Design and Biological Evaluation of Novel Acridines

Abstract

In this thesis, synthesis of thirty six new final compounds of substituted acridines is presented . The aim of this work was to prepare hybrid molecules of 4-ary l-3-cyano pyridin-6-yl-2-ones or 4-aryl-3-cyano pyridine-2-imino-6-y l with 9-anilinoacridine, 9-anilino-3-nitroacridine or 9-anilino-2-methoxyacridine moiety. Screenin g of the antitumor activity of twenty one selected members against mammary carcinoma cell line (MCF-7) was also explored; meanwhile molecular modeling through docking with topoisomerase enzyme I of the seven active compounds was a lso reported to confirm their sta bility at the receptor site.

The thesis consists of the following parts:

(1) Introduction:

This part includes a review on acridines as antitumor agents.

(2) Research objectives:

This part includes the aim of the present work and the biological basis upon which the synthesized compounds were chosen is discussed .

(3) Discussion of the experimental:

This part deals with the explanation of the reactions involved in the synthesis of both synthetic intermediates and new final compou nds. Schemes for synt hesis of the suggested compounds are also given.

(4) Experimental:

This part includes practica l proced ures for the synthesis of eight known intermediates, one new interm ediate and thirty si x new final com pounds as well as di fferent spectroscopic charts confirming their structures.

(6) Molecular modeling:

This part includes dockin g of the compounds that were fou nd active from the in vitro antitumor screening on topoisomerase I enzyme using Molsoft ICM 3.4-SC program. The study revealed that these active compounds form complexes with the enzyme with low energy values i ndicating their stability at the receptor site. The ligand used m this study was Topotecan 46 (S)-1 O­ [(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-(IH)-pyrano[3',4':6,7]ino lizino [I ,2-b]-quinolino-3,14-(4H ,1 2H )-dione

(7) Conclusions:

An overview on results revealed that acridine derivatives substituted with

3-nitro group were more active than unsubstituted or 2-methoxy ones. A lso results revealed that p-substitution with 4-aryl-3-cyano-2-imino pyridine ring on the 9-anilino ring gave more active compounds than their 2-oxo counterparts.

(8) References: include 87 references from 1903 till 2007.

(9) Arabic summary.