Design, synthesis, and biological evaluation of novel thiazole derivatives as PI3K/mTOR dual inhibitors

Faggal, Samar I.; El-Dash, Yara; Sonousi, Amr; Abdou, Amr M.; Hassan, Rasha A.

doi:10.1039/d4md00462k

RSC Med. Chem.

2024

DOI: 10.1039/d4md00462k

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Design, synthesis, and biological evaluation of novel thiazole derivatives as PI3K/mTOR dual inhibitors

Samar I. Faggal,

Yara El-Dash,

Amr Sonousi

et al.

Abstract: A series of new thiazole derivatives 3a–q were synthesized and tested against 60 cancer cell lines at the NCI, USA. Compound 3b showed the highest activity against PI3Kα with IC50 = 0.086 ± 0.005 μM and IC50 of 0.221 ± 0.014 μM against mTOR.

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New S‐substituted‐3‐phenyltetrahydrobenzo[4,5]thieno[2,3‐d]pyrimidin‐4(3H)‐one scaffold with promising anticancer activity profile through the regulation and inhibition of mutated B‐RAF signaling pathway

Seif,

Wardakhan,

Hassan

et al. 2024

Drug Development Research

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Novel 3‐phenyltetrahydrobenzo[4,5]thieno[2,3‐d]pyrimidine derivatives were synthesized and screened for their antiproliferative activity against a panel of 60 cancer cell lines. Derivatives 5b, 5f, and 9c showed significant antitumor activity at a single dose with mean growth inhibition of 55.62%, 55.79%, and 71.40%, respectively. These compounds were further investigated against HCT‐116, colon cancer cell line, and FHC, normal colon cell line. Compound 9c showed the highest activity with IC50 = 0.904 ± 0.03 µM and SI = 20.42 excelling doxorubicin which scored IC50 = 2.556 ± 0.09 µM and SI = 6.19. Compound 9c was also the most potent against B‐RAFWT and mutated B‐RAFV600E with IC50 = 0.145 ± 0.005 and 0.042 ± 0.002 µM, respectively in comparison with vemurafenib with IC50 = 0.229 ± 0.008 and 0.038 ± 0.001 µM, respectively. The cell cycle analysis showed that 9c increased the cell population and induced an arrest in the cell cycle of HCT‐116 cancer cells at the G0‐G1 stage with 1.23‐fold. Apoptosis evaluation showed that compound 9c displayed an 18.18‐fold elevation in total apoptosis of HCT‐116 cancer cells in comparison to the control. Compound 9c increased the content of caspase‐3 by 3.52‐fold versus the control. A molecular modeling study determined the binding profile and interaction of 9c with the B‐RAF active site.

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New S‐substituted‐3‐phenyltetrahydrobenzo[4,5]thieno[2,3‐d]pyrimidin‐4(3H)‐one scaffold with promising anticancer activity profile through the regulation and inhibition of mutated B‐RAF signaling pathway

Seif,

Wardakhan,

Hassan

et al. 2024

Drug Development Research

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show abstract

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Design, synthesis, and biological evaluation of novel thiazole derivatives as PI3K/mTOR dual inhibitors

Abstract: A series of new thiazole derivatives 3a–q were synthesized and tested against 60 cancer cell lines at the NCI, USA. Compound 3b showed the highest activity against PI3Kα with IC50 = 0.086 ± 0.005 μM and IC50 of 0.221 ± 0.014 μM against mTOR.

Cited by 1 publication

References 44 publications

New S‐substituted‐3‐phenyltetrahydrobenzo[4,5]thieno[2,3‐d]pyrimidin‐4(3H)‐one scaffold with promising anticancer activity profile through the regulation and inhibition of mutated B‐RAF signaling pathway

New S‐substituted‐3‐phenyltetrahydrobenzo[4,5]thieno[2,3‐d]pyrimidin‐4(3H)‐one scaffold with promising anticancer activity profile through the regulation and inhibition of mutated B‐RAF signaling pathway

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