadi et al, 1993), antiinflammatory and anti-microbial (Shul'ga et al, 1974;Gaiukevich et al, 1973) activity. They are also components of effective analgesics (Taraporewala & Kauffman, 1990;Gaidukevich et al, 1987).…”

Anticancer Activity of Pyrazole via Different Biological Mechanisms

“…Compound 394b was found most active in all aspects. Capps et al [108] prepared 2-aminoalkyl-5-nitropyrazolo[3,4,5-kl]acridines (Fig. 24).…”

Evaluation Of The Potential Anticancer Activity Of Pyrazole-Acridine Derivative Synthesis In The SH-SY5Y Human Neuroblastoma Cell Line

“…Additionally, phase 2 clinical studies have been conducted for breast and ovarian cancer 13,14 . Sugaya et al (1994) synthesized novel pyrazole-acridine derivatives, which exhibited significant inhibition of Hela S 3 cell proliferation in vitro and demonstrated remarkable suppression of P388 leukemia and sarcoma 180 solid tumors in vivo . Notably, these compounds exhibit superior antitumor activity at lower doses compared to Adriamycin 15 .…”