Preprint Article Version 1 This version is not peer-reviewed

Development of Novel Imipridones with Alkyne- and Triazole-linked Warheads on the Tricyclic Skeleton, Showing Superior Ability to Eradicate PANC-1 and Fadu Cells Compared to ONC201

Tamás Czuczi
,
József Murányi
,
István Móra
ORCID logo ,
Bianka Gurbi
,
Attila Varga
,
Dávid Papp
ORCID logo ,
Gitta Schlosser
,
Miklós Csala
* ORCID logo ,
Antal Csámpai
*
Version 1 : Received: 24 October 2024 / Approved: 24 October 2024 / Online: 24 October 2024 (18:17:25 CEST)

How to cite: Czuczi, T.; Murányi, J.; Móra, I.; Gurbi, B.; Varga, A.; Papp, D.; Schlosser, G.; Csala, M.; Csámpai, A. Development of Novel Imipridones with Alkyne- and Triazole-linked Warheads on the Tricyclic Skeleton, Showing Superior Ability to Eradicate PANC-1 and Fadu Cells Compared to ONC201. Preprints 2024, 2024101974. https://doi.org/10.20944/preprints202410.1974.v1 Czuczi, T.; Murányi, J.; Móra, I.; Gurbi, B.; Varga, A.; Papp, D.; Schlosser, G.; Csala, M.; Csámpai, A. Development of Novel Imipridones with Alkyne- and Triazole-linked Warheads on the Tricyclic Skeleton, Showing Superior Ability to Eradicate PANC-1 and Fadu Cells Compared to ONC201. Preprints 2024, 2024101974. https://doi.org/10.20944/preprints202410.1974.v1

Abstract

Our ongoing research focuses on developing imipridone derivatives capable of complete and selective eradication of cancer cells after relatively short treatment. We have synthetized systematically designed novel hybrids and evaluated their antiproliferative activity on PANC-1 and Fadu cell lines. We have also conducted preliminary studies on the mechanism including colony formation as well as dose-response tests in HEK293T wild-type (WT) and HEK293T CLPP-/- cells. Following gradual structural fine-tuning based on high throughput screening we identified two imipridone hybrids as the most potent derivatives. Their unique substitution pattern includes N-methylated propargylamine and ferrocenyl/phenyltriazole moieties on the benzyl groups attached to opposite sides of the imipridone core. The compounds with IC50 values similar to those of ONC201 were found capable of complete eradication of cancer cells at ca. 4 M, while ONC201 treatment at even higher concentrations left 30-50% of viable cells behind. Both compounds were found to exert equal activity in WT and CLPP-/- HEK293T cells, indicating a ClpP-independent mechanism. Further development is needed to improve the tumor selectivity of the two potent imipridone derivatives in order to develop novel drug candidates that evade resistance and can be applied in a sufficiently broad therapeutic window.

Keywords

imipridone; propargylamine; 1,2,3-triazole; CuAAc reaction; Sonogashira coupling; PANC-1 and Fadu cells; cell viability; dose-response measurements; colony formation; complete eradication of cancer cells; ClpP-independent mechanism

Subject

Medicine and Pharmacology, Oncology and Oncogenics

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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