6-[(Aminoalkyl)amino]-substituted 7H-benzo[e]perimidin-7-ones as novel antineoplastic agents. Synthesis and biological evaluation

Abstract

A class of chromophore-modified anthracenediones with an additional pyrimidine ring incorporated into the chromophore system has been obtained in an attempt to provide compounds with diminished peroxidation activity and thus potentially lowered cardiotoxicity. Their synthesis was carried out by the reaction of 6-amino- or 6-hydroxy-7H-benzo[e]perimidin-7-one with a number of alkylamines. Potent activity was demonstrated in vitro against murine L1210 leukemia cells (equipotent with ametantrone) as well as against P388 leukemia in vivo (% T/C = 130-255). We observed that the benzoperimidines did not stimulate free radical formation, perhaps due to their poor substrate properties for NADH dehydrogenase.

Photoreduction of Azaoxoisoaporphines by Amines: Laser Flash and Steady‐State Photolysis and Pulse Radiolysis Studies

“…Taking into account the sequence of reactions (Eqs. [13][14][15][16][17][18] and on the basis of our earlier LFP observations (vide supra), these absorptions can be tentatively assigned to the neutral hydrogenated radicals (A1H • /A2H • ). Interestingly, absorptions recorded at k = 400 and 520 nm for both AOIA A1 and A2 decay faster (k = 2.9 9 10 3 s À1 and 3.8 9 10 3 s À1 respectively) compared with absorption recorded at k = 430 nm (k = 2.1 9 10 3 s À1 and 3.0 9 10 3 s À1 respectively).…”

“…In N 2 O-saturated 2-propanol solutions containing AOIA, their neutral hydrogenated radicals are generated by a sequence of reactions displayed in equations (Eqs. [13][14][15][16][17][18].…”

“…Moreover, some of them that contain two N atoms, for example, the 7H-benzo[e]perimidin-7-one derivatives, also called azaoxoisoaporphines (AOIA), have been synthesized as noncardiotoxic alternatives to anthraquinone antitumor drugs. They have also received considerable attention due to their antineoplastic and cytotoxic activity, in vitro and in vivo, toward multidrug resistant cell lines (13)(14)(15)(16)(17)(18)(19).…”

Synthesis of 1‐(phenylsulfanyl/phenoxy)‐3H‐naptho[1,2,3‐de]quinoline‐2,7‐diones

“…The majority of DNA-intercalating anticancer drugs possess linear or angular polycyclic chromophores. An increasing number of examples of "fused" tetracyclic systems have been reported, including the azonafides 3 [7,8], imidazoacridones 4 [9][10][11], pyrimido[5,6,1-de]acridines 5 [12], benzo[e]pyrimidines 6,7 [13,14], and 3(H)-naptho[1,2,3-de]quinoline-2,7-dione 1,2 [15]. Although the presence of a fused heterocyclic ring is essential to overcome the multidrug resistance, appropriate substituents were necessary to achieve the optimal results.…”

DNA-binding Antitumor Agents: from Pyrimido[5,6,1-de]acridines to Other Intriguing Classes of Acridine Derivatives

“…The noticeable results obtained in the field of antitumor drugs with the fully synthetic DNAinteracting agents of anthracenedione and acridine groups, such as mitoxantrone [1] and amsacrine [2] respectively, have raised in the last years a great interest in the synthesis and structural modifications of these two classes of compounds. The most representative examples of the research in this area include: anthrapyrazoles [3,4], azaanthracendiones [5], aza-anthrapyrazoles [6], benzoperimidine [7], belonging to anthracenedione group, pyrazoloacridines [8], acridinecarboxamides [9−11], imidazoacridones [12,13], and triazoloacridones [14], belonging to the acridine group. Many of these derivatives are currently undergoing clinical trials.…”