Synthesis and Antiproliferative Effect of Ethyl 4‐[4‐(4‐Substituted Piperidin‐1‐yl)]benzylpyrrolo[1,2‐a]quinoxalinecarboxylate Derivatives on Human Leukemia Cells

Abstract

Acute leukemia is a hematological malignancy with high incidence and recurrence rates and is characterized by an accumulation of blasts in bone marrow due to proliferation of immature lymphoid or myeloid cells associated with a blockade of differentiation. The heterogeneity of leukemia led us to look for new specific molecules for leukemia subtypes or for therapy‐resistant cases. Among heterocyclic derivatives that attracted attention due to their wide range of biological activities, we focused our interest on the pyrrolo[1,2‐a]quinoxaline heterocyclic framework that has been previously identified as an interesting scaffold for antiproliferative activities against various human cancer cell lines. In this work, new ethyl 4‐[4‐(4‐substituted piperidin‐1‐yl)]benzylpyrrolo[1,2‐a]quinoxalinecarboxylate derivatives (1 a–o) were designed, synthesized, and evaluated against five different leukemia cell lines, including Jurkat and U266 (lymphoid cell lines) and K562, U937, and HL60 (myeloid cell lines), as well as on normal human peripheral blood mononuclear cells (PBMCs). This new pyrrolo[1,2‐a]quinoxaline series showed interesting cytotoxic potential against all tested leukemia cell lines. In particular, pyrroloquinoxalines 1 a and 1 m,n seem to be interesting due to their high activity against leukemia and their low activity against normal hematopoietic cells, leading to a high index of selectivity.

1-Methyl-3-{4-[(4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl)benzyl]}-2-phenylindole

“…Substituted indole 5 was synthesized by a Suzuki-Miyaura cross-coupling reaction of 3-bromoindole 4 with 4-formylphenylboronic acid in the presence of Pd(PPh 3 ) 4 as a catalyst and potassium carbonate as the base [17]. The aldehyde 5 was then engaged in a reductive amination with NaBH 3 CN and the 4-(2-ketobenzimidazolin-1-yl)piperidine to give the final substituted indole 1 by using our previously described methodology [17,18]. The structure of the synthesized compound 1 has been confirmed by FTIR, 1 H/ 13 C-NMR, and HRMS analysis (see Supplementary Materials).…”

“…The cytotoxic activity of the title compound 1 was initially evaluated against K562, U937, HL60, Jurkat, and U266 cell lines with the MTS assay using compound A6730 as the reference standard drug [17,18]. As listed in Table 1, the 50% inhibitory concentration (IC 50 ) values of 1-methyl-3-{4-[(4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl)benzyl]}-2-phenylindole 1 were found in the same range as those observed for the reference drug A6730.…”

1-Phenyl-8-[[4-(pyrrolo[1,2-a]quinoxalin-4-yl)phenyl]methyl]-1,3,8-triazaspiro[4.5]decan-4-one: Synthesis, Crystal Structure and Anti-Leukemic Activity

“…Thus, we recently published a few series of new pyrrolo [1,2-a]quinoxaline derivatives endowed with promising biological activity towards the human leukemia cells [13][14][15][16]. These antileukemial pyrroloquinoxaline derivatives were previously reported as new structural analogues of derivative A6730 (Figure 1), a reference Protein kinase B (PKB, also known as Akt) inhibitor that presents antiproliferative activity against various human leukemia cell lines [13][14][15][16]. In this context, and as an extension of our work on the development of new anticancer heterocyclic drugs, we decided to further modulate and substitute our pyrrolo[1,2-a]quinoxaline heterocyclic pharmacophore.…”

“…In this context, and as an extension of our work on the development of new anticancer heterocyclic drugs, we decided to further modulate and substitute our pyrrolo[1,2-a]quinoxaline heterocyclic pharmacophore. Thus, taking into account the experience of our group in the field of the synthesis of new bioactive heterocyclic derivatives based on this pyrrolo[1,2-a]quinoxaline heterocyclic core [6][7][8][9][10][11][12][13][14], we use our previously described anti-leukemic JG454 pyrrolo[1,2-a]quinoxaline moiety ( Figure 1) [15] as a template for the design of a new derivative in which the 4-(2-ketobenzimidazolin-1-yl)piperidine was replaced by the 1-phenyl-1,3,8-triazaspiro [4.5]decan-4-one, a new piperidyl structural analogue.…”

Consensus Predictive Model for Human K562 Cell Growth Inhibition through Enalos Cloud Platform

“…Several of the organic molecules profoundly inhibited proliferation of K562 cells and exhibited satisfactory toxicity profiles. K562 cells are also commonly used for the screening of various inhibitors, including Bcr‐Abl kinase inhibitor candidates and antitumor compounds that induce cell differentiation . Differentiation treatment is an advanced strategy for neoplasia therapies and is based on the identification and use of pharmaceutical agents that act as differentiation promoters …”