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. 2024 Apr 12;15(5):1652-1663.
doi: 10.1039/d4md00076e. eCollection 2024 May 22.

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

Mees M Hendrikx  1 , Adelino M R Pereira  1 , Ana B Pereira  1 , Carla S C Carvalho  2 , João L P Ribeiro  1 , Maria I L Soares  1 , Lucília Saraiva  2 , Teresa M V D Pinho E Melo  1
Affiliations

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

Mees M Hendrikx et al. RSC Med Chem. .

Erratum in

Abstract

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.

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Conflict of interest statement

One patent application protecting the compounds disclosed in this manuscript has been filed by the following authors M. I. L. S., L. S., and T. M. V. D. P. M.

Figures

Fig. 1
Fig. 1. Chemical structure and key features of (3S)-6,7-bis(hydroxymethyl)-5-methyl-3-phenyl-1H,3H-pyrrolo[1,2-c]thiazole (MANIO) (1).
Scheme 1
Scheme 1. Synthesis of chiral 6,7-bis(hydroxymethyl)-1H,3H-pyrrolo[1,2-c]thiazoles 4.
Scheme 2
Scheme 2. Synthesis of (3S)-6,7-bis(hydroxymethyl)-1H,3H-pyrrolo[1,2-c]thiazole 7.
Scheme 3
Scheme 3. Synthesis of hydroxymethyl-1H,3H-pyrrolo[1,2-c]thiazoles 11 and 12. ayield over two steps.
Scheme 4
Scheme 4. Reduction of dimethyl (3R)-5-methyl-2,2-dioxo-3-phenyl-1H,3H-pyrrolo[1,2-c]thiazole-6,7-dicarboxylate (13).
Scheme 5
Scheme 5. Synthesis of chiral 3-methyl- and 3-benzyl-6,7-bis(hydroxymethyl)-1H,3H-pyrrolo[1,2-c]thiazoles.
Fig. 2
Fig. 2. Chemical structures of previously synthesized 1H,3H-pyrrolo[1,2-c]thiazoles and 1H,3H-pyrazolo[1,5-c]thiazole.
Fig. 3
Fig. 3. Structural modulation approaches based on SAR data.
Fig. 4
Fig. 4. Chemical structures of new chiral hydroxymethyl- and bis(hydroxymethyl)-1H,3H-pyrrolo[1,2-c]thiazoles.
See this image and copyright information in PMC

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