Oxoazabenzo[de]anthracenes Conjugated to Amino Acids:  Synthesis and Evaluation as DNA-Binding Antitumor Agents

Abstract

We report the synthesis of an original series of oxoazabenzo[de]anthracenes conjugated to an amino acid: Ala, Phe, Pro, Lys, or Gly (4a-e, respectively). The compounds, derived from 1,8-dihydroxyanthracene-9,10-dione, were studied for DNA binding and cytotoxicity. Melting temperature, fluorescence quenching, and surface plasmon resonance methods all indicated that the lysine derivative 4d binds to DNA much more strongly that the Pro, Ala, and Gly conjugates whereas the Phe analogue showed the lowest DNA binding capacity. These compounds form intercalation complexes with DNA, as judged from electric linear dichroism and topoisomerase I-based DNA unwinding experiments. Preferential binding of 4d to defined sequences such as 5'-CTAAAGG and 5'-ATGC was evidenced by DNase I footprinting. This Lys conjugate was found to be over 20 times more cytotoxic to CEM human leukemia cells than the other conjugates, with an IC50 in the submicromolar range. A high antiproliferative activity, likely attributable to the enhanced DNA binding capacity, is maintained despite the incapacity of the compound to stabilize topoisomerase-DNA covalent complexes. The cell cycle effects of 4d consisted in an S phase accumulation of cells coupled with a pro-apoptotic action (appearance of hypodiploid sub-G1 cells) which were confirmed by measuring the inhibition of BrdU incorporation into DNA and labeling of phosphatidylserine residues with annexin V-FITC by means of flow cytometry. Altogether, the work provides interesting structure-activity relationships in the oxoazabenzo[de]anthracene-amino acid conjugate series and identifies the lysine derivative 4d as a promising candidate for further in vivo evaluation and drug design.

Preparation of Fused Tetracyclic Quinazolinones by Combinations of Aza‐Wittig Methodologies and CuI‐Catalysed Heteroarylation Processes

“…Although the 4H-3,1-benzoxazine ring system displays important biological activity, and a wide variety of derivatives of this ring system have been used as fungicidal and anti-inflammatory agents, as ostheoclasis inhibitors, as antirheumatics and as DNA-binding antitumour agents, [19] only a limited number of methods for the preparation of 4-alkylidene-4H-3,1-benzoxazines have been reported. A very recent approach involves the palladium-catalysed cyclization/ alkoxycarbonylation of various substituted 2-[(trimethylsilyl)ethynyl]aniline amide or urea derivatives.…”

Copper‐Catalyzed Domino Synthesis of Benzimidazo[2,1‐b]quin‐ azolin‐12(6H)‐ones Using Cyanamide as a Building Block

“…[5] Quinazolinones act as anti-inflammatory, [6] antifungal, [7] hypnotic, [8] sedative, [9] analgesic, anticonvulsant, [10] antibacterial, [11] anticancer agents and AMPA receptor antagonists. [12] The combined structure of benzimidazole and quinazolinone frameworks, the benzimidazoA C H T U N G T R E N N U N G [2,1-b]quinazolin-12(6H)-one ring system (Figure 1), has attracted much attention for its application in antitumor agents [13] and potential immunosuppressors. [14] To the best of our knowledge, no natural product with the benzimidazoquinazolinone skeleton has been found thus far.…”

Optical and Electrochemical Properties of Anthraquinone Imine Based Dyes for Dye‐Sensitized Solar Cells

“…[19,20] In this work, we treated acetal 13 in toluene with 2-aminoethan-1-ol in air to obtain oxazinone 8 (Y p = 49 %; Scheme 7).…”