Synthesis and Cytotoxicity of Indolopyrrolemaleimides

Abstract

Cancer is the second leading cause of death in the world. Currently, there are many different targets in cancer chemotherapy. Among them, DNA topoisomerase I has been shown to be an important target. [1][2][3][4] The development of DNA topoisomerase I inhibitors as cancer chemotherapy agents is currently an active area of research.5) Indolocarbazoles including NB-506 and rebeccamycin exhibit antitumor properties very likely via topoisomerase I inhibition. To improve their cytotoxicitives, various modifications were performed. [6][7][8][9][10] In addition, many bisarylmaleimide compounds, which were prepared by replaceing one of the indolo groups with other aryl/heteroarylcycle, exhibited remarkable cancer cells poisons. [11][12][13][14] These prompted us to design a new series of bisindolomaleimide ( Fig. 1) analogues in order to find more potent cytotoxic compounds and to carry out a structure-activity relationship study. Because pyrrole is a pharmacophore with many biological properties, it was chosen to replace one of the indolo groups of bisindolomaleimides. In this paper, we describe the synthesis of the indolopyrrolemaleimide derivatives 6 and 11 ( Fig. 1), the evaluation of these compounds as topoisomerase I inhibitor, and their cytotoxic activity in vitro against various human cancer cell lines. Results and DiscussionThe general synthetic approach to the indolopyrrolemaleimides 6 is outlined in Chart 1. Indole adducts 3a-d were prepared starting from appropriate indole. 15,16) The NH of indole adducts 3a-d were protected by di-tert-butyl dicarbonate ((Boc) 2 O) to form the key intermediates 4a-d. 5a-d were prepared by reacting pyrrole with 4a-d using lithium hexamethyldisilazide (LiHMDS) as a base. Deprotection of BOC groups of 5a-d with methylamine or ethylamine afforded 6ac, 6bc, 6cc, 6dc, 6ad, 6bd, 6cd and 6dd, respectively. 17) Treatment 5a with ammonium acetate (NH 4 OAc) yielded 6aa and 6ab (1 : 1). Similarly, treatment 5b or 5c with NH 4 OAc got 6ba and 6bb or 6ca and 6cb, respectively. 17,18) Preparation of compounds 11 were performed according to the procedure of Chart 2. Treating 3a or 3b with methylamine afforded 7a or 7b. 8a or 8b was prepared by protecting the NH of 7a or 7b with (Boc) 2 O, and then condensation of 8a or 8b with pyrrole obtained 9a or 9b. 17) Treating 9a or 9b with KOH-dioxane achieved 10a or 10b [17][18][19] which were converted to indolopyrrolemaleimide compounds 11 by treating with various compounds containing-NH 2 . 20)All the prepared compounds were evaluated for their cytotoxicity against cancer cells in vitro.First, compounds 6 were evaluated for their cytotoxic activity in vitro against human leukemia cell line (HL60), and four human solid cancer cell lines: human prostate cancer cell line (PC-3), human esophageal cancer cell line (ECA-109), human liver cancer cell line (Bel-7402) and non-smallcell lung cancer cell line (A549) according to the reported methods.21) The results are summarized in Table 1. As outlined in Table 1, most tested compounds exhibited cytotoxic...

Palladium-Catalyzed Aminocarbonylation of Alkynes to Succinimides

“…18,19 N-phenyl-succinimides may be converted to their nonaromatic analogues via a simple exchange reaction at room temperature. 20 The reverse reaction, however, is not facile.…”

“…In this respect, it should be noted that the majority of routes to succinimide derivatives have focused on N -alkyl-succinimides, and the synthesis of N -phenyl-succinimides is more challenging. Moreover, N -phenyl-succinimides, and the structurally related N -phenylmaleimides (which may be obtained from N -phenyl-succinimides via dehydrogenation), have a number of important applications. , N -phenyl-succinimides may be converted to their nonaromatic analogues via a simple exchange reaction at room temperature . The reverse reaction, however, is not facile.…”

Transition-Metal-Catalyzed Carbonylative Multifunctionalization of Alkynes

“…Substituted maleimides and succinimides represent an interesting class of bioactive N -heterocycles , that show various biological activities including antibacterials, cytotoxicities, inhibition of different kinases, and so on. Owing to these interesting biological properties, the development of efficient methods for the synthesis of maleimide and succinimide derivatives has attracted considerable interest.…”

“…Then the intermediate A was inserted into the alkyne to give the vinylrhodium(I) complex B, which went through oxidative addition of C−Br on the adjacent phenyl ring to afford the rhodium(III) species C. Finally, the insertion of CO in C followed by reductive elimination gave the target indenones. Substituted maleimides and succinimides represent an interesting class of bioactive N-heterocycles 38,39 that show various biological activities including antibacterials, 40 cytotoxicities, 41 inhibition of different kinases, 42 and so on. Owing to these interesting biological properties, the development of efficient methods for the synthesis of maleimide and succinimide derivatives has attracted considerable interest.…”