New 1, 3, 4-thiadiazoles as potential anticancer agents: pro-apoptotic, cell cycle arrest, molecular modelling, and ADMET profile
Hekal, Mohamed H; Soliman Farag Saad, Paula; Hemdan, Magdy M.; El-Sayed, Amira A; Hassaballah, Aya I; El-Sayed, Wael;
Abstract
A series of novel 1,3,4-thiadiazoles was synthesized via the reaction of N-(5-(2-cyanoacetamido)-1,3,4-
thiadiazol-2-yl)benzamide (3) with different carbon electrophiles and evaluated as potential anticancer
agents. The chemical structures of these derivatives were fully elucidated using various spectral and
elemental analyses. Out of 24 new thiadiazoles, derivatives 4, 6b, 7a, 7d, and 19 have significant
antiproliferative activity. However, derivatives 4, 7a, and 7d were toxic to the normal fibroblasts, and
therefore were excluded from further investigations. Derivatives 6b and 19 with IC50 at less than 10 mM
and with high selectivity were selected for further studies in breast cells (MCF-7). Derivative 19 arrested
the breast cells at G2/M probably through inhibition of CDK1, while 6b significantly increased the sub-G1
percent of cells probably through induction of necrosis. These results were confirmed by the annexin V PI assay where 6b did not induce apoptosis and increased the necrotic cells to 12.5%, and compound 19
significantly increased the early apoptosis to 15% and increased the necrotic cells to 15%. Molecular
docking showed that compound 19 was like FB8, an inhibitor of CDK1, in binding the CDK1 pocket.
Therefore, compound 19 could be a potential CDK1 inhibitor. Derivatives 6b and 19 did not violate
Lipinski's rule of five. In silico studies showed that these derivatives have a low blood–brain barrier
penetration capability and high intestinal absorption. Taken together, derivatives 6b and 19 could serve
as potential anticancer agents and merit further investigations
thiadiazol-2-yl)benzamide (3) with different carbon electrophiles and evaluated as potential anticancer
agents. The chemical structures of these derivatives were fully elucidated using various spectral and
elemental analyses. Out of 24 new thiadiazoles, derivatives 4, 6b, 7a, 7d, and 19 have significant
antiproliferative activity. However, derivatives 4, 7a, and 7d were toxic to the normal fibroblasts, and
therefore were excluded from further investigations. Derivatives 6b and 19 with IC50 at less than 10 mM
and with high selectivity were selected for further studies in breast cells (MCF-7). Derivative 19 arrested
the breast cells at G2/M probably through inhibition of CDK1, while 6b significantly increased the sub-G1
percent of cells probably through induction of necrosis. These results were confirmed by the annexin V PI assay where 6b did not induce apoptosis and increased the necrotic cells to 12.5%, and compound 19
significantly increased the early apoptosis to 15% and increased the necrotic cells to 15%. Molecular
docking showed that compound 19 was like FB8, an inhibitor of CDK1, in binding the CDK1 pocket.
Therefore, compound 19 could be a potential CDK1 inhibitor. Derivatives 6b and 19 did not violate
Lipinski's rule of five. In silico studies showed that these derivatives have a low blood–brain barrier
penetration capability and high intestinal absorption. Taken together, derivatives 6b and 19 could serve
as potential anticancer agents and merit further investigations
Other data
Title | New 1, 3, 4-thiadiazoles as potential anticancer agents: pro-apoptotic, cell cycle arrest, molecular modelling, and ADMET profile | Authors | Hekal, Mohamed H; Soliman Farag Saad, Paula ; Hemdan, Magdy M. ; El-Sayed, Amira A; Hassaballah, Aya I; El-Sayed, Wael | Issue Date | 2023 | Publisher | Royal Society of Chemistry | Journal | RSC Advances | Volume | 2023 | Issue | 13 | Start page | 15810 | End page | 15825 | DOI | 10.1039/d3ra02716c | PubMed ID | 37250214 | Scopus ID | 2-s2.0-85161291077 |
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