Chiral hydroxymethyl-1H,3H-pyrrolo[1,2-c]thiazoles: the search for selective p53-activating agents for colorectal cancer therapy

• Type: Article in International Scientific Journal
• Date: 2024-01-01

Authors

Lucilia Saraiva (Author) FFUP

Journal

Title: RSC Medicinal Chemistry

Vol. 15

Pages: 1652-1663

Publisher: Royal Society of Chemistry

Indexing

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Other information

Authenticus ID: P-010-BAX

DOI: 10.1039/d4md00076e

Abstract (EN): MANIO is an efficient p53-activating anticancer agent with remarkable selectivity to the p53 pathway and promising antitumor activity against colorectal cancer (CRC). Herein, a library of novel MANIO derivatives, including hydroxymethyl- and bis(hydroxymethyl)-1H,3H-pyrrolo[1,2-c]thiazoles, was synthesized by rational structural modulation. The antiproliferative activity of twenty derivatives was evaluated in a panel of human CRC cells with different p53 status. From this library, five compounds with R- and S-configuration and with aromatic or heteroaromatic groups at position 3, including the enantiomer of MANIO, were identified as selective towards p53-expressing cancer cells. On the other hand, two compounds with S-configuration, 6-hydroxymethyl- and 7-hydroxymethyl-5-methyl-3-phenyl-1H,3H-pyrrolo[1,2-c]thiazoles, showed high cytotoxicity against WTp53-expressing HCT116 colon cells but, unlike MANIO, exhibited p53-independent inhibitory activity in CRC. The results described provide relevant structural and pharmacophoric data for the design of new p53-activating agents for precision therapy of CRC or other p53-related cancers harboring both wild-type or mutated p53 forms.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 12