Synthesis and Cytotoxic Activity of pyridazino[1′,6′:1,2]pyrido[3,4-b]indol-5-inium derivatives as anti-cancer agents

Abstract

The term intercalator is applied to those compounds having a planar chromophore capable of stacking between the DNA base pairs. 1,2 Intercalation provokes conformational changes in the double helix, with consequences on the normal mechanisms of DNA replication, transcription, and repair. 3 Interferences with these functions usually results in non-specific cell killing. 4 Thus, potential applications can be devised in the field of antitumor drugs. 5À7 A class of DNA intercalating agents is constituted by charged molecules, with azinium 8 and quinolizinium 9À13 salts being the most representative examples of this kind of polycyclic cations (Fig. 1). Our interest in the field focussed our studies on DNA intercalators having a bridgehead quaternary nitrogen, and led us to prepare some benzimidazolium 9,10 and g-carbolinium 11À13 cations, which showed intercalating properties 10À13 and in vitro antiproliferative activity. 9 The very related pyridazino[1 0 ,6 0 :1,2]pyrido[3,4-b]indol-5-inium system has been also previously prepared in our laboratory by condensation of a b-carbolinium salt with 1,2-dicarbonyl 14 derivatives (Westphal reaction). The method was applied to the synthesis of the naturally occurring alkaloid flavocorylene and related zwitter- (2) or harmine (3), a series of compounds 4 (harmane series), 5 (harmol series) and 6 (harmine series) were prepared, with variations at the domains 1 (bromo, nitro, amino, alkoxy or hydroxy), 2 (carbamate, ester, amide, aliphatic saturated or unsaturated) and 3 (aliphatic saturated, unsaturated or aromatic) (Fig. 2). From 1, bromo or nitro derivatives 7 were prepared. 16,17 On the other hand, 1 was alkylated at the indolic nitrogen to give 8. Amination of 7 and 8 with O-(mesitylsulfonyl)hydroxylamine (MSH) 18,19 gave N-amino-b-carbolinium derivatives 9, which then were reacted with 1,2-diketones through a Westphal reaction, to give 4a-c and 4f-h. Some 4 derivatives, unsubstituted at the indolic position, were then treated with base to give the ylide 10, which was then alkylated to give 4d-e. Finally, for 4h, reduction with stannous chloride yielded 4i (Scheme 1 and Table 1).From 2, indolic nitrogen was first protected as tercbutoxy carbamate 11. Amination with MSH yielded 12, which was then reacted with 3,4-hexanedione under Westphal process to give 13. Carbamate was deprotected in acidic media to yield 5a. On the other hand, 11 was reacted through a Williamson reaction with several alkyl halides to give 14. Further reaction with MSH to give 15 and then, Westphal reaction with several 1,2-diketones led to 5b-l. For compounds 5k and 5l, treatment with hydrobromic acid yielded 5m and 5n (Scheme 2 and Table 1).The last series were prepared from 3. First, alkylation at the indolic nitrogen gave 16, which was then reacted with MSH to give 17. On the other hand, 3 was aminated by MSH to yield 18. 15 Then, Westphal reaction was performed on 17 and 18 to give 6c-g and 6a,b respectively. Finally, compounds 6a and 6b were treated with base to give 19 which was then alkyla...

An Improved Synthesis of α-Carbolines under Microwave Irradiation

“…As part of a wider project aimed at finding heteroaromatic structures bearing a bridged nitrogen atom and having selective DNA-intercalative properties as well as cytotoxic activities, we previously studied the synthesis, reactivity, and biological behavior of structures with a quinolizinium-type core . For instance, a number of compounds derived from β- and γ-carbolines have been reported by us . We have now turned our attention to the α-carboline core.…”

Westphal Reaction in Solid-Phase

“…An interesting class of charged heterocycles is polycyclic nitrogen bridgehead cycloimmonium salts. As an example, quinolizinium salts have shown DNA intercalative properties and antiproliferative activity . An easy way to access to cycloimmonium and related salts is the Westphal condensation (Scheme ).…”