Semi-Synthesis of Small Molecules of Aminocarbazoles: Tumor Growth Inhibition and Potential Impact on p53.

Solida Long,Emília Sousa,Ploenthip Puthongking,Luís Gales,Madalena M M Pinto,Lucília Saraiva,Carla Carvalho,Joana B Loureiro

doi:10.3390/molecules26061637

Abstract

The tumor suppressor p53 is inactivated by mutation in approximately 50% of human cancers. Small molecules that bind and stabilize those mutants may represent effective anticancer drugs. Herein, we report the tumor cell growth inhibitory activity of carbazole alkaloids and amino derivatives, as well as their potential activation of p53. Twelve aminocarbazole alkaloids were semi-synthesized from heptaphylline (1), 7-methoxy heptaphylline (2), and 7-methoxymukonal (3), isolated from Clausena harmandiana, using a reductive amination protocol. Naturally-occurring carbazoles 1–3 and their amino derivatives were evaluated for their potential effect on wild-type and mutant p53 activity using a yeast screening assay and on human tumor cell lines. Naturally-occurring carbazoles 1–3 showed the most potent growth inhibitory effects on wild-type p53-expressing cells, being heptaphylline (1) the most promising in all the investigated cell lines. However, compound 1 also showed growth inhibition against non-tumor cells. Conversely, semi-synthetic aminocarbazole 1d showed an interesting growth inhibitory activity in tumor cells expressing both wild-type and mutant p53, exhibiting low growth inhibition on non-tumor cells. The yeast assay showed a potential reactivation of mutant p53 by heptaphylline derivatives, including compound 1d. The results obtained indicate that carbazole alkaloids may represent a promising starting point to search for new mutp53-reactivating agents with promising applications in cancer therapy.

Highlights

The reaction mixtures were stirred under nitrogen gas until no further developments to yield aminocarbazole alkaloids derivatives 1a–1e, 2a–2f, and 3a (Table 1)
Products were treated with different work-up procedures before purification, as described in the experimental section
Authentication was identified by comparison with the herbarium specimen at the Faculty of Science, Khon Kaen University

Summary

Introduction

Natural-occurring carbazole alkaloids have been reported to exhibit a broad pharmacological profile, including activities such as antitumor (i.e., heptaphylline 1, Figure 1) [5], 7-methoxy-heptaphylline (2) [6], 2-hydroxy-7-methoxy-9H-carbazole-3-carbaldehyde or 7-methoxy-mukonal (3) [7]), antiplasmodial (i.e., compounds 1 [8] and 3 [7]), antiplatelet aggregation, and vasorelaxing (i.e., clausine E (4) [9]), antibacterial (i.e., clausamine B (5), clausine F (6) [10], and Molecules 2021, 26, 1637 antiplasmodial compounds [8](i.e., and 3compound [7]), antiplatelet aggregation, and vasorelaxing clausenal (7) Heptaphylline (1) was reported to induce apoptosis in a human colon (7) [11]), antifungal (i.e., compound 7 [11]), and antidiabetic (i.e., koenidine (8) [12]). Readenocarcinoma cell line [13] and was considered a promising model for new anticancer cently, heptaphylline (1) was reported to induce apoptosis in a human colon adenocarcidrugs

Methods

Results

Conclusion