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

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

Molecules (Basel, Switzerland), 2021-03, Vol.26 (6), p.1637 [Periódico revisado por pares]

Switzerland: MDPI AG

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Título:
Semi-Synthesis of Small Molecules of Aminocarbazoles: Tumor Growth Inhibition and Potential Impact on p53
Autor: Long, Solida ; Loureiro, Joana B ; Carvalho, Carla ; Gales, Luís ; Saraiva, Lucília ; Pinto, Madalena M M ; Puthongking, Ploenthip ; Sousa, Emília
Assuntos: Alkaloids ; Alkaloids - chemical synthesis ; Alkaloids - pharmacology ; Amination ; aminocarbazoles ; Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - pharmacology ; Apoptosis ; Biotechnology ; Cancer ; Carbazole ; Carbazoles ; Carbazoles - chemical synthesis ; Carbazoles - pharmacology ; Cell cycle ; Cell growth ; Cell Line ; Cell Line, Tumor ; Clausena - chemistry ; Growth inhibition ; HCT116 Cells ; heptaphylline ; HT29 Cells ; Humans ; mutant ; Mutants ; Mutation ; Mutation - drug effects ; Neoplasms - drug therapy ; Neoplasms - metabolism ; p53 ; Proteins ; Semisynthesis ; Small Molecule Libraries - chemical synthesis ; Small Molecule Libraries - pharmacology ; tumor ; Tumor cell lines ; Tumor cells ; Tumor suppressor genes ; Tumor Suppressor Protein p53 - metabolism ; Tumors ; Yeast ; Yeasts
É parte de: Molecules (Basel, Switzerland), 2021-03, Vol.26 (6), p.1637
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
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Descrição: 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 ( ), 7-methoxy heptaphylline ( ), and 7-methoxymukonal ( ), isolated from , 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 ( ) the most promising in all the investigated cell lines. However, compound 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 . 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.
Editor: Switzerland: MDPI AG
Idioma: Inglês

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

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

Switzerland: MDPI AG

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